The Human Nervous System S Tructure and Function

The Human Nervous System S tructure and Function

S ixth Ed ition The Human Nervous System Structure and Function

S ixth Edition

Charles R. Noback, PhD Professor Emeritus Department of Anatomy and Cell Biology College of Physicians and Surgeons Columbia University, New York, NY

Norman L. Strominger, PhD Professor Center for Neuropharmacology and Neuroscience Department of Surgery (Otolaryngology) The Albany Medical College Adjunct Professor, Division of Biomedical Science University at Albany Institute for Health and the Environment Albany, NY

Robert J. Demarest Director Emeritus Department of Medical Illustration College of Physicians and Surgeons Columbia University, New York, NY

David A. Ruggiero, MA, MPhil, PhD Professor Departments of Psychiatry and Anatomy and Cell Biology Columbia University College of Physicians and Surgeons New York, NY © 2005 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher.

All papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher.

This publication is printed on acid-free paper. h ANSI Z39.48-1984 (American Standards Institute) Permanence of Paper for Printed Library Materials.

Production Editor: Tracy Catanese

Cover design by Patricia F. Cleary

Cover Illustration: The cover illustration, by Robert J. Demarest, highlights synapses, synaptic activity, and synaptic-derived proteins, which are critical elements in enabling the nervous system to perform its role. Neural information derived from sensory receptors, both outside and within the body, activate the spines of the dendrites. As a consequence, neural information is communicated, via the dendrites, to the nucleus of the neuron. This activates the genomic system to release mRNA, which is transported by ribosomes, to the spines. This enables each spine to generate synaptic-specific proteins for the neuron.

For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected]; or visit our www.humanapress.com

Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press, provided that the base fee of US $30.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-039-5/05 $30.00]. eISBN: 1-59259-730-0

Printed in the United States of America. 10 9 8 7

Library of Congress Cataloging in Publication Data Library of Congress Cataloging-in-Publication Data

The human nervous system : structure and function / Charles R. Noback ...[et al.].-- 6th ed. p. cm. Previous ed. cataloged under: Noback, Charles Robert, 1916-. Includes bibliographical references and index. ISBN 1-58829-039-5 (hardcover : alk. paper) -- ISBN 1-58829-040-9 (pbk. : alk. paper) 1. Neurophysiology. I. Noback, Charles Robert, 1916- Human nervous system. QP361.H85 2005 612.8--dc22 2004018287 Dedication

This book is dedicated to

Peter, Elizabeth, Norma, and Teddy Noback; Sarah and Evan Bracken; Jessica, William, and Nathan Strominger; Robert and Steven Demarest; Nancy O’Donnell; Anke Lunsmann Nolting and members of the Ruggiero, Mirra, Nolting, von Holsten, Mahler-Welch, and Tanya-Datoek families.

v Preface

This sixth edition represents the combined for online searches, which are now readily avail- efforts of three neuroscientists and a medical able. The book incorporates many of the signifi- illustrator to succinctly present the fundamental cant recent advances made in neurobiology and principles of the organization, structure, and molecular biology during the last several years. function of the human nervous system. Information on the dynamics of the dendritic The book is intended to meet the basic needs spines, basic neurophysiology, development and primarily of (1) medical and dental students who growth of the nervous system, auditory and ves- want to get a general overview of this discipline; tibular systems, neurotransmitters as the chemi- (2) beginning students in the allied health sci- cal messengers of certain circuits and pathways, ences and psychology students who need an and basal ganglia and extrapyramidal system have introductory yet reasonably comprehensive sur- been substantially expanded and revised. In addi- vey of the subject; (3) residents in neurology, tion, some 24 new drawings have been added. neurosurgery, and neuroradiology who wish to We wish to thank numerous students and review this subject matter; and (4) readers with colleagues for their many invaluable comments a background in biology who want to gain an and input. We wish to thank Drs. Krystal understanding of some general concepts and Archer-Arroyo, Anthony Cacace, Peter Greene specific details. W. Michael King, Lois Laemle; Martha Welch, The text is designed so that the student who is Sara Glickstein, and Adele, Robert, and Mitchell first exposed to neuroscience can get an orga- Strominger, Yuansheng Tan, and Jed Peterson nized view of the bewilderingly complex human of Albany Medical College, class of 2006, for nervous system. The illustrations have been spe- their efforts on our behalf. We would also like cifically prepared for this book to simplify and to thank Dr. David Carpenter for his many cour- clarify items in the text. Clinical correlations and tesies. relevant symptoms from lesions are integrated in We thank the people at Humana Press for the text to elucidate important features of the their patience and good will. It has been a plea- substrate of the brain, spinal cord, and periph- sure working with them. We especially want to eral nervous system. Two chapters specifically acknowledge Ms. Donna Niethe for her pains- deal with “Lesions of the Spinal Nerves” and taking efforts in bringing the illustrations into “Spinal Cord and Lesions of the Brainstem.” the digital age. Each chapter contains a list of selected references as a guide to readers who wish to pursue Charles R. Noback topics in greater detail. It is anticipated that stu- Norman L. Strominger dents who wish further information on specific David A. Ruggiero areas will use the references as a starting point Robert J. Demarest

vii Introduction and Terminology

Divisions of the Nervous System Orientation in the Brain Organization of Neurons in the Central Nervous System: Brain and Spinal Cord

Most students feel a baffling uncertainty The peripheral nerves convey neural messages when beginning the study of neuroanatomy. Not from (1) the sense organs and sensory receptors until many of the facets of the subject blend in in the organism inward to the CNS and from (2) the latter half of the course, do they feel in con- the CNS outward to the muscles and glands of trol over the material. To ameliorate the uncer- the body. tain feeling, the text and figures in the first five The somatic nervous system consists of those chapters (especially Chap. 1) should be perused neural structures of the CNS and PNS respon- for a general understanding only, then used later sible for (1) conveying and processing conscious for reference. Chapters 8 through 13 give basic and unconscious sensory (afferent) information, information about pathway systems, as well as vision, pain, touch, unconscious muscle sense background knowledge for the remaining chap- from the head, body wall, and extremities to the ters in the book. CNS and (2) motor (efferent) control of the vol- It deserves mention that the nervous system untary (striated) muscles. The autonomic ner- functions together with the endocrine system in vous system is composed of the neural structures harmonizing the many complex activities of the responsible for (1) conveying and processing sen- body. The former is a rapid coordinator, whereas sory input from the visceral organs (e.g., diges- the latter is more deliberate in its action. tive system and cardiovascular system) and (2) motor control of the involuntary (smooth) and cardiac musculature, and of glands of the viscera. DIVISIONS OF THE NERVOUS Many authors, however, consider the autonomic SYSTEM nervous system to be exclusively concerned with visceral motor activities. The nervous system essentially exhibits a bi- Sensory signals originating in sensory recep- lateral symmetry with those structural features tors are transmitted through the nervous system and pathways located on one side of the midline along sensory pathways, e.g., pain and tempera- also found on the other side. It is subdivided an- ture pathways and visual pathways. These sig- atomically into the central nervous system and nals may reach consciousness or may be utilized the peripheral nervous system and functionally at unconscious levels. Neural messages for mo- into the somatic nervous system and the auto- tor activity are conveyed through the nervous nomic (visceral) nervous system. system to the muscles and glands along motor The central nervous system (CNS) comprises pathways. Both the sensory (ascending) and mo- the brain and spinal cord. The brain is encapsu- tor (descending) pathways include processing lated within the skull and the spinal cord is at the centers (e.g., ganglia, nuclei, laminae, cortices) center of the vertebral column. The peripheral for each pathway located at different anatomic nervous system (PNS) consists of the nerves levels of the spinal cord and brain. The process- emerging from the brain (called cranial nerves) ing centers are the computers of these complex and from the spinal cord (called spinal nerves). high-speed systems. From receptors in the body

ix x Introduction and Terminology to the highest centers in the CNS, each sensory through the brainstem and spinal cord are cut pathway system follows, in a general way, a ba- rostrocaudally, parallel to the front and back of sic sequence: (1) sensory receptors (e.g., touch the neuraxis. A midsagittal or median sagittal corpuscles of Meissner in the skin), transmit section is cut in a vertical plane along the mid- along (2) nerve fibers to (3) processing centers line; it divides the CNS into symmetric right and in the spinal cord and brain, whence signals are left halves. Parasagittal sections are also in the conveyed by (4) other nerve fibers, which may vertical plane, but lateral to the median sagittal ascend on the same side of the CNS or may cross section. A coronal section of the cerebrum is cut the midline (decussate) and ascend on the oppo- at a right angle to the horizontal plane. An axial site side of the CNS before terminating in (5) section of the brainstem and spinal cord is cut higher processing centers; from these centers (6) perpendicular to the neuraxis, giving a cross sec- other nerve fibers ascend on the same side be- tion or transverse section (see Figs. 7.5 and fore terminating in (7) the highest processing 13.10). Afferent (or -petal, as in centripetal) re- centers in the cerebral cortex. Differences in the fers to bringing to or into a structure such as a basic sequence are present in some ascending nucleus; afferent is often used for sensory. Ef- systems. In a general way, the motor systems are ferent (or -fugal, as in centrifugal) refers to go- organized (1) to receive stimuli from the sensory ing away from a structure such as a nucleus; systems at all levels of the spinal cord and brain, efferent is often used for motor. and (2) to convey messages via motor pathways to neuromuscular and neuroglandular endings at ORGANIZATION OF NEURONS IN muscle and gland cells in the head, body, and extremities. The motor pathways comprise (1) THE CENTRAL NERVOUS SYSTEM: sequences of processing centers and their fibers BRAIN AND SPINAL CORD conveying neural influences to other processing centers within the CNS, and (2) the final link- The central nervous system (CNS) comprises ages extending from the CNS via motor nerves gray matter and white matter. Gray matter con- of the PNS to muscles and glands. sists of neuronal cell bodies, dendrites, axon terminals, synapses, and glial cells, and is highly vascular. White matter consists of bundles of ORIENTATION IN THE BRAIN axons, many of which are myelinated, and oligodendrocytes; the white color is imparted by the The long axis through the brain and spinal myelin. It lacks neuronal cell bodies and is less cord is called the neuraxis. It is shaped in the vascular than gray matter. form of a T, with the vertical part being a line Groupings of neuronal cell bodies within the passing through the entire spinal cord and brain- gray matter are variously known as a nucleus, stem (medulla, pons, and midbrain) and the hori- ganglion, lamina, body, cortex, center, formation, zontal part being a line extending from the or horn. A cortex is a layer of gray matter on the frontal pole to the occipital pole of the cerebrum surface of the brain. Two major cortices are rec- (Fig. I.1). In essence, the long axis of the cere- ognized: cerebral and cerebellar cortices. The brum is oriented at right angles to the long axis superior and inferior colliculi of the midbrain of the brainstem-spinal cord. The term rostral and the hippocampal formation also form cor- (“toward the beak”) means in the direction of the tex-like structures. The gray matter, when exam- cerebrum. Caudal means in the direction of the ined under a microscope, resembles a tangle of coccygeal region. These terms are used in rela- nerve and glial processes, called neuropil; this is tion to the neuraxis. In this usage, the cerebrum actually a functionally organized entanglement is rostral to the brainstem and the frontal pole of of processes. Bundles of nerve fibers, many my- the cerebrum is rostral to the occipital lobe. elinated, are given such special names as tract, Horizontal sections through the brainstem are fasciculus, brachium, peduncle, lemniscus, com- parallel to the neuraxis. Horizontal sections missure, ansa, and capsule. A commissure is a through the cerebrum are cut from the frontal bundle of fibers crossing the midline at right pole to the occipital pole, parallel to a plane angles to the neuraxis; it usually interconnects passing through both eyes. Horizontal sections similar structures of the two sides of the brain, Introduction and Terminology xi

Figure 1: Geometry of the brain. Vertical axis is parallel to the long axis of the brainstem and spinal cord. Horizontal axis is parallel to the cerebrum from frontal pole to occipital pole. The broken arched line illustrates the curving of some structures of the horizontal axis during development exemplified here by the laterally positioned temporal lobe. Core structures along the horizontal axis such as the diencephalon depicted in the drawing are straight. Arching structures that follow a curve include the lateral ventricles, fornix, and hippocampus, among others (see Figs. 1.7 and 5.3).

but sometimes is merely a location where fibers the auditory pathways are organized functionally decussate en-route to dissimilar locations. with respect to different frequencies or tones Contralateral refers to the opposite side; it is (tonotopic organization). used primarily to indicate, for example, that pain or paralysis occurs on the side opposite to that Measurements and Dimensions of a lesion. Ipsilateral, or homolateral, refers to The following information is provided for the same side; it is used primarily to indicate, for readers who may not have backgrounds in bio- example, that pain or paralysis occurs on the logical or physical sciences. Linear measure- same side as that of a lesion. A modality refers ments and dimensions generally are given in to the quality of a stimulus and the resulting microns or micrometers (μm) (1 μm equals one- forms of sensation (e.g., touch, pain, sound, vi- millionth of a meter) or nanometers (nm) (1 nm sion). Some pathways (tracts, nuclei, or areas of or millimicron equals one-billionth of a meter). cortex) are somatotopically (topographically) About 240,000 μm equal one inch. organized; specific portions of these structures As a reference, the following are the dimen- are associated with restricted regions of the sions of some non-neural structures: human body. For example, (1) fibers conveying posi- ovum, 100 μm; cross-section of a skeletal muscle tion sense from the hand are in definite locations fiber, 10-100 μm; erythrocytes, 8–10 μm; bacte- within the posterior columns (sensory pathway), ria, 0.1–8 μm; and viruses, 0.15–0.5 μm. and (2) certain areas of the motor cortex regu- Cell bodies of neurons range from 4–140 μm late movements of the thumb. Some structures in diameter, nerve fibers (axis cylinders and of the visual pathway are topographically related sheaths) 1 or 2–20 μm diameter, chemical syn- to specific regions within the retina (retinotopic apses 20–30 nm, synaptic vesicles 20–120 nm organization), and similarly some structures of and ribosomes are about 15 nm. Contents

Dedication ...... v Preface ...... vii Introduction and Terminology ...... ix

1 Gross Anatomy of the Brain ...... 1 2 Neurons and Associated Cells ...... 11 3 Basic Neurophysiology ...... 41 4 Blood Circulation ...... 77 5 Meninges, Ventricles, and Cerebrospinal Fluid...... 89 6 Development and Growth of the Nervous System ...... 101 7 The Spinal Cord ...... 129 8 Reflexes and Muscle Tone ...... 141 9 Pain and Temperature ...... 155 10 Discriminative General Senses, Crude Touch, and Proprioception ...... 177 11 Motoneurons and Motor Pathways ...... 193 12 Lesions of the Spinal Nerves and Spinal Cord ...... 207 13 Brainstem: Medulla, Pons, and Midbrain ...... 219 14 Cranial Nerves and Chemical Senses ...... 243 15 Neurotransmitters as the Chemical Messengers of Certain Circuits and Pathways ...... 267 16 Auditory and Vestibular Systems ...... 285 17 Lesions of the Brainstem ...... 305 18 Cerebellum ...... 315 19 The Visual System ...... 329 20 Autonomic Nervous System ...... 349 21 Hypothalamus ...... 371 22 The Reticular Formation and the Limbic System ...... 387 23 Thalamus ...... 405 24 Basal Ganglia and Extrapyramidal System ...... 419 25 Cerebral Cortex ...... 439 Index ...... 463

xiii 1 Gross Anatomy of the Brain

Subdivisions of the Brain Cerebrum Brainstem: Midbrain, Pons, and Medulla

The average human brain weighs about On the basis of the location of the tentorium 1500 g (3 lbs) or approximately 2% of the body (the double layer of inner dura mater located weight of a 150-lb adult. The brain, a gelati- between the cerebellum and cerebral hemi- nous mass, is invested by a succession of three spheres) (Fig. 5.1), the brain is separated into connective tissue membranes called meninges supratentorial and infratentorial divisions. and is protected by an outer capsule of bone, Thus, the diencephalon is supratentorial in loca- the skull. The brain floats in cerebrospinal tion, whereas the brainstem is infratentorial. fluid, which supports it and acts as a shock The ventricular system (Chap. 5) is a contin- absorber in rapid movements of the head. The uous series of cavities within the brain filled major arteries and veins supplying the brain lie with cerebrospinal fluid (CSF). It is subdivided among the meninges. as follows: The paired lateral ventricles are the cavities of the telencephalon (cerebral hemispheres); the third ventricle, a median struc- SUBDIVISIONS OF THE BRAIN ture, is within the diencephalon; the tubelike

The major subdivisions of the brain (encephalon) are derived from vesicles (small bladderlike fluid-filled structures) present in the embryo. They are the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon (Fig. 6.7). The telencephalon develops into the cerebral hemispheres, the diencephalon into the diencephalon (between brain), the mesencephalon into the midbrain, the metencephalon into the pons and cerebellum and the myelencephalon into the medulla oblongata (shortened to medulla) (Fig. 1.1). The brain is divided into the cerebrum, brainstem, and cerebellum. The term cerebrum is generally used to include the paired cerebral hemispheres and the diencephalon. The brainstem comprises the midbrain, pons, and medulla. The cerebellum is located dorsal to the pons. The lower brainstem (pons and medulla) is Figure 1.1: The major subdivisions of the called the bulb or bulbar region. These subdivi- central nervous system viewed in the sagittal sions are summarized in Table 1.1. section.

1 2 The Human Nervous System

Table 1-1: Subdivisions of the The cortex lining a sulcus is considered part of Brain and Their Antecedents the adjacent gyrus. The hemispheres are sepa- Telencephalon rated from one another in the midline by the Cerebrum Diencephalon } longitudinal fissure (Fig. 1.4). Each hemisphere is conventionally divided into six lobes: frontal, Mesencephalon (midbrain) parietal, occipital, temporal, central (insula), Metencephalon (pons portion) Brainstem Myelencephalon (medulla) } and limbic (Figs. 1.3 and 1.7). The portion of the frontal, parietal and temporal lobes that Metencephalon (roof portion) Cerebellum overlie the insula is called the operculum.

Lobes. The lobes are delineated from each other by several major sulci, including the later- cerebral aqueduct of Sylvius is the midbrain al sulcus of Sylvius, central sulcus of Rolando, portion, and the fourth ventricle is within the cingulate sulcus, and parietooccipital sulcus. pons and rostral medulla (Figs. 5.1, 5.3, and The lateral sulcus is a deep furrow that extends 5.4). The ventricular system continues through posteriorly from the basal surface of the brain the caudal medulla and spinal cord as the cen- along the lateral surface of the hemisphere, to tral canal, which terminates without outlet in terminate usually as an upward curve within the the coccygeal segments of the latter. inferior part of the parietal lobe (Figs. 1.2 and 1.3). The central sulcus of Rolando extends obliquely from the region of the lateral sulcus CEREBRUM across the dorsolateral cerebral surface and, for a short distance, onto the medial surface (Figs. The cerebrum includes the paired cerebral 1.2 to 1.7). The cingulate sulcus is a curved cleft hemispheres, a small median segment (derived on the medial surface extending parallel to the from the telencephalon) and the diencephalon. curvature of the corpus callosum. The pari- The cerebral hemispheres consist of the cere- etooccipital sulcus is a deep cleft on the medial bral cortex (gray matter), underlying white surface located between the central sulcus and matter, corpus striatum (gray matter, see later), the occipital pole (Fig. 1.7). corpus callosum, anterior commissure, hip- The boundaries of the lobes on the lateral pocampal formation, and the amygdala (Figs. cerebral surface are as follows: (1) The frontal 1.2 to 1.7). The corpus callosum is a massive lobe is located anterior to the central sulcus and commissure and the anterior commissure is a above the lateral sulcus; (2) the occipital lobe is small commissure consisting of nerve fibers posterior to an imaginary line parallel to the that interconnect the cortices of the two hemi- parietooccipital sulcus, which is on the medial spheres (Figs. 1.1 and 1.5 to 1.7). The hip- surface; (3) the parietal lobe is located posteri- pocampal formation and amygdala are or to the central sulcus, anterior to the imagi- structures of the limbic system (Fig. 1.7). The nary parietooccipital line, and above the lateral unpaired median portion of the telencephalon sulcus and a projection toward the occipital is a small region in the vicinity of the lamina pole before it takes an upward curve; (4) the terminalis and adjacent hypothalamus. temporal lobe is located below the lateral sulcus and anterior to the imaginary parietooccip- Cerebral Topography ital line; and (5) the central lobe is located at The hemispheres are marked on the surface, the bottom (medial surface) of the lateral sul- by slitlike incisures called sulci (Figs. 1.2 to cus of Sylvius, which is actually a deep fossa 1.7). The term fissure is sometimes used to des- (depression). It can be seen only when the tem- ignate a particularly deep and constant sulcus. poral and frontal lobes are reflected away from The raised ridge between two sulci is a gyrus. the lateral sulcus. Chapter 1 Gross Anatomy of the Brain 3

Figure 1.2: Lateral surface of the brain. Numbers refer to Brodmann’s areas shown in Fig. 25.5 and 25.6.

Figure 1.3: Photograph of the lateral surface of the brain. Figure 1.2 can be used to identify surface structures. (Courtesy of Dr. Howard A. Matzke.) 4 The Human Nervous System

Figure 1.4: Photograph of the dorsal surface of the cerebrum. Figure 1.2 can be used to identify some of the gyri and sulci. (Courtesy of Dr. Howard A. Matzke.)

Figure 1.5: Midsagittal section of the brain. Chapter 1 Gross Anatomy of the Brain 5

Figure 1.6: Photograph of the midsagittal section of the brain. Figures 1.5 and 1.7 can used for identifying structures. (Courtesy of Dr. Howard A. Matzke.)

The boundaries of the lobes on the medial the central sulcus. The paracentral lobule, on cerebral surface (Fig. 1.7) are as follows: (1) the medial surface, is continuous with the pre- The frontal lobe is located rostral to a line central and postcentral gyri on the lateral sur- formed by the central sulcus; (2) the parietal face and is partially divided by the central lobe is between the central sulcus and the pari- sulcus (Figs. 1.5 to 1.7). etooccipital sulcus; (3) the temporal lobe is The cortex anterior to the central sulcus is located lateral to the parahippocampal gyrus; motor in function; that posterior to the central (4) the occipital lobe is posterior to the pari- sulcus is sensory in function. The postcentral etooccipital sulcus; and (5) the limbic lobe is a gyrus and the posterior part of the paracentral synthetic one formed by parts of the frontal, lobule are known as Brodmann areas 1, 2, and 3 parietal, and temporal lobes. It is located cen- of the cerebral cortex (Figs. 25.5 and 25.6). The tral to the curved line formed by the cingulate posterior part of the precentral gyrus and adja- sulcus and the collateral sulcus (the latter is cent portion of the paracentral gyrus are called located lateral to the parahippocampal gyrus). area 4 or the motor cortex. The transverse gyri The limbic lobe is the ring (limbus) of gyri bor- of Heschl, located in the upper part of the tem- dered by this line; it includes the subcallosal poral lobe on the floor of the lateral sulcus, area, cingulate gyrus, parahippocampal gyrus, make up the primary receptive areas for audi- hippocampus, dentate gyrus, and uncus (Figs. tion (areas 41 and 42). The cortex on either side 1.7 and 1.9). of the calcarine sulcus is the primary receptive area for vision (area 17). The areas outside the Gyri. The precentral gyrus is anterior and primary receptive areas are called association parallel to the central sulcus of Rolando. The areas; Broca’s area (Fig. 1.4), for example, is a postcentral gyrus is posterior and parallel to cortical area associated with the formulation of 6 The Human Nervous System

Figure 1.7: Medial surface of the cerebral hemisphere. The limbic lobe consists of the cingulate gyrus, isthmus, and parahippocampal gyrus. White lines represent the amygdala and the hippocampal formation. The amygdala is located within the uncus. The hippocampal formation (hippocampus and dentate gyrus) is located in the floor of the temporal horn of the lateral ventricle (see Fig. 1.9).

speech. The functional aspects of the Brodmann the cerebral hemispheres. The lenticular nucle- areas are discussed in Chapter 25. us is subdivided into the putamen and globus pallidus (pallidum, paleostriatum). The puta- Basal Ganglia men and the caudate nucleus are called the The term basal ganglia refers to several striatum (neostriatum). The subthalamic nucle- subcortical nuclei together with a nucleus of us is located within the ventral thalamus (Chap. the diencephalon and a couple in the midbrain 23). The substantia nigra is a nucleus located (Figs. 1.8 and 24.2 and Table 1.2). These are within the midbrain (Chap. 13). the caudate nucleus, lenticular nucleus, subthalamic nucleus, and substantia nigra. No Diencephalon longer included are the claustrum and amyg- The diencephalon, located in the ventrome- dala (amygdaloid body or amygdaloid nucle- dial portion of the cerebrum, is continuous cau- us); the latter is a component of the limbic dally with the midbrain (Fig. 1.1). It consists of system (Chap. 23). The caudate nucleus and four subdivisions: epithalamus, thalamus (dor- the lenticular nucleus are collectively called sal thalamus), hypothalamus, and ventral thala- the corpus striatum; they are the deep nuclei of mus (subthalamus). The epithalamus, choroid Chapter 1 Gross Anatomy of the Brain 7

Figure 1.8: Horizontal section through the cerebrum. Note the location of the head of the caudate nucleus, lenticular nucleus, thalamus relative to the ventricles, and the internal capsule. Some constituents of the internal capsule are indicated on the left side, where the topographic distribution of the motor pathways from motor cortex is indicated; U, upper extremity; T, trunk; L, lower extremity.

plexus of the third ventricle (Fig. 1.5), and the the cerebral cortex and from the cerebral cortex pineal body (Fig. 1.8) form the upper margin to subcortical structures in the cerebrum, brain- (roof) of the diencephalon. Ventral to the thal- stem, and spinal cord (Fig. 13.4). It is divided amus is the hypothalamus, which includes the into an anterior limb, genu, and posterior limb mamillary bodies, and the hypophysis (pitu- (Fig. 1.8). Retrolenticular and sublenticular itary gland) (Figs. 1.5 and 1.9). The ventral parts of the posterior limb are recognized (Figs. thalamus is located lateral to the hypothalamus. 1.8 and 23.3). The anterior (caudatolenticular) limb is located between the caudate nucleus Internal Capsule and the lenticular nucleus. The genu (knee) is The internal capsule is a massive bundle of located between the anterior and posterior nerve fibers, which contains almost all of the limbs. The posterior (thalamolenticular) limb fibers projecting from the subcortical nuclei to is located between the thalamus and lenticular 8 The Human Nervous System

Table 1-2: The Basal Ganglia Lenticular nucleus Globus pallidus Corpus striatum Putamen Striatum } Caudate nucleus } Subthalamic nucleus Substantia nigra Note: See Tables 24-1 and 24-2 for more complete details.

Figure 1.9: Basal surface of the brain. Note roots of the cranial nerves. A horizontal section through the right temporal and occipital lobes reveals the hippocampus, dentate gyrus, fimbria of the fornix, and temporal horn of the lateral ventricle. The fimbria of the fornix consists of fibers entering the fornix from the hippocampus. The hypophysis and the mammillary body are components of the diencephalon. n, cranial nerve. Chapter 1 Gross Anatomy of the Brain 9

emerges from the brainstem immediately caudal to the latter (Figs. 13.2 and 13.3). The trigeminal nerve (fifth cranial nerve, composed of a small motor root and a large sensory root) emerges on the lateral aspect of the massive pons. The pyramids, olives, and roots of seven cranial nerves are features visible on the anteri- or surface of the medulla. The pyramids are formed by the fibers of the pyramidal tracts (corticospinal tract). The olive is a protuber- ance formed by the inferior olivary nucleus (Figs. 13.3 to 13.5). From medial to lateral, the abducent (sixth), facial (seventh),andvestibu- locochlear (eighth) nerves emerge at the junction of the pons and medulla. The glossopharyngeal (ninth) and vagus (tenth) nerves emerge as a series of rootlets from the sulcus on the posterior margin of the olive. The spinal accessory (eleventh) nerve emerges in the form of rootlets from the medulla and from the spinal cord (between the dorsal and ventral roots of the first six cervical spinal Figure 1.10: Photograph of the basal surface of the brain. Figures 1.9 and 13.4 can be nerves). The hypoglossal (twelfth) nerve used for identification. (Courtesy of Dr. Howard emerges from the sulcus between the olive and A. Matzke.) pyramid (Fig. 1.9). Note that the third, sixth, and twelfth cranial nerves emerge from the anterior brainstem in a longitudinal line just lateral to the midsagittal nucleus. The retrolenticular (postlenticular) plane. The fifth, seventh, ninth, tenth, and part of the posterior limb is located lateral to eleventh cranial nerves emerge from the lateral the thalamus and posterior to the lenticular aspect and the trochlear from the posterior nucleus and the sublenticular part is ventral to aspect of the brainstem (Fig. 13.2). For a more the lenticular nucleus. complete description of the surface anatomy of the brainstem, see Chapter 13.

BRAINSTEM: MIDBRAIN, PONS, AND MEDULLA SUGGESTED READINGS

Several prominent landmarks are present on Agur AM, Dalley AF II. Grant’s Atlas of Anatomy. the anterior surface of the brainstem (Figs. 1.9, 11th ed. Philadelphia, PA: Lippincott Williams & 1.10, and 13.4). In the midbrain, the paired Wilkins; 2004. The Human Brain: Essentials of Behav- cerebral peduncles (crus cerebri) are lateral to Beatty J. ioral Neuroscience. Thousand Oaks, Ca.: Sage, the interpeduncular fossa through which passes 2001. the oculomotor nerve (third cranial nerve). The Benarroch E. Medical Neurosciences: An Approach superior and inferior colliculi form four protu- to Anatomy, Pathology, and Physiology by Sys- berances on the posterior surface of the mid- tems and Levels. Philadelphia, PA: Lippincott brain; the trochlear nerve (fourth cranial nerve) Williams & Wilkins; 1999. 10 The Human Nervous System

Brodal A. Neurological Anatomy in Relation to Nolte J, Angevine JB. The Human Brain: In Pho- Clinical Medicine. 3rd ed. New York, NY: tographs and Diagrams. 2nd ed. St. Louis, MO: Oxford University Press; 1991. Mosby; 2000. Brodal P. The Central Nervous System: Structure Nolte J, Sundsten JW. The Human Brain: An Intro- and Function. 3rd ed. New York, NY: Oxford duction to its Functional Anatomy. 5th ed. St. University Press; 2004. Louis, MO: Mosby; 2002. Burt A. Textbook of Neuroanatomy. Philadelphia, Petras J, Noback C., eds. Comparative and Evolu- PA: Saunders; 1993. tionary Aspects of Vertebrate Central Nervous Clemente CD. Anatomy: A Regional Atlas of the System. Ann. NY Acad. Sci. 1969;167:1–573. Human Body. 4th ed. Baltimore, MD: Williams Purves D, GJ Augustine, D Fitzpatrick, WC Hall, & Wilkins; 1997. A-S LaMantia, JO McNamara, et al., eds. Neuro- England MA, Wakely J. Color Atlas of the Brain & science. 3rd ed. Sunderland, MA: Sinauer Asso- Spinal Cord: An Introduction to Normal Neu- ciates; 2004. roanatomy. St. Louis, MO: Mosby Year Book; Riley HA. An Atlas of the Basal Ganglia, Brainstem 1991. and Spinal Cord. Baltimore: Williams and Felten D, Józefowicz R, Netter F. Netter’s Atlas of Wilkins; 1943. Human Neuroscience. Teterboro, NJ: Icon Rowland LP, ed. Merritt’s Neurology. Philadelphia, Learning Systems; 2003. PA: Lippincott Williams & Wilkins; 2000. Gilman S, Winans S. Manter and Gatz’s Essen- Schnitzlien H, Murtaugh F. Imaging Anatomy of the tials of Clinical Neuroanatomy and Neurophys- Head and Spine: A Photographic Color Atlas of iology. 10th ed. Philadelphia, PA: FA Davis; MRI, CT, Gross, and Microscopic Anatomy in 2003. Axial, Coronal, and Sagittal Planes. 2nd ed. Bal- Haines D. Neuroanatomy: An Atlas of Structures, timore, MD: Urban & Schwarzenberg; 1990. Sections, and Systems. Philadelphia, PA: Lippin- Squire LR, Bloom FE, McConnell S, Roberts JL, cott Williams & Wilkins; 2004. Spitzer NC, Zigmond MJ. Fundamental Neuro- Heimer L. The Human Brain and Spinal Cord: science. New York, NY: Academic; 2003. Functional Neuroanatomy and Dissection Guide. Victor M, Ropper A. Adams and Victor’s Principles New York, NY: Springer-Verlag; 1995. of Neurology. New York, NY: McGraw-Hill Kandel E, Schwartz J, Jessell T, editors. Principles Medical; 2002. of Neural Science. 4th ed. New York, NY: Warwer I. Atlas of Neuroanatomy. Boston, MA: McGraw-Hill; 2000. Butterworth-Heineman; 2001. Kiernan JA. Barr’s the Human Nervous System: An Williams PL. Gray’s Anatomy: The Anatomical Anatomical Viewpoint. 7th ed. Philadelphia, PA: Basis of Medicine and Surgery. 38th ed. New Lippincott-Raven; 1998. York, NY: Churchill Livingstone; 1996. Marshall L, Magoun H. Discoveries in the Human Wong-Riley MTT. Neuroscience Secrets. Philadel- Brain: Neuroscience Prehistory, Brain Structure, phia, PA: Hanley & Belfus; 2000. and Function. Totowa, NJ: Humana; 1998. Woolsey TA, HJ, Gado MH. The Brain Atlas: A Martin JH. Neuroanatomy: Text and Atlas. New Visual Guide to the Human Central Nervous Sys- York, NY: McGraw-Hill Medical; 2003. tem. Hoboken, NJ: Wiley; 2003. 2 Neurons and Associated Cells

Neuroplasticity Organelles and Components Neurotrophic Factors and Tropic Factors Structure of Peripheral Nerves and Ganglia Neuroglia (GLIA) Paraneurons Nerve Regeneration Plasticity and Axonal Sprouting

resulting excitation rapidly to other portions of NEUROPLASTICITY the nerve cell, and to influence other neurons, muscle cells, and glandular cells. Neurons are Some 100–200 billion ([1–2] × 1011) neu- so specialized that most are incapable of repro- rons (nerve cells), as well as many more glial ducing themselves and they lose viability if cells, are integrated into the structural and denied an oxygen supply for more than a few functional fabric that is the brain. They exhibit minutes. a wide diversity of form and sizes. The neuron is the basic unit of the nervous system and is composed of four structurally defined regions: a cell body (soma) that emits a single nerve ORGANELLES AND COMPONENTS process called an axon, which ends at presynaptic terminals, and a variable number of Each neuron consists of a large nucleus, a branching processes called dendrites (Figs. 2.1 plasma (cell) membrane and cytoplasm con- and 2.2). Each axon, including its collateral sisting of cytosol (fluid phase of cytoplasm), branches, usually terminates as an arbor of fine and a number of organelles, including the fibers; each fiber ends as an enlargement called endoplasmic reticulum, Nissl substance, Golgi a bouton, which is part of a synaptic junction. apparatus, mitochondria, lysosomes and cyto- At the other end of the neuron, there is a three- skeleton (Figs. 2.3 to 2.5). dimensional dendritic field, formed by the branching of the dendrites (Fig. 2.2). Nucleus The cell body is the genomic and metabolic The nucleus is delineated from the cyto- center of the neuron. Dendrites are the main plasm by a double-layer unit membrane called recipients of neural signals for communication the nuclear envelope. This membrane is perfo- between neurons and contain critical process- rated by nuclear pores, through which macro- ing complexes (Chap. 3). The axon is the molecules synthesized in the nucleus pass into conduit for conducting messages (action poten- the cytoplasm. In humans, the nucleus contains tials) to the presynaptic terminals where each 46 chromosomes formed from DNA (deoxyri- neuron is in synaptic contact with other neu- bonucleic acid) and proteins. The DNA that rons and, thus, is part of the network that encodes some functions is present in the mito- constitutes the nervous system. A neuron is chondria. The outer layer of the nuclear enve- designed to react to stimuli, to transmit the lope is continuous with the membranes of the

11 12 The Human Nervous System

Figure 2.1: Diagram of (A) a neuron located wholly within the central nervous system and (B) a lower motoneuron located in both the central and peripheral nervous systems. The latter synapses with a voluntary muscle cell to form a motor end plate. Note the similarities, as reconstructed from electron micrographs, between (C) a synapse between two neurons and (D) a motor end plate. The X represents the border between the central nervous system (above the X) and the peripheral nervous system (below the X). The myelin sheath of neuron (A) is entirely the product of a glial cell, and that of neuron (B) is produced by a glial cell inside the central nervous system and by a Schwann (neurolemma) cell in the peripheral nervous system. Chapter 2 Neurons and Associated Cells 13

Figure 2.2: (A) The degrees of densities among dendritic arborizations are expressed as a sequence of selective arbors (A), sampling arbors (A') and space-filling arbors (A").Theselective arbor (A) of an olfactory receptor neuron (ORN) is comprised of a receptive dendritic arbor of cilia, a cell body located within the olfactory mucosa in the nasal cavity (OM), and an axon (Ax) that terminates in the olfactory bulb (OB) (Chap. 14). The sampling arbor (A') with its intermediate arborization pattern is in a pyramidal neuron of the neocortex (Chap. 25). The space-filling arbor (A") is oriented in a plane as in the dendritic branches of Purkinje neurons of the cerebellum (Chap. 18). Arrow indicates axon. (B) Examples of some geometric shaped radiation domains of dendritic arbors. The dendritic arbor (B) radiates from the cell body to form a cylindrical domain (note axon). The dendritic arbor (B') radiates from the cell body to form a cone domain. The dendritic arbor (B") radiates bipolarly from the cell body to form two-cone domains. (C) Outline of an electron micrograph segment of a spiny dendrite illustrating a variety of shapes and sizes of spines described as simple to branched and with spine heads ranging from stubby to mushroom shaped. In vivo imaging has demonstrated that dendritic spines (S) form, collapse and reform, and rapidly change size and shape in response to a diverse array of stimuli. Spine morphology is activity dependent and dynamically responsive (Chap. 3). The arrow indicates the direction of the passage of the nerve impulse of an axon. (Adapted from Fiala and Harris, 1999). 14 The Human Nervous System

Figure 2.3: Some of the cytoplasmic organelles and associated structures of a postganglionic neuron of the autonomic nervous system. The junction between the varicosity and smooth muscle cell A is a typical synapse (Fig. 15.3). The junction between two smooth muscle cells B is an electrical synapse (gap junction, nexus). The small circles in the cell body represent lysosomes. endoplasmic reticulum. The inner layer of the the cytosol to the messenger RNA to be syn- envelope has filaments that attach to the thesized into the peptide. Importantly, DNA nuclear chromatin and to other structures specifies RNA through the process known as involved in pore-diameter control. transcription. The RNA then specifies proteins The chromosomes contain sequences of via translation. Thus, the information coded DNA called genes. Through a process known into the DNA sequence of the gene is tran- as transcription, the genes determine the amino scribed to the mRNA, which carries it to the acid sequences of polypeptides and, thus, the ribosome, where it is translated into a specific structure and properties of proteins. The trans- amino acid sequence to the corresponding pep- lation of the DNA code into a protein is accom- tide. The ribosomes are the sites of protein syn- plished by a special ribonucleic acid (RNA) thesis. called messenger RNA (mRNA). The mRNA Like other cells, each neuron synthesizes migrates from the nucleus through the nuclear three classes of proteins, each with a specific pores to the cytoplasm and becomes associated physiological role. Except for a few proteins with a ribosome, which contains another RNA encoded by mitochondria, essentially all of the called ribosomal RNA (rRNA). The rRNA acts macromolecules of a neuron are made in the as a template upon which the amino acids are cell body from mRNAs. These three classes are assembled. Another RNA, called transfer RNA as follows: (1) Proteins synthesized in the (tRNA), conducts the activated amino acids in cytosol by free ribosomes and polysomes; they Chapter 2 Neurons and Associated Cells 15 remain in the cytosol. These proteins, distrib- and secretory (transmitter containing) vesicles uted by slow axoplasmic transport, include and to the plasma membrane for the mainte- enzymes essential to catalyze metabolic nance of its protein composition. processes of the cytoskeleton. (2) Proteins syn- The prominent nucleolus within the nucleus thesized in the cytosol by free ribosomes and is a ribosome-producing machine consisting polysomes, which are incorporated into the largely of RNA and protein along with some nucleus, mitochondria, and peroxisomes. These DNA. It is the site of ribosomal (rRNA) pro- include enzymes that are involved in the syn- duction and initial assembly. The nucleolus is thesis of RNA, DNA, transcription factors well developed in cells such as neurons, which regulating gene expression, and other proteins are active in peptide and protein synthesis. required by these organelles. Mitochondria are The brain utilizes more genes than any other distributed by slow axoplasmic flow. (3) Pro- organ in the body, estimated to be 30,000– teins synthesized in association with the mem- 40,000 genes, with about 15,000 unique to the brane systems attached to or within the lumen neural tissue. of the endoplasmic reticulum and Golgi appa- In females, nuclei of cells throughout the ratus (GA). They are disbursed by vesicles that body, including neurons, contain a condensa- bud off the GA and are distributed via fast axo- tion of one of the two X chromosomes (sex plasmic flow to such organelles as lysosomes chromatin) called a Barr body (Fig. 2.3). It

Figure 2.4: Plasma membrane of a neuron. Several types of integral proteins (I) are embedded in the bilipid layer of the 5-nm-thick plasma membrane. The carbohydrate chains of the glycoproteins are located on the outer membrane surface. The differential distribution of specific proteins is a basis for regional differences in the functional activities expressed by the membrane. The carbohydrate chains of the glycolipids are not illustrated. At right, integral proteins are schematized as (1) a transmembrane channel (ionophore) with about a 0.5-nm-wide pore and (2) a coupled sodium–potassium pump (Chap. 3). An ionophore acts as a selective channel for the preferential passage of an ion such as sodium or potassium (Chap. 3). The disk on the outer margin of the ionophore represents the receptor site (receptor protein) acting as a binding subunit for a neurotransmitter, which is represented as an irregular object above the receptor site. The pump is specialized to transport sodium ions (open circles) out of the neuron in exchange for pumping potassium ions (solid circles) into the neuron. Peripheral proteins (P) are attached to the integral proteins. 16 The Human Nervous System

Figure 2.5: A motoneuron (lower motor neuron, alpha α motor neuron) of the anterior horn of the spinal cord. (A) The neuron includes a cell body and its processes (dendrites and axons). Note the axon collateral branching at a node of Ranvier. (B) Axons terminate as telodendria; each telo- dendritic terminal has a bulbous ending, forming either an axosomatic or an axodendritic synapse. (C) The synapse as reconstructed from electron micrographs. Note similarities between the synapse and motor end plate in E. (D) Motor end plate as visualized with the light microscope. The sarcolemma (plasma membrane of muscle cell) is the postsynaptic membrane of the motor end plate. (E) Section through motor end plate as based on electron micrographs. Portion of terminal ending fits into synaptic gutter of muscle fiber. Neurolemma (Schwann) cells cover the portion of axon not in the gutter. The secondary clefts (junctional folds) are modifications of the sarcolemma. Chapter 2 Neurons and Associated Cells 17 appears as a small clump near the nuclear enve- permeable to particular ions under certain cir- lope. This structure, first described in cat spinal cumstances (Chap. 3). motoneurons, can be seen in smears of cells There is continuous traffic of small mole- inside the mouth (buccal smears). A normal cules crossing the plasma membrane. This male has an XY configuration and lacks Barr movement involves (1) the regulation of the bodies. neuron’s concentration of such inorganic ions as Na+,K+,Ca2+ and Cl– by shifting the ions in Plasma (Cell) Membrane (Fig. 2.4) one or the other direction across the plasma The plasma (cell) membrane is a highly membrane, (2) taking in oxygen for cellular organized, dynamic 8- to 10-nm-thick organelle. respiration and expelling carbon dioxide, and Many cellular processes are initiated as a con- (3) transporting nutrients into and metabolic sequence of molecular reactions within the waste products out of the cell. Some substances membrane. It is a flexible nonstretchable struc- diffuse across the membranes from a region of ture consisting of two layers of lipid molecules higher concentration to one of lower concentra- (bilipid layer of phospholipids) and associated tion. This diffusion down the concentration proteins, lipids (cholesterol and glycolipids), gradient is called passive transport because the and carbohydrates (Fig. 2.4). Its surface area neuron does not expend energy to effect the can only be changed by the addition or sub- movement. The concentration gradient repre- traction of membrane. The lipids are oriented sents the potential energy that powers the diffu- with their hydrophilic (polar) ends facing the sion. Another form of passive transport is outer surface and the hydrophobic (nonpolar) called facilitated diffusion because the ions and ends projecting to the middle of the membrane. molecules diffuse across the membrane with Thus, the hydrophilic heads face the water on the help of transport proteins that span the both sides of the membrane. The membrane membrane. In this diffusion, the transport pro- proteins (peptide chains) embedded in the teins apparently remain in place and help the bilipid layer are called integral or intrinsic pro- ions across the membrane by undergoing a sub- teins to which peripheral proteins are attached. tle change that translocates the binding site On the external side of the membrane are car- from one side of the membrane to the other. bohydrate chains; those linked to proteins form These changes can trigger both the binding and glycoproteins and those linked to lipids form the release of the transported ions. glycolipids. These carbohydrates can act as The movement of substances across a semi- mediators in cell and molecular recognition permeable plasma membrane from sites of low and of cell adhesion. As a result, the side facing concentration to sites of high concentration the tissue fluids differs from that facing the (“uphill”) occurs by active transport, exocyto- interior of the neuron, not only structurally but sis, and endocytosis. Active transport has a crit- also in function. ical role in a neuron to maintain the internal All biologic membranes are organized (1) to concentration of small molecules that differ block the diffusion of water-soluble molecules, from the concentrations in the extracellular (2) to be selectively permeable to certain mole- environment. The process is called active cules via specialized pores or channels (iono- transport because in order to pump the mole- phores), and (3) to transduce information by cules “uphill,” the neuron must expend its own protein receptors responsive to chemical or energy. Active transport is carried out by spe- physical stimulation by neurotransmitters, hor- cific proteins inserted in the membrane, with mones, light, vibrations, or pressure (Chap. 3). adenosine triphosphate (ATP) supplying the The lipid layers act as a barrier to diffusion by energy. ATP powers the active transport by being impermeable to ions; the proteins are transferring its terminal phosphate group organized as specific receptors, ion channels, directly to the transport ion. This presumably transporters, and carriers that make them quite induces the protein to change its configuration 18 The Human Nervous System in a manner that translocates the ions bound to continuous pores through the membrane the protein across the membrane. One such (transmembrane) that allow some ions to transport system is the sodium–potassium flow at rates as high as 100 million ions per pump, an integral membrane protein, which second per channel. Some channels are per- exchanges sodium for potassium ions across manently open; others only transiently open. the plasma membrane. This pump transport The latter are said to be “gated.” When the system drives the ions against steep gradients. gate opens, ions pass through the channel, The pump oscillates between two conforma- and when the gate closes, ions do not pass tional states in a pumping cycle that translo- through (Chap. 3). A calculation indicates cates three Na+ ions out of the neuron for every that a chemically gated acetylcholine chan- two K+ ions pumped into the neuron. ATP pow- nel (a channel that opens in the presence of ers the changes in conformation by transferring acetylcholine) will open for 1 ms and then a phosphate group to the pump transport pro- close. During the 1 ms, about 20,000 Na+ tein. The two conformational states differ in ions flow into the neuron, and somewhat their affinity for Na+ and K+ and in the direc- fewer K+ ions flow out of the neuron, tional orienting of the ion-binding sites. Prior through each channel. to phosphorylation, the binding sites face the 2. Pumps that serve to transport certain ions cytoplasm and only the Na+ sites are receptive. (sodium–potassium pump, Chap. 3) or Sodium binding induces phosphate transfer metabolic precursors of macromolecules. from ATP to the pump, triggering the confor- Pumps work against an ionic gradient and mational change. In its new conformation, the thus extrude Na+ from the neuron. Energy pump’s binding sites face the extracellular side for this activity is obtained from the hydrol- of the plasma membrane, and the protein now ysis of ATP. has a greater affinity for K+ than it does for Na+. 3. Receptor protein sites are involved with the Potassium binding causes the release of the recognition of neurotransmitters and hor- phosphate and the pump returns to its original mones. They act as binding sites for these conformation. Because the pump also acts as substances on the outer surface of the an enzyme that removes phosphate from ATP, it plasma membrane. The sites initiate the is also called ATPase. responses of the neuron, muscle fiber, or In the process called exocytosis, the neuron gland cell to specific stimuli (chemical or releases macromolecules (e.g., neurotransmit- mechanical). ters) by fusion of presynaptic vesicles with the 4. Transducer proteins are involved in cou- plasma membrane and secretion of their con- pling receptors to enzymes following the tents to the outside (see Synapses at the Motor binding of a ligand, such as a transmitter or End Plate, Chap. 3). In the process called endo- a hormone, to the receptor. The term ligand cytosis, the neuron takes in macromolecules refers to any molecule that binds to a recep- and particulate matter by forming vesicles tor on the surface of a cell. Through the derived from the plasma membrane (see Recy- action of a transducer, an enzyme could ini- cling of Synaptic Vesicles, Chap. 3). tiate the action of a second messenger such Physiologically, the membrane proteins can as cyclic adenosine monophosphate (cAMP) be characterized in functional terms. These (see Second Messenger–G Protein, Chap. 3). include the following: 5. Structural proteins are proteins that form junctions with other neurons, such as cell 1. Channels (ionophores) that allow for the adhesion molecules (CAMs). Intercellular passage of certain ions (such as Na+,K+,Cl– recognition between neural cells and their and Ca2+), across the membrane down con- adhesion one to the other in functionally centration and voltage gradients (Chap. 3). meaningful patterns involves glycoproteins The channels are glycoproteins surrounding called neural cell adhesion molecules Chapter 2 Neurons and Associated Cells 19

(NCAMs). These molecules are present on plate during early development, ACh receptors the cell surface of all developing neural are distributed throughout the plasma mem- cells, where they influence pathways of cell brane of the embryonic muscle fiber. Within migration and terminal axonal outgrowths. hours following the contact of an axon with the NCAMs also have important roles in adult embryonic muscle, a motor end plate begins to tissues, where they are responsible for the form. ACh receptors accumulate in the subsy- affinity of nerve terminals to their targets naptic membrane largely by the insertion of and for the interactions between neurons and newly formed receptors and by migration of other cell types. NCAMs also contribute to some receptors from non-end-plate plasma. the general adherence property of all neural This clustering, induced by putative chemo- cells. Each is a glycoprotein with a high tropic factors, is accompanied by a drastic content of a carbohydrate called sialic acid. reduction of receptors on the non-end plate It appears that this molecule is important in plasma membrane. At this stage, the muscle promoting the outgrowth of the developing can no longer be innervated by another axon. If axon and is involved in responding to guid- the axon is cut and the muscle denervated and ance cues during neural development (Chap. allowed to degenerate, there is a reduction in 6). The NCAMs and another glycoprotein the number of ACh receptors at the former end family called cadherins form the basis of plate accompanied by their wide distribution cell-specific adhesion, where identical mol- all over the plasma membrane. If this muscle is ecules on different cells bind to each other. reinnervated, the ACh receptors again accumu- Another glycoprotein family called integrins late in the new subsynaptic membrane and are mediates between the neuronal surface and reduced in the non-end-plate plasma mem- molecules in the extracellular matrix. The brane. Regional differences in the biochemical NCAM is present in most neural induction properties of the plasma membrane result in and is presumed to contribute to the general local functional specializations of the mem- adhesive properties of neural cells. brane (Chap. 3). 6. Neurotransmitter transporter proteins are plasma membrane glycoproteins involved Nissl Bodies, Ribosomes, with the uptake from the synaptic cleft of and Endoplasmic Reticulum such transmitters as serotonin, dopamine, Nissl bodies (chromophilic substance) are and glutamate for recycling (Fig. 3.10). The basophilic aggregates located in the cell body energy stores in the transmembrane electro- and dendrites of each neuron, but absent in the chemical gradients are utilized to drive these axon and axon hillock located at the junction of chemical agents into the axon terminal. cell body and axon (Fig. 2.1). Each Nissl body is composed of (1) flattened sacs (called cister- The cell membrane has a dynamic fluidity in nae) of granular endoplasmic reticulum (rough that the proteins, which are suspended in a ER) studded with ribosomes facing the cytosol, “solution of membrane lipids,” can shift later- (2) free ribosomes, and (3) clusters of ribo- ally and even rotate within the bilipid layer somes linked together, called polysomes unless restrained by the binding of the protein (Fig. 2.3). Ribosomes are the intracellular to some underlying cytoplasm. organelles that carry out the protein synthesis. The movement and addition of acetylcholine They are composed of several species of (ACh) receptors within the plasma membrane mRNA and a number of proteins. The granular is a graphic example of this fluidity. ACh ER is continuous with the smooth ER (ER receptors of the plasma membrane of a muscle without ribosomes). The rough ER is the fiber are normally clustered and confined in the organelle involved in the synthesis of neurose- subsynaptic membrane of the motor end plate cretory proteins, integral membrane proteins (Fig. 2.5). Prior to the formation of a motor end of the plasma membrane, and proteins of the 20 The Human Nervous System lysosomes (see Golgi Apparatus later). The free Several developmental neurological disor- ribosomes and polysomes are associated with ders, called mitochondrial myopathies,have the synthesis of the proteins of the cytosol and been attributed to the inheritance of mtDNA nonintegral proteins of the plasma membrane. abnormalities. Such a congenital myopathy is The smooth ER is the locale where triglyc- myoclonic epilepsy with ragged red fibers erides, cholesterol, and steroids are synthe- (with special stains, abnormal mitochondria sized. appear red, hence ragged red fibers). Neurons require prodigious amounts of pro- Myopathies are conditions in which the symp- teins to maintain their integrity and to perform toms are the result of the dysfunction of muscle their functional activities. In 1–3 days, they but with no evidence of nerve degeneration. synthesize an amount equal to the total protein Mitochondria are present in the ovum but not in content of the neuron. Much of it is distributed sperm. Thus, mtDNA inheritance is said to be within the neuron by axonal transport (see matrilineal and independent of nuclear inheri- later). Neurons are actually neurotransmitter tance. secretory cells rivaling glandular cells as the Peroxisomes are organelles that function to most prolific protein synthesizing cells. detoxify, with the enzyme catalase, by hydrolyzing hydrogen peroxide, thereby pro- Mitochondria and Peroxisomes tecting the neuron from this chemical agent. Mitochondria are membrane-bound organelles, which, as the cell’s power plants, are the Lysosomes chief source of energy for each cell (Fig. 2.3). Lysosomes are membrane-bound vesicles Energy, water, and carbon dioxide are the prod- that act as an intracellular digestive system. ucts of aerobic cell respiration and enzymatic They contain a variety of hydrolytic enzymes activity, mainly of carbohydrates and, to a that digest and degrade substances originating lesser degree, of amino acids and fats. The both inside and outside of the neuron. The energy released from the oxidation of food is hydrolytic enzymes and lysosome membranes converted to phosphate-bound energy as ATP. are synthesized in the rough ER and then trans- ATP-bound energy is essential for several cel- ferred to the GA for further processing. After lular processes, including the maintenance of budding from the GA, these products are trans- the pumps for the transport of ions across the ported via vesicles to the lysosomes. The plasma membrane, muscle contraction, and digested materials include many cell compo- protein synthesis (Chap. 3). nents such as receptors and membranes, some Neurons, unlike most cells, lack the ability of which can be recycled. The so-called yellow to store glycogen as an energy source. As a lipofuscin granules found in neurons of consequence, they are dependent for their advanced age are said to represent the effects of energy on circulating glucose and oxygen. Glu- “wear and tear’’ and could be insoluble cose is the substrate utilized by mitochondrial residues of lysosomal activity. enzyme systems of neurons for the aerobic generation of ATP. (Neurons do not utilize fat Golgi Apparatus (GA) as a substrate for the process of anaerobic gen- The GA is a complex organelle composed of eration of ATP.) This explains why we lose con- stacks of flattened cisternal sacs, vesicles, and sciousness if the blood supply to the brain is membranous tubules (Fig. 2.3). Newly ER- interrupted for a short time. synthesized protein molecules move through The mitochondria have a small amount of the ER tubules and then bud off into vesicles their own DNA (mtDNA), which enable them that are transported to the GA and sequentially to produce some constituent proteins, RNA, through several cisternal compartments. While and enzymes. Many substances required by the passing through, the proteins are modified and mitochondria are derived from the cytoplasm. sorted out before finally emerging from the GA Chapter 2 Neurons and Associated Cells 21 by budding off the cisternal membranes as plus end oriented toward the cell body and the vesicles containing glycoproteins and secretory other half with the minus end oriented toward products. These glycoproteins are then dis- the cell body. The tubules and filaments consist persed to their destinations via plasmic trans- of a polymer of repeating subunits that are in a port as (1) the integral proteins of the plasma dynamic state of flux, continuously growing membrane, (2) the secretory proteins packaged longer or shorter. into secretory vesicles that are released in Neurotubules are unbranched cylinders response to an external signal, and (3) enzymes composed of polymers of the protein tubulin. of the lysosomes. Each membranous vesicle They are involved in the transport of membra- budded from the GA apparently has external nous organelles throughout the neuron. Neuro- molecules that recognize “docking sites” on the filaments are unbranched cylinders formed by surface of the specific organelle to which they actin and other proteins. The neurofilament are destined to join. proteins, found only in neurons, are members of a family of proteins that include intermedi- Cytoskeleton: Neurotubules ate filament proteins seen in other cells and a and Neurofilaments protein in glial cells called glial fibrillary Adaptation to various shapes (and to carry acidic protein (GFAP). out coordinated and directed movements) is The special properties of these cytoskeletal dependent on complex internal scaffolds of elements enable them to undergo transitions protein filaments and tubules and their associ- from stable to dynamic structures. In the fully ated proteins called the cytoskeleton. The differentiated neurons the cytoskeleton gives cytoskeletal network extends throughout the each neuron and its processes (axon and den- cell body, dendrites, and axon. The cyto- drites) (1) mechanical strength and (2) via its skeleton is not a fixed structure but undergoes neurotubules, the tracks to transport materials changes during development and growth and between the cell body and its axon terminals. A after injury. highly plastic cytoskeleton is exhibited during The cytoskeleton consists of numerous fib- the development of a neuron or in nerve regen- rillar organelles called (1) neurotubules (micro- eration following the transection of a peripheral tubules), each roughly 20–25 nm in diameter, nerve. In these situations, growth cones utilize (2) neurofilaments (microfilaments), roughly the cytoskeleton to elongate, retract or rapidly 10 nm in diameter, and (3) actin microfila- change their shape and to act as mobile sensors ments, about 5 nm in diameter. The tubules and (Chap. 6, Fig. 6.4). filaments comprise about 25% of the total protein of a neuron. Neurotubules and neurofila- Axonal Transport (Axoplasmic or ments are found throughout the cytoplasm. As Axon Transport or Axoplasmic Flow) molecular motors, they mediate movement of The distribution of many substances from organelles by transport. The actin microfila- the cell body throughout the neuronal ments, primarily located close to the plasma processes and from the processes to the cell membrane, are critical organelles in growth body is carried out by axonal transport. It is cones (Chap. 6). These tubules and filaments called anterograde or orthograde axonal trans- are of variable length with no single element port when the direction of movement is away extending the entire length of an axon or den- from the cell body into the dendrites and axon drite. The tubules are polar structures. Within and retrograde axonal transport when the an axon, the so-called plus end of each tubule direction is from the dendrites and axon toward is oriented toward the axon terminus and the the cell body. Transport comprises two general minus end is oriented toward the cell body rates, which occur in all dendrites and axons: (Fig. 2.6). In a dendrite, the polarities of the (1) a fast rate with movement of 200–400 mm tubules are mixed, with about half having the per day and (2) a slow rate of about 1–5 mm 22 The Human Nervous System

Figure 2.6: Schema illustrating the anterograde and retrograde transport of synaptic vesicles and other organelles along neurotubules. After their components are synthesized within the endoplasmic reticulum and GA, the organelles are assembled within the cell body. While in the cell body, the organelles bind with the motor proteins kinesin and dynein. Kinesin has the means to power their rapid movement via fast axonal anterograde transport to the plus (+) end of each neurotubule toward the nerve terminals. The motor is presumed to be transported back to the cell body in an inactive form. The organelle-bound kinesin molecules interact transiently with the microtubule during the anterograde transport via the neurotubule. The retrograde motor protein dynein is transported to the terminal in an inactive form, becomes activated, binds to degraded membranes and organelles, and then is conveyed by retrograde transport to the minus (–) end of the microtubules toward the cell body for disposal. Kinesin appears to have a fan-shaped tail that binds to the organelle to be moved and two globular heads that bind to the neurotubule. A hingelike site is present midway along the kinesin molecule. The similarities between kinesin and myosin of muscle suggest that the movement is produced by the sliding of kinesin molecules along the tracks of the neurotubules. Neurons have adapted an ancient mechanism of transport, in that kinesin and dynein are present in single-celled organisms and eukaryotic cells. Chapter 2 Neurons and Associated Cells 23 per day. There is both anterograde and retro- body ends. Each neurotubule contains several grade fast transport, but only anterograde slow tracks along which different particles move. On transport. The anterograde fast transport con- a single neurotubule, (1) a vesicle can pass veys mitochondria and the precursors of another vesicle moving in the same direction smooth endoplasmic reticulum, synaptic vesi- on a separate track or (2) two vesicles can move cles, and plasma membrane. The fast retro- bidirectionally in opposite directions simulta- grade system includes conveying of such neously on separate tracks. In addition, a vesi- structures as mitochondria, “multivesiculate” cle can shift from one to another tubule. bodies (can be degradative structures), and The slow axonal transport is anterograde vesicles containing such ligands as nerve and involved with the movement of soluble growth factors (see “Neurotropic Factors and enzymes and the components of the cytoskele- Tropic Factors”) taken up by receptor-mediated ton and plasma membrane. Proteins and other endocytosis. Mitochondria travel in both, or substances are conveyed to renew and maintain either, the anterograde and retrograde direction. the axoplasm of mature neurons and to supply The neurotubules in association with certain the axoplasm for axon and dendrite growth of force-generating motor proteins (neurotubule- developing and regenerating neurons. The pro- based motors) act as intracellular molecular tein dynamin has been suggested to be the engines for fast transport, also called neuro- motor protein with a role in slow transport. tubule-dependent transport. This fast transport Conceptually, axonal transport is an expres- is generated by the molecular motor proteins sion of the unity of the neuron in that, through kinesin and dynein that are linked with ATP transport, a continuous communication is main- (Fig. 2.6). They are responsible for generating tained between the cell body and its processes. the forces for the organelle movements that By this means, the cell body is kept informed of underlie neurotubular axonal transport. ATP is the metabolic needs and condition of its most obligatory, as it furnishes the energy for the fast distal parts. Through axonal uptake of extracel- transport in either direction. These proteins and lular substances, such as nerve growth factor ATP seem to provide a mechanistic basis for followed by retrograde transport, the cell body microtubules-associated movement. can sample the extracellular environment. How- The following is a current scheme describ- ever, retrograde transport has its debit side, in ing the role of these molecular motor (motility) that through this mechanism, neurotropic proteins in fast transport (Fig. 2.6). Both ante- viruses such as rabies, herpes simplex, and rograde motor kinesin and retrograde dynein poliomyelitis are conveyed to the central nerv- attach to appropriate binding sites on the pre- ous system. Defects in microtubules might be cursors or organelle to be transported. The involved in some human neurologic disorders. organelle is conveyed by anterograde transport along the “rail” of the track on the neurotubule Dendrites, Axons, and Presynaptic Terminals by the “molecular motors” of kinesin and is Dendrites contain the same cytoplasmic powered by ATP on the organelle toward the organelles (e.g., Nissl bodies and mitochon- plus (+) or axon terminal end of the neuro- dria) as the cell body of which they are true tubule. During this phase, the dynein is trans- extensions. The axon is specialized for transported in an inactive form. The kinesin is then mission of coded information as all-or-none transported back in an inactive form to the cell action potentials. The axon arises from the body for recycling. The retrograde motor axon hillock of the cell body at a site called the dynein, after being transported in an inactive initial segment and extends for a distance of form to the terminal, is activated and becomes less than 1 mm to as much as 1 m before the motor to organelles that are destined to be arborizing into terminal branches (Figs. 2.1 transported along the rails of the track on the and 2.5). The axon hillock, initial segment, and neurotubules toward their minus (–) or cell the axon lack Nissl bodies. The branches of an 24 The Human Nervous System axon could have two types of bouton. Each The cell membrane of the axon at the branch ends as a terminal bouton (bouton ter- synapse is the presynaptic membrane, and the minaux or end-foot) that forms a synapse with cell membrane of dendrite-cell body complex, the dendrite, cell body, or axon of another neu- muscle, or glandular cell is the postsynaptic ron. In addition, along some branches, there are membrane. The subsynaptic membrane is that thickenings called boutons en passage, which region of the postsynaptic membrane that is form synapses with another neuron or smooth juxtaposed against the presynaptic membrane muscle fiber. The dendrites of many neurons at the synapse. A concentration of mitochon- are studded with tiny protuberances called dria and presynaptic vesicles is present in the spines (e.g., pyramidal neurons of the cerebral cytoplasm of the bouton; none are present in cortex; see Figs. 25.1 and 25.2). These den- the cytoplasm adjacent to the subsynaptic dritic spines increase the surface area of the membrane. Most neurons contain at least two membrane of the receptive segment of the neu- distinct types of vesicle: (1) small vesicles 50 ron. Located on them are over 90% of all the nm in diameter and (2) large vesicles from 70 excitatory synapses in the central nervous sys- to 200 nm in diameter. The vesicles contain the tem (CNS). Because of their widespread occur- precursors of the active neurotransmitter agents rence on neurons of the cortical areas of the (Chaps. 3 and 15). cerebrum, they are thought to be involved in learning and memory (Chap. 25). The term neuropil applies to a dense tangle of axons, NEUROTROPHIC FACTORS dendrites, synapses, and neuroglia within the AND TROPIC FACTORS CNS, which is seen in gray matter, notably in the cerebral cortex. Trophism refers to the ability of certain molecules, called trophic (nutritional) factors, to Synapse promote cell survival. Neurotrophic factors are The synapse is the site of contact of one neu- polypeptides that support survival, growth, ron with another (Fig. 2.1). A submicroscopic regeneration, and plasticity of neurons. Most space, the synaptic cleft, which is about 200 Å, types of neuron are generated in excessive exists between the bouton of one neuron and numbers, followed later by the death of “sur- the cell body of another neuron (axosomatic plus” cells soon after axons reach the vicinity synapse), between a bouton and a dendrite of their target (see Apoptosis, Chap. 6). This (axodendritic synapse), and between a bouton type of neuronal cell death is regarded to be a and an axon (axoaxonic synapse). In addition, consequence of the competition for the limited dendrodendritic synapses (between two den- amount of neurotrophic factors released by tar- drites) have been noted (e.g., in the olfactory get cells (e, g., embryonic muscle cells). This is bulb and retina). The axon of one neuron might an adaptive means of adjusting the number of terminate in only a few synapses or up to many neurons of each type to the number of target thousands of synapses. The dendrite–cell body cells to be innervated. The “trophic effect” complex might receive synaptic contacts from exerted on neurons is illustrated by the trophic many different neurons (up to well over 15,000 influences of “taste nerve fibers” upon the taste synapses). The termination of a nerve fiber in a buds (Chap. 14). Not only do the gustatory muscle cell (neuromuscular junction) or a glan- nerve fibers convey taste information, but they dular cell (neuroglandular junction) is basically also have critical roles in both the maintenance similar to the synapse between two neurons. and regeneration of taste buds. Following tran- The synapse of each axon terminal of a section of the gustatory nerve fibers, the taste motoneuron on a voluntary muscle cell is buds degenerate. In time, if and when the called a motor end plate (Figs. 2.1, 2.5, 8.1, transected fibers regenerate into the oral epithe- and 8.2). lium, new functional taste buds will differenti- Chapter 2 Neurons and Associated Cells 25 ate from epithelial cells, Presumably, only taste awarded the 1986 Nobel Prize. NGF is a fibers elaborate the essential trophic factors to polypeptide with a defining role in the survival induce the formation of new taste buds from and maturation of neurons of the sensory (dor- the oral epithelium. Trophic activity could sal root) ganglia and of ganglia of the auto- occur at any time from embryonic life through nomic nervous system, both derivatives of the adulthood. Although a progressive reduction in neural crest (Chap. 6). NGF is also a trophic activity occurs with age, it is never completely factor for such CNS cholinergic neurons as lost. To many neurobiologists, the terms growth those of the basal forebrain that project to the factor and trophic factor are synonymous. hippocampus. NGF is derived from the cells of In addition to trophic effects, there are tropic an appropriate target tissue at the correct time effects. Tropism refers to the ability of certain during development and is capable of main- molecules to promote or to guide the outgrowth taining the viability of the innervated neurons. and directional growth or extension of neuronal This is substantiated by the demonstration that processes (axons and dendrites) (Chap. 6). an injection of antibodies to NGF into newborn Neurotrophins are a class among many neu- mice results in total degeneration of sympa- rotrophic factors that have important roles in thetic ganglia. NGF of the target tissue is inter- the survival of neurons and have widespread nalized into the appropriate neuron following effects throughout the CNS and peripheral binding with specialized high-affinity mem- nervous system (PNS). Neurotrophins include brane protein receptors (transmembrane recep- nerve growth factor (NGF), brain-derived neu- tor tyrosine kinases) located on axon terminals. rotrophic factor (BDNF), neurotrophin 3 The molecules of NGF are conveyed by retro- (NT3), and neurotrophin 4/5 (NT 4/5). Exam- grade transport to the cell body. Presumably, ples of related trophic factors include fibroblast the resulting signal transduction involves the growth factor (FGF), the epidermal growth fac- expression of proto-oncogenes that act to pro- tor family (EGF) and cytokines. The cytokines mote neuronal survival. When the axoplasmic (e.g., interleukin, a leukemia-inhibitory factor) transport to the cell body is disrupted, the neu- are extracellular or membrane-anchored poly- ron degenerates despite the release of NGF by peptides that mediate communication between the target tissue. cells via cell surface receptors. Considerable interest currently is being Trophic factors, as indicated, have roles in directed to the possible therapeutic uses of neu- promoting the successive stages in the cycle of rotrophic factors. They could have roles in neuronal differentiation, growth, survival, and slowing, preventing, and even reversing the programmed cell death (see Apoptosis, Chap. course of such neurodegenerative afflictions 6). In addition, neuronal cells respond selec- such as Alzheimer’s disease (see AD, Chap. tively to trophic factors. For example, all olfac- 25), amyotrophic lateral sclerosis (see ALS, tory receptor neurons (ORNs) have a short Chap. 12), Huntington’s disease (Chap. 24), life-span of 4–6 weeks (Chap. 14) during and Parkinson’s disease (Chap. 24). Because which they are regulated by trophic factors. different cell types respond selectively to indi- They are continually being replaced throughout vidual growth factors, these factors could life. Evidence indicates that the expression of become important in the treatment of these genes encodes the polypeptide trophic factors conditions. to regulate the generation and differentiation of precursor olfactory neuroepithelial cells to become mature ORNs and then to be replaced STRUCTURE OF PERIPHERAL following apoptosis (Chap. 14). NERVES AND GANGLIA Nerve growth factor is the prototypical neurotrophic factor. NGF was characterized Peripheral nerves include both cranial and by Levi-Montalcini and Cohen, who were spinal nerves. Peripheral ganglia are collections 26 The Human Nervous System of cell bodies associated with the peripheral perineurium form a sheath that acts as a physi- nerves. Each nerve consists of three basic tis- ological barrier preventing substances from sue elements: (1) axons, (2) Schwann cells reaching the fascicles of axons. This is a means (neurolemma) and myelin sheaths (interstitial of maintaining an optimal environment for element), and (3) endoneurium, perineurium, axonal activity. The numerous generally longi- and epineurium (connective tissue component). tudinally organized collagen fibers are so A peripheral ganglion consists of the same oriented as to resist the stretching of axons. three elements: (1) neuronal cell bodies and Impulse conduction is altered in slightly axons, (2) inner satellite cells (interstitial ele- stretched axons. ment), and (3) outer satellite cells (connective The myelin sheath, which surrounds an tissue element). axon, is a structure composed of many contin- A peripheral nerve with its numerous nerve uous spiral laminated layers of the plasma fibers is comparable to a telephone cable. The membrane resembling the layers of a jelly roll axons are analogous to the wires and the (Fig. 2.7). Schwann cells form the sheath In the Schwann cells and the endoneurium to the PNS, whereas in the CNS, it is elaborated by insulation encapsulating each wire. Groups of oligodendroglia (Fig. 2.10). insulated nerve fibers are bound together into The myelin sheath is interrupted at regular fascicles by the perineurium. In turn, groups of intervals by nodes of Ranvier (Figs. 2.1, 2.5, fascicles are bound together by the epineurium. and 2.7). The interval between adjacent nodes Each of these layers is continuous with its is an internode. Each internode is ensheathed counterpart in most peripheral ganglia. The by one Schwann cell. The length of an intern- connective tissue elements contain the blood ode is roughly proportional to the diameter of vessels that nourish the neurons; they are also the fiber together with its myelin sheath; the essential for the strength and flexibility exhib- thicker the fiber, the longer its internode. In ited by nerves. The flattened cells of the addition, the diameter of a fiber and the length

Figure 2.7: Regions of the nodes of Ranvier in the peripheral nervous system (PNS) compared with those in the central nervous system (CNS). In the PNS, the Schwann (neurolemma) cell has an outer collar (So) of cytoplasm, which loosely interdigitates in the nodal region with the outer collar of the adjacent Schwann cell. In the CNS, the axis cylinder (A) in the nodal region is exposed directly with the extracellular space (ECS). In both the PNS and CN,S the compact-layered myelin surrounding the axis cylinder forms terminal loops (T.L.), which are in close apposition to the axolemma; this apposition might form a “seal” preventing ready movement of materials between the periaxonal space (*) and the nodal region. The Schwann cell is covered by a basement lamina (b.m.). (Courtesy of Dr. R.P. Bunge and the American Physiological Society.) Chapter 2 Neurons and Associated Cells 27

Figure 2.8: Unmyelinated fibers of the peripheral nervous system. (A) Nine unmyelinated fibers enclosed in individual troughs of a Schwann (neurolemma) cell. (B) Clusters of groups of fine fibers enclosed in troughs of neurolemma cells in the olfactory nerve. (After Bunge, 1994.) of an internode are directly related to the speed Schwann cell (Fig. 2.8). The unmyelinated of conduction of the nerve impulse: The greater fibers are separated from one another; each is the diameter of a fiber, the faster the speed of embedded in a private trough of the surface of conduction. Three features of the nodes are a Schwann cell’s plasma membrane. The important: (1) Nerve fibers branch at a node, axons of the olfactory nerve present an (2) a high concentration of mitochondria in the unusual arrangement. Up to two dozen or axis cylinder at these sites indicates a local high more axons are grouped into clusters of sev- level of metabolic activity, and (3) extracellular eral fine fibers enclosed in the same trough of fluids are close to the axis cylinder at each a Schwann cell. node. Nerve fibers are bound together in fascicles by connective tissue. Nearly all nerve fibers over 2 μm in diameter are myelinated NEUROGLIA (GLIA) and those under 2 μm are unmyelinated. Adjacent to the outer surface of each Neuroglia (glia) are the supportive cells that Schwann cell is a basal lamina, which is syn- surround the cell bodies, dendrites, and axons thesized by the Schwann cells. It is a homoge- of neurons in both the CNS and PNS. In mam- neous layer composed of such proteins as type mals, glia outnumber neurons by 10–50 times IV collagen and laminin. The glial cells and depending on the region of the CNS. They con- neurons of the CNS are not associated with a stitute about one-half of the total volume of the basal lamina. This layer could have a critical human brain. Neuroglia (nerve glue) were orig- role in the regeneration of peripheral nerve inally considered to have relatively passive and fibers (see “Regeneration in the Peripheral Ner- limited roles within the CNS, but now are vous System”). known to function at high rates of metabolic Whereas a myelinated nerve fiber is activity. During development, neuroglia guide ensheathed in its private layer of Schwann migrating neuronal precursors from the neu- cells, a group of as many as 20 or more roepithelium to their destinations, where pat- unmyelinated fibers might share a common terns of neuronal circuitry are formed (Chap. 28 The Human Nervous System

6). Throughout life, they are important in the CNS. (6) Astrocytes are important for main- maintenance and sustenance of neurons and taining homeostasis of the microenvironment their circuits and the release of trophic factors. of the extracellular fluid for neuronal function by buffering the pH and regulating the potas- Classification of Glial Cells sium ion concentrations. They act as bridges Like neurons, glial cells defy a rigid classi- that shuttle nutrients from the capillaries to the fication. Those of the CNS include astrocytes neurons (Fig. 2.9). (7) Glial cells are involved (astroglia), oligodendrocytes (oligodendroglia), in the production of cerebrospinal fluid (CSF) microglia, and ependymal cells. The astroglia and of extracellular fluids that coat, support and oligodendroglia are called macroglia (Fig. and protect neurons (Chap. 5). (8) Glia prolif- 2.10). The “glial” cells of the PNS consist of erate to form astrocytic scars to repair nervous Schwann cells that surround nerve fibers and tissue following injury (reactive gliosis). perineuronal satellite cells surrounding the cell body. These cell types, now considered to be Astrocytes functionally indistinguishable, are collectively Astroglia constitute a heterogeneous morpho- called neurolemma cells. All of these cells logic and functional population occupying the except microglia are derived from ectoderm spaces surrounding each CNS neuron. There are (Chap. 6). The Schwann cells and satellite cells protoplasmic astrocytes in the gray matter and originate from the neural crests derived from fibrous astrocytes in white matter. Others include ectoderm. Microglia are mainly of mesodermal Bergmann cells in the cerebellum, Muller’s cells origin. Glial cells can divide mitotically in the retina, pinealocytes in the pineal gland, throughout life in contrast to neurons, which do and pituicytes located in the posterior lobe of the not. In the CNS, the neurons and glial cells are pituitary gland. These cells contain 8- to 10-nm- separated from each other by an extracellular wide microfilaments composed of polymerized fluid in the 10- to 20-nm-wide intercellular strands of glia fibrillary acetic protein (GFAP),a space (Fig. 5.6) comprising 15–20% of the specific biochemical marker for astrocytes that brain’s volume. The glial cells have no can be revealed through immunohistochemistry. synapses, do not generate action potentials, and Thus, astroglia can be distinguished from neu- presumably are not directly involved in infor- rons for diagnostic purposes. mation processing. The cell bodies and processes of astrocytes are interconnected by gap junctions to form a Multiple Roles of Glia matrix in which the neurons are embedded and The following are some of the essential roles separated from each other. In addition, astro- in which glial cells are actively involved: (1) cytes can act synergistically as a functional Glia provide the organized scaffolds that give syncytium, allowing for the interchange of ions the CNS structural support for neurons and and molecules between the astrocytes and the their circuitry (Chap. 6). (2) Certain glial cells extracellular fluids. (radial glia) are critical in guiding the develop- Both glial cells and neurons have negative ing neurons during migration from their sites of membrane potentials, indicating that their cell origin to their correct destination and in direct- membranes are permeable to potassium ions. ing the paths for the outgrowth of their axons. Because their cell membranes have only a few (3) Glial cells produce growth and trophic fac- potassium channels, astrocytes do not generate tors that are key elements in CNS regeneration action potentials (Chap. 3). Each astrocyte and plasticity. (4) Oligodendrocytes and could have several processes that extend among Schwann cells produce myelin sheaths. (5) the neurons before terminating in different Microglia function (a) as scavengers removing places as expansions called end-feet (Fig. 2.9) debris produced following injury or neuronal that (1) form a jacket in contact with the base- death and (b) in the immune surveillance of the ment membrane of a capillary, (2) are juxta- Chapter 2 Neurons and Associated Cells 29

Figure 2.9: Relation of a neuron, astroglia, oligodendroglia, and nerve terminals. Note axosomatic synapse, axodendritic synapse, and axoaxonic synapse. Astroglia have processes extending to a capillary and to neurons.

posed with the free surfaces of the cell bodies channels. Additionally, following intense neu- and dendrites and envelop the synapses, ronal activity, they take up glutamate and neu- thereby insulating synapses from each other, rotoxins that accumulate in the extracellular (3) come into contact with the pia mater of the spaces and synaptic clefts. Following the pial-glial limiting membrane adjacent to the uptake of excess potassium ions from focal subarachnoid space, and (4) make contact with high-concentration sinks, the astrocytes can ependymal cells of the ventricular system (Fig. then transfer the excess ions via their gap junc- 5.5). Astrocytes store and transfer metabolites tions to regions within the astrocytic syn- such as glucose from the capillaries to the neu- cytium, where the potassium ion concentration rons, and they take up excess potassium from is lower (known as spatial buffering). This pre- the extracellular potassium sinks via potassium vents the spreading depression that results from 30 The Human Nervous System the presence of high extracellular concentra- phages). Other sources of macrophages are tions of potassium ions that can trigger exces- monocytes (its precursor cell in the blood) and sive neuronal depolarization (Chap. 3). In meningial and perivascular cells of CNS blood essence, astrocytes have roles in regulating and vessels. They become scavengers after being maintaining the homeostatic composition of activated by foreign bodies, brain injury, degra- the extracellular fluid (ionic microenvironment dation products, or inflammation and thus and pH) essential to the normal functioning of function as phagocytes to remove debris from the neurons of the CNS. The ability of these the CNS. The resident microglia are small cells cells to divide throughout life could explain, in that comprise from 5% to 10 % of all glial cells. part, why tumors of astrocytic origin are the They contain lysosomes and vesicles character- most common CNS tumors. Astrocytes might istic of macrophages, only sparse ER, and a secrete such neurotrophins as NGF and BDNF, few cytoskeletal fibers. They are found in the which are important in promoting the survival CNS as parenchymal microglia, in the choroid of some neurons. plexus, and in the circumventricular organs (Chap. 21). Microglia could participate in Oligodendrocytes shaping of neuronal circuits by actively elimi- These CNS cells are the equivalents of nating “extra” axon collateral branches without Schwann cells of the PNS (Figs. 2.1 and 2.10). affecting the viability of the neuron itself. They are the cells that make and maintain CNS Microglia are the representatives of the myelin. There are two types of oligoden- immune system, with activated microglia hav- droglia: perineuronal satellite cells, which are ing a key role in immune processing in the closely associated with cell bodies and den- CNS. They are the cornerstones for the interac- drites in the gray matter, and (2) interfascicular tion between the domains of the CNS (neuro- cells, which are involved in myelination of logical) and the peripheral immune system axons in white matter. The numerous processes (non-neurological). Microglia join astrocytes in of Individual oligodendrocytes form the myeli- responding to immune factors and are associ- nated internodes for as many as 70 axons. As ated with the synthesis of growth factors and noted earlier for peripheral nerve axons, the adhesion molecules. They can produce and myelin sheath is a continuous layering of spiral secrete cytokines—the soluble proteins associ- lamellae of the oligodendroglial plasma mem- ated with the magnitude of the inflammatory brane (Fig. 2.10). Myelination of many axons and immune response. Glia can participate in commences prenatally. Most pathways in the autoimmune disease process by being able to human brain are not fully myelinated until 2 act as antigen-presenting cells and, thus, they years after birth. Oligodendrocytes can partici- serve in the immune surveillance of the CNS. pate in the remyelination that can occur follow- In brief, microglia are dynamic immunocom- ing acute or chronic demyelination. This petent cells that function as vigilant ever-pres- so-called spontaneous remyelination takes ent guardians protecting the vital and place in such diseases as multiple sclerosis and vulnerable brain and spinal cord. Microglia can could explain the clinical improvement be imaged in vivo by positron-emitting tomog- observed in different demyelinating diseases. raphy (PET) as a means of evaluating microglial activation following a stroke in humans. Microglia In this procedure, PET scanning images benzo- Microglia exist as (1) resting microglial diazepine receptors of the activated microglia. cells in normal CNS (called resident brain macrophages), which can become converted Ependyma into (2) activated or reactive nonphagocytic The ependymal cells are simple cuboidal microglia capable of producing cytokines that glial cells that line the central canal of the become (3) phagocytic microglia (macro- spinal cord and the ventricles of the brain, Chapter 2 Neurons and Associated Cells 31

Figure 2.10: Relation of oligodendroglia to the axons of the CNS, as reconstructed from electron micrographs. The three unmyelinated axons on the left are naked. The two myelinated axons of the right share one oligodendroglia cell. The myelin sheaths of each of the myelinated fibers are continuous through the protoplasmic tongue with the glial cell body. The glial tongue spreads out as a ridge, which extends throughout the entire length of an internode. The loop of the cell membrane at the ridge makes the site where the membrane is doubled (myelin unit of two plasma cell membranes) and is continuous as a laminated myelin sheath. (Adapted from Bunge, Bunge, and Ris, 1961.) including a layer of the tela choroidea. They are comprise a brain–CFS interface The cellular involved in the production of cerebrospinal elements of this interface along with that of the fluid (CSF, Chap. 5). These cells are ciliated in pial–glial membrane on the surface of the brain the embryonic stages of humans. The ependy- and spinal cord permit (are not barriers) the mal cells and the adjacent astrocyte end-feet exchange of substances between the CSF and 32 The Human Nervous System the CNS (Chap. 5). In the floor of the third ven- rons are cells with neurosecretory roles. In tricle are patches of specialized ependymal cells response to stimuli acting upon receptors within called tanycytes (elongated cell) with basal the cell membrane, the paraneuron releases processes that extend through the neuropil to “neurosecretions” from synapticlike granules or terminate with end-feet on blood vessels and vesicles. Many are identical with or related to neurons. They have a role in transporting sub- neurotransmitters. Some are called “sensory” or stances between the ventricles and blood. One “receptor cells because a receptor role is domi- suggestion is that they transport molecules from nant (e.g., hair cells of the inner ear, Chap. 16). the CSF to hypothalamic neurons involved with Others are called “endocrine cells” when the the regulation of gonadotropic hormone release secretory function is primary (e.g., enterochro- from the pituitary gland. maffine cells of the enteroendocrine system of the gut, Chap. 20). Examples of paraneurons Schwann Cells and Satellite Cells include the following: (1) rods and cones of the Schwann cells of peripheral nerves and per- retina. Each has a photoreceptive outer segment ineuronal satellite cells of sensory and auto- that is actually a modified cilium. (2) Olfactory nomic ganglia in the PNS are the equivalent of receptor cells (neurons of the olfactory nerve) of the three types of CNS supportive cell (astrog- the nasal mucosa. In contrast to all other neu- lia, oligodendroglia, and microglia). Except for rons, these chemoreceptive cells are unique in differences in location, Schwann cells and that they continuously regenerate throughout life satellite cells are indistinguishable from each from the basal cells of the olfactory mucosa other and, hence, are collectively called neu- (Chap. 14). (3) Neuroepithelial taste (gustatory) rolemma cells. Like astroglia, neurolemma receptor cells. These chemoreceptors are inner- cells both (1) enclose and separate unmyeli- vated by afferent taste fibers of cranial nerves nated nerve fibers from each other (Fig. 2.8) VII, IX, and X (Chap. 14). (4) Hair cells of the and (2) are located in the interneuronal space cochlea, semicircular canals, utricle, and saccule between neurons. Like oligodendroglia, they (Chap. 16). The cochleovestibular nerve inner- produce myelin sheaths around axons and a vates these ciliated mechanoreceptors. (5) few cell bodies of ganglia. Like microglia, Merkel cells of the basal cells of the epidermis Schwann cells can become phagocytes in (Chap. 10). These mechanoreceptors are inner- response to nerve injury and inflammation. vated by general somatic afferent nerve fibers. Unlike glial cells, the Schwann cells secrete (6) Chief cells of the carotid body, which act as collagen, laminin, and fibronectin (extracellu- chemoreceptors monitoring the oxygen, carbon lar adhesive proteins). These proteins are the dioxide, and pH levels of the blood. (Chap. 14). main constituents of the basal lamina and (7) Enterochromaffine cells of the enteroen- extraneuronal matrix and also of the basement docrine system (enteric nervous system, Chaps. lamina that surrounds the cell membrane of 15 and 20). These are the source of a variety of axons. The Schwann cells invest the peripheral gut hormones and neuropeptides, including gas- neurons and, thus, are effective in isolating trin, secretin, cholecystokinin, somatostatin, sub- their immediate environment from the extra- stance P, and vasoactive intestinal peptide (VIP). neuronal space of about 20 μm intercalated between a Schwann cell and a neuron. NERVE REGENERATION

PARANEURONS Axon Reaction Axonal injury acts as a potent stimulus that Paraneurons are cells that, although not usu- sets in motion a series of events directed to pre- ally classified as neurons, possess several serve a neuron and regenerate its processes features associated with neurons. Some paraneu- (Fig. 2.11). This response, known as the axon Chapter 2 Neurons and Associated Cells 33

Figure 2.11: Degeneration and regeneration of peripheral somatic motor nerve fibers. (A) Sev- eral days after transection (at the wedge). Note the central chromatolysis and eccentric nuclei, increase in number of neurolemma cells, and fragmentation of myelin sheaths. (B) Several weeks later, the neurolemma cord receives regenerating axis cylinders from the transected fibers and collateral branches from the adjacent normal fiber. (C) Several months later, collateral branches of axis cylinders that failed to innervate motor end plates degenerate. The regenerated portions of the fibers contain more internodes than before: hence, they conduct nerve impulses more slowly. reaction, mobilizes a neuron’s cell body, ulated by an axoplasmic pathway activated by including the nucleus, its axon both proximal factors released in the vicinity of the injury site and distal to the trauma, and the surrounding probably derived from the damaged cell mem- neurolemma, and applies to all neurons in the brane and associated neurolemma. This path- nervous system. The axon reaction is initiated way has two phases: (1) retrograde axonal by the release of injury signals, mainly axo- transport of DNA transcription factors (molec- plasmic proteins that are activated at the injury ular “signals”) to the cell body followed by (2) site and transported retrogradely to the cell import into its nucleus for translation (Sung, body. With few exceptions, following serious Povelones, and Ambron, 2001). These factors injury, axons located wholly within the brain affect the transfer of information from DNA and spinal cord do not regenerate. molecules to RNA molecules. The transforma- The axon reaction encompasses the expres- tion (translation) of information from RNA sions of transcription and translation that occur occurs within ribosomes to create the polypep- after the cell body of an injured neuron is stim- tides essential for regeneration. 34 The Human Nervous System

The molecular injury signals are of two trauma, the myelin sheaths and axis cylinders types: (1) “positive signals” and (2) “negative of the axons in the distal stumps break up. The signals.” Positive signals are the axoplasmic fragmented products are ultimately phagocy- factors associated with growth and survival. tized by macrophages and removed. At this Some “positive signals” are intrinsic to the axo- juncture, events in the PNS and CNS differ. plasm and others are derived from the glial and neurolemma cells at the site of injury. Such a signal can activate a kinase cascade that initi- NERVE REGENERATION ates and coordinates the essential biosynthetic machinery. The “negative signals” originate Regeneration in the Peripheral from target tissues. This implies the existence Nervous System (Fig. 2.11) of convergent pathways for the activation of the Following the severance of an axon (axo- protein synthesis machinery of the cell body. tomy), the evoked axon reaction is expressed Proteins synthesized in the cell body are con- by the cell membrane sealing each cut end fol- veyed via anterograde axonal transport to the lowed by formation of a growth cone from site of trauma. In a sense, the successful regen- which filopodial sprouts extend into the narrow eration of nerve fibers seen in the mature PNS gap between the two stumps. The Schwann recapitulates the differentiation and growth of cells in the proximal and distal stumps divide neurites during early development (neurite is mitotically to form a scaffold of neurolemma the generic term that refers to a nerve process cords (also called perineurial tubes) that bridge when it is not possible to distinguish axon from the gap. Each cord is surrounded by a basal dendrite, as during embryogenesis (Chap. 6). lamina containing various neurotrophic factors As a concept, mammalian PNS neurites retain and extends distally to the location of the orig- some embryonic “wanderlust” throughout life, inal nerve terminal. This applies to both myeli- as they regenerate in a microenvironment con- nated and unmyelinated fibers. taining growth factor that nurtures and guides Growth cones grow randomly into the gap their growth in the virtual absence of inhibitory by a combination of chemoattraction of the growth factors (Chap. 6). During developmen- growth cones to neurotropic factors and of the tal stages, the local neural environment of the sprouts following contact with a neurolemma CNS contains an optimal number of “positive cell of a cord (contact guidance). The growth molecular signals” to enhance neurite growth. cones contain actin, a structural and contractile In contrast, the mature CNS generates a num- protein. Each axon elongates and eases forward ber of “inhibitory molecular signals” that limit by contact, like an inchworm. Neurotubules regenerative neurite growth. (microtubules), built of the protein tubulin that During the axon reaction, the cell body stiffens the trailing axon, develop just behind. swells and the nucleus becomes eccentrically Later, the axon is infiltrated with neurofila- located. There is an increase and a redistribu- ments that act as a permanent rigid cytoskele- tion of the ribosomes (RNA). They concentrate ton. The cords of neurolemma cells upregulate near the plasma membrane, resulting in a lack the synthesis of many neurotrophic factors that of staining in the central part of the soma, are secreted and diffuse toward the growing known as central chromatolysis. This is indica- axons. These factors have roles in specific tive of an enhanced synthesis of proteins prior axonal guidance and target finding. The neu- to their distribution via axonal transport to the rolemma cells could even carry a “molecular regenerating axons. The severed end of the axis memory” of whether they had previously cylinder proximal to the transection is sealed ensheathed a sensory, motor, or autonomic axis within a day by newly formed plasma mem- cylinder. In addition, neurolemma cells provide brane just prior to differentiating into a growth membrane proteins that aid axonal growth. The cone (Chap. 6). During the weeks following the sprouts of each axis cylinder can enter several Chapter 2 Neurons and Associated Cells 35 different cords and, in turn, each cord can the neurolemma cords serve both in trophic receive and act as a guide for the growth cones (growth) roles and in directive guidance roles of the sprouts of several different axons. In a for each axon to reach its target (e.g., a muscle crush site, it is likely that each regenerating to a motor end plate). In early embryonic devel- axon extends into and remains within its parent opment, the growth cone of an elongating axon cord. Each branch elongates in a cleft between precedes the neurolemma cells to reach and the basal lamina and the neurolemma cells at a contact the target myotube (embryonic muscle rate of 1–3 mm/day. Remyelination of the cell) prior to the formation of a motor end plate. regenerating branches by the neurolemma In this, the neurolemma cells have a trophic could, occur after several weeks. In a sense, the role but not a guidance directive role (Chap. 6) growth of each axon and its remyelination recapitulates early development. The basal lamina Collateral Sprouting is a critical element because it contains such A denervated neurolemmal cord exerts neurotrophic factors as glycoproteins, laminin, trophic influences upon nearby intact nerve fibronectin and tenacin. These factors, espe- fibers, which, in the PNS, respond by sprouting cially laminin, are effective substances for the new collateral branches at nodes of Ranvier. attraction and guidance of axonal outgrowth. This is known as preterminal axonal sprouting Each axon that enters the appropriate cord and or collateral axonal sprouting. The collateral then terminates in a suitably matched ending sprout joins the axonless neurolemmal cord can form a functional connection—motor and elongates along the cord to form a compo- fibers to reconstituted motor endplates and sen- nent of a new motor end plate. Collateral nerve sory fibers to reconstituted sensory endings. sprouting also occurs in the CNS, but in the lat- Axons that do not reach appropriate endings ter, neurolemmal cords are absent (Fig. 2.11). eventually degenerate (Fig. 2.11). Nerve cell Those regenerating axons that do not enter a adhesion molecules such as NCAM (Chap. 6), cord might grow and survive locally to form a and neurotrophic factors might have guidance neuroma. The resulting tender mass, when irri- roles during regeneration. The internodal dis- tated, can produce severe pain, called causal- tance between nodes of Ranvier is shorter fol- gia, which is perceived as coming from the lowing regeneration, which accounts for the original region supplied by the nerve (see slower conduction velocities (about 80% of the Phantom Limb, Chap. 9). original) of remyelinated nerves. A regenerating motoneuron axon might Regeneration in the Central Nervous System innervate the original synaptic site on a dener- An injury to the brain or spinal cord can be vated muscle fiber, or at times, a synapse might severe and irreversible as a result, in part, of form at an “ectopic site” on the muscle fiber. difficulty in regenerating functionally normal The neurolemma cords provide guidance to axonal connections. About 3 million Ameri- regenerating axons. Schwann cells guide sprout- cans are victims of traumatic brain injury each ing axons. Presynaptic myoblasts proliferate year. Over 200,000 (about 10,000 per year) and synthesize growth-promoting matrix mole- individuals have survived severe spinal injuries, cules. Axons might recognize components of followed by spastic paralysis, sensory loss, and the synaptic basal lamina that remained as autonomic disturbances. These impairments “basal lamina ghosts” and thus effect selective primarily are attributed to the severed CNS axons regeneration to the original synaptic site (Sanes being unable to regenerate and re-establish and Lichtman, 1999). functional synaptic connections. In contrast to There are a few significant differences the PNS, in the CNS the physical pathway does between the roles of the neurolemma cells dur- not remain after an axon is damaged. Instead, ing adult axon regeneration compared to axon the oligodendroglial-lined pathway distal to the elongation in early development. In the adult, injury degenerates and becomes disorganized. 36 The Human Nervous System

In addition and most importantly, any attempt injured axons and the formation of new func- of an axon to regenerate is blocked by the tional synaptic connections is possible. These release of neurotoxic molecular barriers. factors are expressed in higher vertebrates During development, both the CNS and PNS including mammals and humans. contain laminin and fibronectin, proteins that Positive factors favoring regeneration of neu- promote neurite growth. Although these pro- rites include (1) the intrinsic feature of neurons to teins are present in the mature PNS, they are regenerate branches of neurites, (2) the presence virtually absent in the mature CNS. of trophic (growth) promoting factors, and (3) a Experimental evidence shows that the axons local environment in which the regenerating of mature CNS neurons possess an innate sprouts can grow in length. Such conditions are capacity to regenerate (Ayuago et al., 1991). present in the gray matter, where the axon collat- For example, in rats, segments of peripheral eral sprouts are observed to regenerate for some nerve were grafted into the spinal cord, creat- distance in the spinal cord (Olson, 1997). Pro- ing a lesion. Many severed CNS axons grew duction of antibodies capable of neutralizing through the graft for considerable distances myelin-associated neurite-inhibiting proteins and (Ayuago et al., 1991). Thus, the structural and the possibility that stem cells might help facili- chemical microenvironment provided by tate regeneration of axons at the site of a CNS peripheral nerve neurolemma cords supports lesion are currently being investigated (Chap. 6). regrowth in the CNS just as in the PNS. Other Negative factors inhibiting the regeneration experiments designed to suppress CNS pro- of neurites include axonal outgrowths that can teins produced by oligodendroglia that inhibit be blocked by two physical impediments: (1) regeneration have had some success and sug- the development at the lesion sites of glial scars gest that ultimately functional recovery from (gliosis by reactive astrocytes and activated spinal cord injury might be achievable. microglia) that form impenetrable barriers to There are a couple of examples in which CNS the advance of axonal growth cones and (2) the axons in adult mammals exhibit regeneration. morphologic disorganization of the original One comprises the neurosecretory hypothalamic structural chain of oligodendroglia in the neurons that project to the neurohypophysis. columns of white matter that deprive the grow- Another includes the aminergic and serotoner- ing axons of guidance routes. gic fibers projecting from brainstem nuclei that The regenerative response of the axon to the regenerate through the gray matter at the site of CNS trauma is associated with a change in the a spinal cord injury. molecular factors in the microenvironment of the CNS. Many potent inhibitory or neurotoxic Regeneration Associated With Transection agents are produced or released following the of the Adult Spinal Cord injury that limit or block axonal outgrowth in Many phenomena are associated with neu- the CNS of higher vertebrates. Among these are ronal regeneration following trauma involving (1) the inhibitory nature of the white matter, the transection of the adult spinal cord as which is derived from the membrane proteins of expressed in paraplegia (Chap. 12). These the oligodendroglia and the myelin-associative include (1) positive events and (2) negative fac- proteins resulting in the collapse of the axonal tors associated with the regeneration of the growth cones and (2) the secretion of inhibitory axons, their branches, and synaptic connec- neurotoxic molecules into the extracellular tions. The positive events comprise the recov- matrix (ECM) by reactive astrocytes. This ery of the vascular circulation and the capacity includes upregulation of the powerful of the injured neurons to express the axon reac- inhibitory proteoglycans (modified core pro- tion. This is followed by a number of negative tein with highly sulfated oligosaccharide factors, which must be recognized and over- chains) that are components of the ECM. (3) come before successful regeneration of the The resultant production of oxygen from free Chapter 2 Neurons and Associated Cells 37 radicals produces oxidative excess that inhibits (axonal sprouting), to form new synapses neurite growth, as does the release of high lev- (synaptic replacement), and, thus, to renew els of glutamate and other inhibitory sub- neuronal circuits. The expression of this poten- stances from cells in the injured area, including tial, known as neuronal plasticity (Chap. 6), is inflammatory cells such as neutrophils, macro- maximal during development, but it is retained phages, and microglia. Relevant comments on in part in the adult CNS. In the mature brain, nerve regeneration are noted in the following neuronal plasticity is manifest as a response to section and in Chapter 6. such changes as hormonal levels, learning new In summary, to enable the regenerating axons skills, response to changes in the environment, of tracts to bridge the gap above and below a and injury. This indicates that although the cell spinal cord lesion, three strategies have been body of each neuron is a relatively fixed com- adopted. These involve the use among others of ponent within each processing center, the neurotrophic factors, various chemical subsynaptic connections it makes with other neu- stances, stem cells, and antibodies: (1) applica- rons are modifiable throughout life. In this tion of chemical substances and antibodies that respect, the CNS is not a static, “hard-wired” suppress and block the inhibitors (e.g., myelin) organ but, rather, a sensitive organ capable of of axonal sprouting, growth, and migration; (2) limited change induced by natural stimuli. use of neurotrophic factors and chemical sub- Neuronal plasticity is, in essence, the capability stances that stimulate and enhance axonal of synaptic connections of a neuron to be sprouting, and lengthening of the neuritis; and replaced, to be increased or decreased in quan- (3) attempts to devise a method using a chemical tity, and to modify functional activity. Presum- substance to form fibrinlike scaffolds within the ably, it is influenced by chemical factors such gap for the guidance of the migrating growth as NGF, the neurotrophin released by the target cones to and into the “axonless glial cord” (e.g., cells. This plasticity might be involved in part like a neurolemma cord in a peripheral nerve) in the functional recovery occurring following within the spinal cord beyond the gap. small lesions in the brain. The failure of CNS neurons to regenerate their axons after injury is likely to be multi- SUGGESTED READINGS factoral. Injured CNS glia may inhibit regrowing axons and fail to actively provide Adamikova L, Straube A, Schulz I, Steinberg G. trophic support to regrowing axons, and Calcium signaling is involved in dynein-depend- injured CNS neurons may fail to receive and ent microtubule organization. Mol. Biol. Cell; respond to their trophic signals. This trophic 2004. control problem—deprivation of needed Aguayo AJ, Rasminsky M, Bray GM, et al. Degen- trophic stimuli together with loss of respon- erative and regenerative responses of injured siveness to these stimuli—results either in the neurons in the central nervous system of adult death of the axotomized neuron or in the fail- mammals. Philos. Trans. R. Soc. Lond. B. Biol. ure of the axotomized neuron to reextend. Sci. 1991;331:337–343. Simultaneous attention to these problems may Alberts B, Johnson A, Lewis J, Raff M, Roberts K, be essential to the effective promotion of CNS Walter P. Molecular Biology of the Cell. 4th ed. New York, NY: Garland; 2002 regeneration.” (Goldberg and Barres, 2000). Aldskogius H, Fraher J, eds. Glial Interfaces in the Nervous System: Role in Repair and Plasticity: International Conference on Glial Interfaces. PLASTICITY AND Washington, DC: IOS Press; 2002. AXONAL SPROUTING Altman J. Microglia emerge from the fog. Trends Neurosci. 1994;17:47–49. The neurons of the mammalian CNS pos- Ambron RT, Walters ET. Priming events and retro- sess the capacity to generate new branches grade injury signals. A new perspective on the 38 The Human Nervous System

cellular and molecular biology of nerve regener- LIM-type homeobox gene islet-1 during neuronal ation. Mol. Neurobiol. 1996;13:61–79. regeneration. Neuroscience. 1999; 88:917–925. Ball P. Good little movers: molecular motors. In: Laming PR, Kimelberg H, Robinson S, Salm A, Stories of the Invisible. A Guided Tour of Mole- Hawrylak N, Muller C, et al. Neuronal–glial cules. New York, NY: Oxford University Press; interactions and behaviour. Neurosci. Biobehav. 2001;114–137. Rev. 2000;24:295–340. Bareyre FM, Schwab ME. Inflammation, degenera- Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli tion and regeneration in the injured spinal cord: L, Leon A. Nerve growth factor: from neu- insights from DNA microarrays. Trends Neu- rotrophin to neurokine. Trends Neurosci. 1996; rosci. 2003;26:555–563. 19:514–520. Barres BA, Barde Y. Neuronal and glial cell biology. Levitan I, Kaczmarek L. The Neuron: Cell and Mol- Curr. Opin. Neurobiol. 2000;10:642–648. ecular Biology. 3rd ed. New York, NY: Oxford Bridgman PC. Myosin-dependent transport in neu- University Press; 2001. rons. J Neurobiol. 2004;58:164–174. Miller FD, Kaplan DR. Signaling mechanisms Bunge MB, Bunge RP, Ris H. Ultrastructural study underlying dendrite formation. Curr. Opin. Neu- of remyelination in an experimental lesion in robiol. 2003;13:391–398. adult cat spinal cord. J. Biophys. Biochem. Cytol. Murphy S, ed. Astrocytes: Pharmacology and Func- 1961;10:67–94. tion. San Diego, CA: Academic; 1993. Bunge RP. The role of the Schwann cell in trophic Murshid A, Presley JF. ER-to-Golgi transport and support and regeneration. J. Neurol. 1994; cytoskeletal interactions in animal cells. Cell. 242:S19-S21. Mol. Life Sci. 2004;61:133–145. Cooper G, Hausman R. The Cell: A Molecular Olson L. Regeneration in the adult central nervous Approach. 3rd ed. Sunderland, MA: Sinauer system: experimental repair strategies. Nature Associates; 2003. Med. 1997;3:1329–1335. Cousin MA, Robinson PJ. The dephosphins: Ramón y Cajal S. N Swanson, Swanson L (trans). dephosphorylation by calcineurin triggers synap- Histology of the nervous system of man and tic vesicle endocytosis. Trends Neurosci. 2001; vertebrates. New York, NY: Oxford University 24:659–665. Press; 1995. Curtis R, DiStefano PS. Neurotropic factors, retro- Rezaie P, Male D. Mesoglia & microglia—a histor- grade axonal transport and cell signalling. Trends ical review of the concept of mononuclear Cell. Biol. 1994;4:383–386. phagocytes within the central nervous system. J. De Vellis J, ed. Neuroglia in the Aging Brain. Hist. Neurosci. 2002;11:325–374. Totowa, NJ: Humana Press; 2002. Robinson PJ, Liu JP, Powell KA, Fykse EM, Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo Sudhof TC. Phosphorylation of dynamin I and JF, eds. Peripheral Neuropathy. 3rd ed. Philadel- synaptic-vesicle recycling. Trends Neurosci. phia, PA: Saunders; 1993. 1994; 17:348–353. Fiala JC, Harris KM. Dendritic structures. In: Stuart Sanes JR, Lichtman JW. Development of the verte- G, Sprutson N, Hausser M, eds. Dendrites. New brate neuromuscular junction. Annu. Rev. Neu- York, NY: Oxford University Press; 1999. rosci. 1999;22:389–442. Goldberg JL, Barres BA. The relationship between Satir P. A decade of kinesin, three decades of neuronal survival and regeneration. Annu. Rev. dynein. Trends Cell Biol. 1995;5:266–267. Neurosci. 2000;23:579–612. Schwab ME. Repairing the injured spinal cord. Sci- Goldstein LS. The kinesin superfamily: tails of ence. 2002;295:1029–1031. functional redundancy. Trends Cell Biol. 1991; Schwaiger FW, Hager G, Raivich G, Kreutzberg 1:93–98. GW. Cellular activation in neuroregeneration. Haimo LT. Regulation of kinesin-directed move- Prog. Brain. Res. 1998;117:197–210. ments. Trends Cell Biol. 1995;5:165–168. Setou M, Hayasaka T, Yao I. Axonal transport Harold F. The Way of the Cell: Molecules, Organ- versus dendritic transport. J. Neurobiol. 2004; isms, and the Order of Life. New York, NY: 58:201–206. Oxford University Press; 2001. Shepherd G. The Synaptic Organization of the Brain. Hol EM, Schwaiger FW, Werner A, Schmitt A, 5th ed. New York, NY: Oxford University Press; Raivich G, Kreutzberg GW. Regulation of the 2004. Chapter 2 Neurons and Associated Cells 39

Stuart G, Spruston N, Hausser M, editors. Den- Tsay D, Yuste R. On the electrical function of dendrites. New York, NY: Oxford University dritic spines. Trends Neurosci. 2004;27:77–84. Press; 1999. Vallee RB, Williams JC, Varma D, Barnhart LE. Sung YJ, Povelones M, Ambron RT. RISK–1: a Dynein: an ancient motor protein involved in novel MAPK homologue in axoplasm that is multiple modes of transport. J. Neurobiol. 2004; activated and retrogradely transported after nerve 58:189–200. injury. J. Neurobiol. 2001;47:67–79. Whitford KL, Dijkhuizen P, Polleux F, Ghosh A. Thoenen H, Sendtner M. Neurotrophins: from Molecular control of cortical dendrite develop- enthusiastic expectations through sobering ment. Annu. Rev. Neurosci. 2002;25:127–149. experiences to rational therapeutic approaches. Woolf CJ, Bloechlinger S. Neuroscience. It takes more Nature Neurosci. 2002;5(Suppl):1046–1050. than two to Nogo. Science. 2002; 297:1132–1134. 3 Basic Neurophysiology

Resting Potential Nernst Equation Excitability of the Neuron Graded Potentials and Action Potentials Structural and Functional Organization of the Neuron Receptive Segment and Receptor Potentials Initial Segment and the Integrated Potential Conductile Segment and Action Potential Transmissive Segment (Synaptic or Effector Segment) Synapses and Chemical Transmission in the Central Nervous System First- and Second-Messenger Systems Electric (Electronic) Synapses Neuron as an Integrator Presynaptic Inhibition and Presynaptic Facilitation Functional Roles of Dendrites Some General Concepts Associated With Coding and Neuronal Processing in the Nervous System

Every neuron is said to possess “in mini- interact, important intrinsic physiological and ature the integrative capacity of the entire other properties essential to their function will nervous system.” Neurons can transform infor- be examined. mation and transmit it to other neurons. In most, the dendrite–cell body unit is specialized as a receptor and integrator of synaptic input RESTING POTENTIAL from other neurons, and the axon is specialized to convey coded information from the The resting neuron is a charged cell that is dendrite–cell body unit to the synaptic junc- not conducting a nerve impulse. The plasma tions, where transformation functions take membrane, which acts as a thin boundary place with other neurons or effectors (muscles between the extracellular (interstitial) fluid out- and glands). To serve these tasks, the neuron is side the neuron and the intracellular fluid (neu- thus organized into (1) a receptive segment roplasm) inside the neuron (Fig. 3.2), is critical (dendrites and cell body), (2) a conductile seg- for maintaining this charged state or resting ment (axon), and (3) an effector segment potential. The electric charge across the plasma (synapse) (Fig. 3.1). membrane results form a thin film of positive Prior to describing the connectivity of the and negative ions, unequally distributed across nervous system and the way in which neurons the membrane. These are (1) sodium (Na+) and

41 42 The Human Nervous System

Figure 3.1: Types of electric potential change recorded across the plasma membrane at various sites of a motoneuron. On the surface of the dendrites and cell body are excitatory and inhibitory synapses, which, when stimulated, produce local, graded, nonpropagating potentials. These are exhibited as an excitatory or depolarizing postsynaptic potential (EPSP) and as an inhibitory or hyperpolarizing postsynaptic potential (IPSP). These local potentials are summated at the axon hillock and, if adequate, could trigger an integrated potential at the initial segment and an all-or- none action potential, which is conducted along the axon to the motor end plate. (Adapted from Gray’s Anatomy, WB Saunders.) chloride (Cl–) ions, which are in higher concen- permeable through nongated open channels tration in the interstitial fluid, and (2) potas- (Chap. 2) to Na+,K+, and Cl– ions and imper- sium (K+) and protein (organic) ions that are in meable to large protein ions. These channels, higher concentration in the neuroplasm. A ten- which are always open, are important in deter- dency exists for the Na+,K+, and Cl– ions to dif- mining the resting potential. The ionic concen- fuse across the membrane from regions of high trations on either side of the membrane are to low concentration (along concentration gra- produced and maintained by a system of mem- dients), through Na+,K+, and Cl– channels, brane pumps (Fig. 2.4) called the sodium (or respectively. The passage of ions across the sodium–potassium) pump requiring metabolic membrane is known as conductance. Thus, the energy released by adenosine triphosphate semipermeable plasma membrane is selectively (ATP). The sodium–potassium exchange pump Chapter 3 Basic Neurophysiology 43 is an integral membrane protein that utilizes pump extruding three Na+ ions for every two ATP as an energy source for its role in active K+ ions it brings into the neuron. The passive transport. This transport is an energy-depend- fluxes of ions take place through nongated ent process in which the movement of Na+ and channels. The outward flux of positive charges K+ ions is “uphill” against a concentration gra- by the pump tends to hyperpolarize the mem- dient. The activity of the pump results in the brane. The greater the hyperpolarization, the passage of three Na+ ions out of and two K+ greater the inward electrochemical force driv- ions into the neuron. This causes the restoration ing Na+ into the neuron and the smaller the of a concentration of K+ 30 or more times force driving K+ out. The steady state for the higher within the neuroplasm than in the interneuron is attained when the resting potential is stitial fluid and in a concentration of Na+ that is reached at the point when the net passive 10 times and Cl– that is 14 times higher in the inward current (movement of electrical charge) interstitial fluid than in the neuroplasm. Most through the ion channels exactly counterbal- neurons do not have a Cl– pump; hence, Cl– ances the active outward current driven by the ions diffuse passively across the membrane. pump. The steady state is not basically the These are the ionic concentrations responsible result of passive diffusion, which is the diffu- for establishing an electric potential across the sion of a solute down a concentration gradient membrane. The transmembrane potential, without the expenditure of energy. known as the resting potential, is about –60 to –70 mV (millivolts) inside the neuron (Fig. 3.2). The resting potential is in a steady state NERNST EQUATION (dynamic equilibrium) requiring metabolic energy to maintain the ionic gradients across The Nernst equation is fundamental to the the membrane. When the neuron is “at rest,” its nature of electrical potentials of all cells, membrane potential is the result of a balance including neurons. It is derived from basic ther- (involving Na+ and K+ ions) between the active modynamic principles. From this equation, the fluxes (movements) of ions metabolically magnitude of the membrane potential at which driven by pumps and the passive fluxes caused ions (e.g., K+) are in equilibrium across a mem- by diffusion. The active fluxes result from the brane can be calculated. The Nernst equation is

Figure 3.2: Resting potential. The intracellular neuroplasm potential of the normal nerve fiber “at rest” is negative to the extracellular potential. Sodium (Na+) and chloride (Cl–) ions are in high concentration in the extracellular fluid, and potassium (K+) ions and protein (An–) are in high concentrations in the neuroplasm. The potential across the plasma membrane is –60 to –70 mV. 44 The Human Nervous System

RT C mV measured by microelectrode studies of the E = 2.3 log o FC squid axon and is explained by the fact that Cl– i and Na+ make small contributions. Sodium where does not have a major role, because application E = the difference in the electrical potential of the Nernst equation to the known Na+ con- between inside and outside the neuron, centrations on either side of the membrane called Nernst potential yields a potential of +50 mV. The explanation R = universal gas constant is that Na+ is kept out of the neuron because T = absolute temperature there are only a few open sodium channels in F = electric charge per gram equivalent of the resting membrane. Practically all sodium univalent ions (Faraday’s constant) channels are gated. The Nernst equation expresses a significant Ci = concentration of ions inside the membrane relationship that defines the equilibrium poten- Co= concentration of ions outside the membrane tial inside the cell for the K+ ion in terms of its The following summary is based on concentration on both sides of the plasma Hodgkin and Huxley’s classic studies of the membrane. This relation between K+ concen- giant squid axon. The resting potential of –70 tration and membrane potential is not quite mV is primarily the result of (1) the much perfect, because, as indicated, Cl– and Na+ do greater concentration of K+ ions inside than make small contributions. A more exact rela- outside the neuron and (2) the passive move- tion is expressed by the Goldman–Hodgkin– ment of K+ ions that diffuse freely through per- Katz equation, which takes into account the manently open channels in the membrane. Both actual permeability for several ions. On the of these points have been established experi- basis of actual ionic concentrations and ionic mentally. In addition, only open channels, permeabilities, calculations using the latter without gates, are involved in creating resting equation agree with the measurements of these potentials (gated channels remain closed; see values in living cells (see more comprehensive subsequent discussion regarding gates and gat- references for detailed accounts). ing). Thus, the concentrations of ions on either side of the membrane result from the opposite actions of the diffusion forces (flow of K+ ions EXCITABILITY OF THE NEURON out of cell to regions of low concentration) and the electric forces (negative charge on the Excitability is a property that enables a neu- organic molecules inside the neurons that ron to respond to a stimulus and to transmit attract the positive charge of K+ ions). The dif- information in the form of electrical signals. The fusion of Na+ and Cl– ions contributes only flow of information within a neuron and slightly to the resting potential (see later). The between neurons is conveyed by both electrical distribution of the ions is maintained at a steady and chemical signals. The electrical signals, state by the sodium–potassium pump that called graded potentials (receptor/generator drives the Na+ out of and the K+ into the neu- potentials; synaptic potentials) and action poten- ron. Actually, the pump is a self-regulating sys- tials, are all produced by temporary changes in tem: The more the sodium accumulates inside the current flow into and out of the neuron. the neuron, the more active the pump becomes. These changes are deviations away from the nor- When the known concentrations of K+ ions mal value of the resting membrane potential. Ion inside and outside the squid giant axon are channels within the plasma membrane control applied to the Nernst equation, a resting the inward and outward current flow. The chan- (Nernst) potential of –75 mV is calculated. nels possess three features. They (1) conduct This predicted figure differs slightly but impor- ions across the plasma membrane at rapid rates tantly from the actual resting potential of –70 up to 100,000,000 ions per second, (2) can rec- Chapter 3 Basic Neurophysiology 45 ognize specific ions and be selective as to which receptor protein in the ligand-gated channels, can pass through, and (3) selectively open and (2) from the changes in the membrane voltage close in response to specific electrical, chemical, in the voltage-gated channels, and (3) presum- and mechanical stimuli. Each neuron is pre- ably from the mechanical forces resulting from sumed to have over 20 different types of channel cytoskeletal interaction at the modality-gated with thousands of copies of each channel. The channels. flux (movement of ions) through the ion chan- There are two types of membrane response; nels is passive, requiring no expenditure of it could (1) hyperpolarize or (2) depolarize. metabolic energy. The direction of the flux is During hyperpolarization, the membrane determined by the electrochemical driving force becomes more negative on the inside with across the plasma membrane. respect to its outside (i.e., could go from –70 The primary role of ion channels in neurons mV to –80 mV; Fig. 3.1). During depolariza- is to mediate rapid signaling. These channels, tion, the membrane becomes less negative called gated channels, have a molecular “cap” or inside with respect to its outside and even gate, which opens briefly to permit an ion might reverse polarity with its inside becoming species to pass (Fig. 3.3). Ligand-gated chan- positive with respect to the outside (Figs. 3.1, nels open when a neurotransmitter binds to 3.4, and 3.5); this is still called depolarization them; voltage-gated channels open and close in because the membrane potential becomes less response to changes in membrane potential; negative than the resting potential (e.g., from modality-gated channels are activated by spe- –70 mV to 0 to +40 mV; Fig. 3.1). cific modalities (e.g., touch, pressure, or stretch). Gating is the process by which a channel is opened or closed during activity. Each channel GRADED POTENTIALS AND consists of several plasma membrane-spanning ACTION POTENTIALS polypeptide subunits (proteins) arranged around a central pore. Each of these classes of channel Neurons are specialized to generate electri- belongs to a different gene family. Each member cal signals, which are used to encode and con- of a family shares common structural and bio- vey information. These signals are expressed chemical features, which presumably have by alterations in the resting membrane poten- evolved from a common ancestral gene of that tial. Voltage changes that are restricted to at or family. The channels of the voltage-gated gene near the sites where neurons are stimulated are family are selective for Na+,K+, and Ca2+ ions. called graded potentials. These can lead to the The channels for the transmitter-gated channels production of action potentials (nerve impulses respond to acetylcholine, gamma amino butyric or spikes), which transmit information for sub- acid (GABA), and glycine. In the future, other stantial distances along an axon. Two forms of families will be identified when the genes for graded potential are generator (receptor poten- other ion channels have been sequenced. tials) and synaptic potentials. Generator poten- Most gated-channels are closed with the tials are evoked by sensory stimuli from the membrane at rest. They open when activated environment (both inside and outside the following the binding of a ligand (ligand gat- body). Information that passes from one neuron ing), a change in the membrane potential (volt- to another at synapses produces synaptic poten- age gating), or the stretch of the membrane tials in the postsynaptic neuron. The activity of (modality gating). In the transmitter-gated either generator or synaptic potentials can elicit channel, the transmitter binds to a specific site action potentials, which, in turn, produce on the external face of a channel that activates synaptic potentials in the next neuron. Synaptic it to open briefly. potentials elicited in effectors (skeletal muscle The energy to open the channels is derived and glands) at synapses can result in the con- (1) from the binding of the transmitter to the traction of the muscle or emission of secretory 46 The Human Nervous System

Figure 3.3: Excitatory synapses (A) and inhibitory synapses (B). A-1 and B-1, Synapses prior to release of neurotransmitter. A-2: Excitatory postsynaptic response (EPSP) following release of neurotransmitter with Na+ ion inrush through Na+ gate and K+ ion outrush through K+ gate. B-2: Inhibitory postsynaptic response (IPSP) following release of neurotransmitter with Cl– ion inrush through Cl– gate and K+ ion outrush through K+ gate. product from a gland (see “Synapse at Motor modulation (an FM system). The graded poten- End-Plate”). tials code by response amplitude; that is, weak Generator and synaptic potentials differ stimuli evoke small potentials (small voltage from action potentials in the way they code changes) and strong stimuli evoke large poten- information. In essence, graded potentials code tials (greater voltage changes), hence graded information by amplitude modulation (an AM responses. Within the central nervous system system), and action potentials use frequency (CNS), or at autonomic ganglia, a small depo- Chapter 3 Basic Neurophysiology 47 larization (small voltage change), called an excitatory postsynaptic potential (EPSP), occurs at the postsynaptic membrane of an excitatory synapse; a small hyperpolarization, called an inhibitory postsynaptic potential (IPSP), occurs at the postsynaptic membrane of an inhibitory synapse (Fig. 3.5). The amount of change depends on the strength of the stimulus. In contrast, action potentials code by response frequency; that is, weak stimuli evoke only a few action potentials per unit time, whereas strong stimuli elicit many action potentials per unit time, but the amplitude of the signal is the same. The following outline compares graded (generator and synaptic) potentials with action potentials. More details will be discussed later. Generator and Synaptic Potentials 1. Graded Response: The amplitudes of responses vary in proportion to stimulus intensity—the stronger the stimulus, the larger the change in membrane potential. 2. Maintenance of Response: The membrane potential change could last as long as the stimulus is sustained. 3. Threshold for Response: There is no discrete threshold. Small potential changes could be evoked with the weakest stimulus. For example, one quantum of light or the transmitter from one synaptic vesicle will elicit a weak receptor (rod or cone of retina) or synaptic potential. 4. Summation of Responses: The potentials will sum when the stimuli are presented Figure 3.4: A neuron with a myelinated close together in time or/and space. axon (A) and a neuron with an unmyelinated 5. Response Remains Local: Potentials will axon (B) showing the charges on the cell mem- spread passively from the stimulus site (site brane and the location of certain ions in each of generation); they are largest at the stimu- neuron “at rest” and at active sites (one in each lus site and become progressively smaller neuron) during conduction of an all-or-none away from that site. action potential. The minus (–) signs within the neurons signify intraneuronal negativity with Action Potentials respect to the positivity (+) within the extracellular fluid outside the neurons. The two large 1. All-or-None Response: Regardless of the arrows indicate the direction in which the nerve strength of the stimulus, the potentials are impulses are propagated. The arrows within the all the same size (about 100 mV or 0.1 V). axons indicate the direction of the flow of cur- 2. Transient Response: The potentials are of rent. Na+, sodium; K+, potassium; Cl–, chloride; constant duration (about 1.5 ms). An– ions, protein. 48 The Human Nervous System

Figure 3.5: Sequences in excitatory (A) and inhibitory (B) transmission from presynaptic neurons (left) across synapses to postsynaptic neuron (right). A. The action potential conducted along the presynaptic axon to an excitatory synapse produces an EPSP, which, in turn, can contribute to the generation of an action potential in the postsynaptic neuron. B. The action potential conducted along the presynaptic axon to an inhibitory synapse produces an IPSP, which, in turn, suppresses generation of an action potential in the postsynaptic neuron.

3. Threshold for Response: Action potentials is of the same strength as at the axon termi- activation requires substantial change in the nal. Thus, the neural code for the message membrane potential (up to 15 mV). conveyed by an axon is based on frequency 4. Size Principle: Smaller neurons require less (number of action potentials per unit time). EPSP to reach threshold for an action poten- Additionally, coding is mediated by the pat- tial than do large neurons. tern (sequencing) of action potentials. 5. Refractory Period: An unresponsive period of about 1.5 ms follows every action potential. During this time, another action poten- STRUCTURAL AND FUNCTIONAL tial cannot be generated, regardless of the ORGANIZATION OF THE NEURON strength of the stimulus. 6. Propagation of Response: Action potentials A typical neuron is a cell with (1) a receptive involve a brief reversal of current limited to segment, (2) an initial segment, (3) a conductile only a small area, which is conducted wave- segment, (4) a transmissive segment, and (5) a like along its length. An action potential at trophic segment (Figs. 3.1 and 3.6). Each com- the beginning of an axon (site of initiation) ponent can be defined by functional criteria. Chapter 3 Basic Neurophysiology 49

The receptive segment is the portion that receptive segment, the local potential is called senses, receives, and integrates information the synaptic (postsynaptic) potential or chemi- from numerous synapses for neural processing. cal potential (see Local Potential later). The It is specialized for the reception of stimuli channels involved in generating these poten- (input), which results in the generation of local tials are chemically (transmitter) gated. In sen- potentials. Each local potential generated at a sory neurons of the peripheral nerves, the synapse is the product of a transient shift of the receptive segment is located in sensory recep- membrane potential in the immediate vicinity tors in the body (e.g., touch receptors). This of the synapse of the receptive segment. The segment contains modality specific gated Na+ membrane can respond by either hyperpolariz- and K+ channels. In these neurons, the local ing or depolarizing. This occurs because of potential as already indicated, are called the local alterations in the permeability to certain receptor or generator potential. ions (i.e., Na+,K+, and Cl–). In those neurons in The initial segment is the junctional or which the dendrites and cell body comprise the trigger zone between the receptive zone and

Figure 3.6: Structural and functional organization of representative neurons. Most neurons are composed of a receptive segment, an initial segment, a conductile segment, and a transmissive segment. The transmissive segment of each neuron is encircled. Arrow indicates the normal direction of conduction of the nerve impulse. (A) Interneuron; (B) lower motoneuron; (C) sensory neuron with cell body in cranial or spinal ganglion; (D) neuron of vestibulocochlear nerve; (E) neuron of olfactory nerve; (F) functional organization of neuron. Note that the cell body (trophic segment) could be located within the receptive segment (A, B, and E) or within the conductile segment (C and D). The receptive segment of the vestibulocochlear nerve is associated with a hair cell. 50 The Human Nervous System conductile zone. It is the locale where the col- called a receptor potential or synaptic poten- lective effects of the receptive zone generate an tial, which is a graded response. Each graded integrated (integral) potential, which is able to response propagates a potential along the cell trigger an action potential in the conductile membrane for a short distance and lasts for segment (Fig. 3.1). only 1 or 2 ms, but is not sufficient to generate The conductile segment is specialized for an action potential (Fig. 3.1). Successive stim- the conduction of neural information from the uli, when timed close together, are additive and receptive segment to the transmissive synaptic enhance or facilitate the graded response. segment. To perform this role, the conductile When a synaptic potential is increased in size, segment conveys all-or-none action potentials it is said to be facilitated. Action potentials are (nerve impulses). This segment contains volt- not generated across the membrane of the den- age-gated Na+ and K+ channels. drites and cell body because these membranes The transmissive segment contains the do not contain voltage-sensitive Na+ and K+ presynaptic membrane and the synaptic vesi- channels. In contrast, in most neurons, action cles. The action potentials arriving from the potentials are generated in the region of the ini- conductile segment activate, through voltage- tial segment because of the high concentration gated channels, the release of the chemical neu- of voltage-sensitive Na+ and K+ channels in the rotransmitter, which, in turn, influences the membrane at this site. receptor sites of the postsynaptic cell. Excitation of the receptor membrane is The trophic segment is the cell body that is explained as the response to a transmitter that the metabolic center essential for the viability partially depolarizes the postsynaptic mem- of the neuron. In most neurons, the trophic cen- brane. Such a response is graded and known as ter is usually located within the receptive seg- an excitatory postsynaptic potential (EPSP) ment. In sensory neurons of peripheral nerves, (Figs. 3.1, 3.3,and3.5). It, like the action the cell body is located within the conductile potential noted later, is associated with Na+ segment (Fig. 3.7). inrush into the segment and K+ outrush through the same chemically gated channels driven by molecular pumps (Fig. 3.3). A single EPSP RECEPTIVE SEGMENT AND does not lower the membrane potential suffi- RECEPTOR POTENTIALS ciently to generate an action potential (Fig. 3.5). However, many EPSPs, generated collec- In most neurons, the receptive segment con- tively, can, by facilitation, become strong sists of the dendrite–cell body unit. In the sen- enough to lower the membrane potential of the sory neurons of the peripheral nerves, it is the initial segment sufficiently to generate an nerve terminals distal to the first node of action potential (nerve impulse). The transmit- Ranvier. ter eliciting EPSPs opens channels that allow both Na+ and K+ to cross the plasma membrane. Dendrite–Cell Body Unit Whereas an EPSP brings a neuron to a state The cell membrane of the dendrite–cell closer to the level where it is more likely to body unit is a postsynaptic membrane, also generate an action potential, an inhibitory post- known as the receptor membrane, because its synaptic potential (IPSP) does the opposite. permeability channels are responsive to the Inhibition is the hyperpolarization of the post- transmitters (neurotransmitters) released by synaptic membrane in response to a transmitter the presynaptic neuron. Thus, its channels are (e.g., –70 mV to –80 mV) (Fig. 3.1). The transmitter gated (chemically gated). In addi- inhibitory response is associated with Cl– tion, each channel is permeable to both Na+ and inrush and K+ outrush through the channels of K+ ions or to both K+ and Cl– ions. When stim- the postsynaptic membrane (Figs. 3.3 and 3.5). ulated, this membrane propagates a response, The transmitter eliciting IPSPs opens channels Chapter 3 Basic Neurophysiology 51

Figure 3.7: A structural and functional schema of a neuron. A neuron can be divided into segments other than the classical dendrite, cell body, axon, and nerve endings. The sensory neuron can be divided as follows: The receptive segment, which conducts with decrement, is the nerve ending; the initial segment (star) is the nodal site where the decremental conduction becomes the non- decremental (all-or-none) conduction of the conductile segment; the conductile segment, which conducts without decrement (all-or-none), extends from the initial segment to the synaptic endings within the spinal cord; the terminal (transmissive) segment includes the synaptic endings. In this neuron, the cell body is located within the conductile segment. The motoneuron can be divided as follows: The receptive segment includes the dendrites and cell body; the initial segment (star) is located just distal to the cell body; the conductile segment goes to the motor end plates; and the terminal segment is located within the motor end plates. In this neuron, the cell body is located within the receptive segment. The cell body is the trophic segment, which is the metabolic center of the neuron. that allow both Cl– and K+ to cross the plasma inhibitory postsynaptic transmitter-gated chan- membrane. The major inhibitory transmitters nels. Both types are able to alter the ionic per- are GABA and glycine. The postsynaptic recep- meability of the receptor membrane. The tors for these transmitters are associated with integration of such synaptic activity is the func- channels permeable to Cl– ions. The resulting tion of the dendrites and cell body of a neuron influx of Cl– ions into the neuron hyperpolarizes (see later). In essence, the receptive segment the membrane and produce IPSPs. integrates synaptic inputs, which, if they sum- Excitatory postsynaptic potentials oppose mate sufficient excitatory activity to reach the IPSPs. A neuron could have numerous excita- initial segment, can trigger an action potential tory postsynaptic channels as well as numerous in the axon (Fig. 3.1). 52 The Human Nervous System

In general, excitatory synapses, evoking (synaptic) segment are recorded and integrated. EPSPs, are found in greater numbers in the It is called the trigger zone or spike-generating dendrites, whereas inhibitory synapses are zone because it can trigger or generate the found in greater numbers in the cell body. This action potential (AP) of the axon. This occurs is a functionally desirable distribution. The because for all neurons it is the site of the low- EPSPs can summate to excite the neuron, est threshold, roughly –45 mV. When this whereas the IPSPs, by being located closer to threshold is reached, the newly generated inte- the initial segment, can effectively control and grated potential of this segment orchestrates modulate the quantity of excitatory influences and initiates the spike. The integrated potential arriving at the initial segment to trigger an will spark the firing of an AP only if the exci- action potential. The nozzle of a hose is analo- tation exceeds the inhibition by a critical mini- gous to the role of the inhibitory synapses; the mum at the trigger zone. If the membrane set of the nozzle (degree of inhibition) regu- potential falls below the spike-firing threshold, lates the amount of water (summated EPSPs) no more action potentials are generated. ejected by the hose. Each receptor transfers the stimulus energy into the electrochemical energy of the neuron Receptive Segment of Peripheral and, thus, establishes a common language for Sensory Neurons all the sensory systems. The sensory or afferent neurons conveying information from the external and internal environments via the peripheral nerves to the CONDUCTILE SEGMENT AND CNS have a particular structural organization. ACTION POTENTIAL The peripheral sensory endings of these fibers, many of which are associated with specialized The conductile segment is the part of a neu- sensory receptors such as the spiral organ of ron specialized to convey an action potential Corti in the inner ear and neuromuscular spin- (AP, nerve impulse), which is a rapidly propa- dles within muscles, have a short receptive gated traveling wave of electrical excitation segment (Fig. 3.6). The plasma membrane con- advancing without decrement in an all-or-none tains modality-specific gated Na+ and K+ chan- fashion along the axon’s plasma membrane. nels. They produce graded potentials that are Because of the sharp inflection recorded on the called receptor or generator potentials. Pres- oscilloscope, it is also called a spike (Fig. 3.1). sure in touch receptors and stretch in muscle All-or-none refers to the fact that an impulse spindle sensory endings open these channels. travels either as a full-blown spike or not at all. When the generator potentials reach the first The integrated potential of the initial segment node of Ranvier, which is the initial segment, activates the voltage-gated channels of the con- an integrated potential is generated. ductile segment. This alters the permeability of the cell membrane. When the stimulus to the axon lowers the resting potential to a critical INITIAL SEGMENT AND voltage level, usually about 10–15 mV less INTEGRATED POTENTIAL negative than the resting potential, an explosive event occurs with the opening of the voltage- The initial segment of an axon of most neu- gated channels of the conductile segment. The rons, or the first nodal site (node of Ranvier) of result is the AP, which is an expression of the peripheral sensory neurons (Figs. 3.6 and 3.7), sudden depolarization. This is the result of is a specialized segment where an integrated changes in conductance associated with the potential is generated. In essence, this is the opening of the voltage-gated Na+ and K+ chan- integrative region where the (algebraic) sum- nels. For a few milliseconds, a polarity reversal mation of the EPSPs and IPSPs of the receptive occurs from the resting potential of –60 to –70 Chapter 3 Basic Neurophysiology 53 mV to the AP of +30 mV with an excess of speed. It regenerates itself from point to point negative charge outside the neuron. The axis along the axon without loss of amplitude; that cylinder gains Na+ and loses K+ ions during the is, it propagates via voltage-gated channels passage of the AP. At each point along the without decrement. The smooth progression of axon, the voltage-gated Na+ channels are acti- the AP is characteristic of unmyelinated fibers. vated first and then followed by the opening of the voltage-gated K+ channels (Fig. 3.4). The Myelinated Fibers and Saltatory Conduction conductance of the Na+ and K+ ion channels The AP in a myelinated nerve fiber is propa- presumably occurs through separate and inde- gated by discontinuous spread or saltatory (hop pendent channels. Through these independent or jump) conduction, in which the AP hops channels, the AP is propagated sequentially along the nerve fiber from node of Ranvier to along the nerve fiber at essentially a constant node of Ranvier (Fig. 3.4A). The current spreads velocity. As soon as the AP passes by each only from an active depolarized node to an inac- patch along the nerve fiber, the K+ conductance tive polarized node by activating its voltage-sen- is increased by the opening of the voltage-gated sitive Na+ and K+ channels. These channels are K+ channels and, thus, the cell membrane highly concentrated in the axis cylinders returns to its resting level. The repolarization of exposed at the nodes. The myelinated internodes the membrane occurs when the K+ conductance act as passive conductors. Myelinated fibers are restores internal negativity. fast conductors of action potentials. The speed The following is a rough approximation. of conduction of the AP is related to the thick- The assumptions that the membrane potential ness of the myelin sheaths and the length of the (1) is solely the result of K+ leads to a value internodes of a nerve fiber. The thicker the near that of the resting potential, and (2) is myelin sheath and the longer the internodes, the solely the result of Na+ leads to a value near faster is the conduction rate. Myelin improves that of the action potential. These assumptions the signaling (conductile) efficiency of an axon. are essentially correct because K+ is primarily responsible for the resting potential and Na+ is primarily responsible for the action potential. TRANSMISSIVE SEGMENT In summary, the movement of ions across (SYNAPTIC OR EFFECTOR SEGMENT) the plasma membrane through voltage-gated channels produces the AP. The movement only The transmissive or synaptic segment is that occurs after the channels are open, which portion (or portions) of a neuron through which results in changes in the distribution of charges it exerts its influence on another neuron, mus- on either side of the membrane. The influx of cle, or gland cell (Fig. 3.7). Anatomically, this Na+ ions reverses the resting charge distribu- is the presynaptic portion of a synapse com- tion. This is followed by an influx of K+ ions, prising the presynaptic membrane and vesicles which repolarizes the membrane by restoring containing neurotransmitters or their precur- the initial charge distribution. sors. Physiologically, the arrival of an AP in the transmissive segment activates the voltage- Unmyelinated Fibers gated calcium channels in the presynaptic In an unmyelinated fiber, the AP is propa- membrane to trigger the inward passage of Ca2+ gated sequentially along all parts of the cell ions. This is the critical final step for the release membrane of the axon. Each depolarized point of neurotransmitter into the synaptic cleft. on the membrane produces a flow of current These voltage-gated Ca2+ channels control (AP) that triggers depolarization of the adja- what is essentially the secretory function of a cent point. This continues the length of the neuron, which is, in essence, a secretory cell. axon (Fig. 3.4B). The AP travels along the cell The synapse acts as a one-way valve permit- membrane as a chain reaction at a constant ting the action potential of a neuron to exert its 54 The Human Nervous System influence through the release of neurotransmit- into the nerve terminal, there is a 100,000 times ters across the synaptic cleft to the receptive surge in ACh molecules as numerous quanta segment of the postsynaptic neuron. An excep- are released by exocytosis into the synaptic tion is the axoaxonic synapse (Fig. 2.9) in cleft. Following exocytosis the vesicle mem- which the synapse is between two transmissive brane is recycled (Fig. 3.10). segments (discussed later in connection with The ACh molecules activate an estimated presynaptic inhibition and excitation). 20–40 million ACh receptor sites on the sarcolemma of a motor end plate. This results in Synapse at Motor End-Plate (Neuromuscular EPPs (end-plate potentials) in the membrane Junction) (Figs. 3.8 and 3.9) that depolarizes the sarcolemma adjacent to the The synapse at the motor endplate between neuromuscular junction (NMJ). This activates an axon terminal and voluntary muscle is a its voltage-sensitive Na+ and K+ channels of the well-documented example of interaction at a sarcolemma to generate APs. The AP is con- synapse. Acetylcholine (ACh) is the transmitter ducted rapidly along the muscle surface and to at this synapse. The ACh is released into the the interior of the muscle fiber via the mem- synaptic cleft from a vesicle as a quantum with brane of the many transverse tubules (T-tubules) each quantum containing about 6000–10,000 (Fig. 3.9). The AP stimulates the release of ACh molecules. The release is continuous, with Ca2+ ions from the sarcoplasmic reticulum (SR) a quantum resulting in the slight activity known of the muscle to initiate contraction of the as miniature end-plate potentials (MEPPs) that muscle fiber as a unit (known as excitation– do not produce an action potential (AP) in the contraction or EC coupling). The relaxation of postsynaptic membrane (sarcolemma of mus- the muscle fiber is associated with the return of cle fiber). Each AP impulse releases from 100 the Ca2+ ions to the sarcoplasmic reticulum. to 200 quanta. A more active synaptic trans- The basal lamina of the muscle in the end plate mission commences with the depolarization of is filled with the enzyme cholinesterase, which the membrane by the arrival of the AP at the inactivates the excess ACh. This enzyme serves presynaptic terminal. Upon depolarization, the two purposes, namely it (1) permits only a voltage-sensitive Ca2+ channels open, resulting small proportion of ACh released to stimulate in an influx of Ca2+ ions into the terminal. The receptors and their channels on the sarcolemma Ca2+ facilitates the binding and confluence of of the end plate and (2) creates breakdown many synaptic vesicles to the presynaptic products, such as choline, which is taken up by membrane. Following the arrival of volleys of the nerve terminals and utilized in the resyn- APs and the increase in the influx of Ca2+ ions thesis of ACh.

Figure 3.8: Structural and molecular features of three types of synapse. A. Neuromuscular junction (NMJ, motor end plate). Morphologically the NMJ comprises the motor nerve terminal (M.N.T.) a striated muscle cell (St. M.) and a Schwann cell (S.C.) (Fig. 2.3) that are embryologi- cally derived from three separate sources. The motor nerve arises from the basal plate of the neural tube, the striated muscle from a myotome, and the Schwann cells from a dermatome of a somite (Fig. 6.2). A Schwann cell caps the motor nerve terminal. The basal lamina (B.L.) of the synaptic cleft is a continuum surrounding both the Schwann cell and the motor nerve ending. The thickened postsynaptic membrane contains ionotropic acetylcholine receptors. B. Central excitatory asymmetric synapse. The axon terminal is capped by astroglial processes (A.P.). The synaptic cleft lacks a basal lamina. The thickened postsynaptic membrane of the dendritic spine (S) contains ionotropic glutamate receptors. Note the postsynaptic density (PS.D.) and dendritic spine apparatus (S.A.) located in the neck of the spine in Fig. 3.12. C. Central inhibitory symmetric synapse. The axon terminal is capped by astroglial processes (A. P.) and the synaptic cleft lacks a basal lamina. The postsynaptic membrane of the dendritic shaft contains ionotropic GABA receptors. Chapter 3 Basic Neurophysiology 55 56 The Human Nervous System

In brief, the neurotransmitter precursor is ending, are essential. Ca2+ ions are the intra- synthesized within a neuron and stored and neuronal messengers. They serve as the only packaged in a vesicle within the nerve terminal, link to transduce depolarization into all the and the activated form is released by exocyto- nonelectrical activities regulated by excitation. sis from the vesicle into the synaptic cleft. Without Ca2+ channels, the neurons and, as a Neither Na+ influx nor K+ efflux is required consequence, the nervous system would have for synaptic transmission. Only Ca2+ ions, no outputs. In essence, synaptic delay (i.e., the which enter the neuron through voltage- time interval between the arrival of the action dependent Ca2+ channels in the presynaptic potential at the transmissive segment and the

Figure 3.9: Neuromuscular linkage. Sequence of events from the action potential of a motor nerve (A), to motor end plate, to action potential of muscle cell membrane (B), to T-tubule, and to sarcoplasmic cisternae. The release and uptake of calcium ions are involved with excitation-contraction (EC) coupling. Chapter 3 Basic Neurophysiology 57

Figure 3.10: A. Chemical synapse—direct gating of an ion channel. In nerve endings, neurotransmitters are packaged in synaptic vesicles and released by exocytosis. Empty synaptic vesicles are rapidly recycled for reuse by endocytosis. The action potential conveyed by the axon depolarizes the nerve terminal to trigger an influx of Ca2+ ions through voltage-gated channels. This activates synaptic vesicles to fuse with the presynaptic membrane and to release transmitter molecules into the synaptic cleft by exocytosis. These transmitters diffuse across the cleft and bind to specific receptor sites on the postsynaptic membrane. Each receptor controls an ion channel (selective to specific ions) by direct gating of the ion channels. The direct gating of an ion channel is mediated by a transmitter receptor that is a part of the ion channel. The resulting ion flux alters the voltage of the postsynaptic membrane. This can either depolarize the membrane to generate excitatory postsynaptic potentials (EPSPs) or hyperpolarize the membrane to generate inhibitory postsynaptic potentials (IPSPs). Transmitter molecules then uncouple from the receptor sites and, thus, their role in the synaptic response is consummated. The transmitter (or its breakdown product) can be conveyed through a membrane transporter into the axon terminal to be recycled. The vesicle membrane is also recycled—the protein clathrin becomes transiently associated with the vesicle membrane to assist its being incorporated into a new vesicle by endocytosis. A critical means for sustaining the vesicle population at the endings in the presence of active transmitter release is by the rapid recycling of synaptic vesicles. The entire process, from the activation of the exocytosed synaptic vesicle for recycling until the vesicle with transmitter is competent to be exocytosed again, 58 The Human Nervous System release of neurotransmitter) is an expression of sists of four steps. They are similar in principle the time it takes for the Ca2+ ions to diffuse to to those at the neuromuscular junction, which the site of action within the terminal and the is actually a synapse between a neuron and a release of transmitter from the synaptic vesi- muscle fiber. These steps are (1) synthesis of cles. At the neuromuscular junction, the normal the transmitter, (2) storage and release of the synaptic potential of –70 mV at the postsynap- transmitter, (3) interaction of transmitter with tic membrane results from the release of about receptors, and (4) removal and recycling of 150 quanta of ACh. synaptic vesicles and transmitters (Fig. 3.10). In the innervated muscle fiber, the channels For signaling, the nervous system utilizes capable of responding to ACh are restricted to two classes of neurotransmitter that are con- the region of the NMJ. Following the denerva- tained within vesicles located in the synaptic tion of a muscle fiber, the fiber becomes sensi- terminals: (1) small molecule transmitters and tive to ACh over its entire surface. In response (2) neuroactive peptides (Chap. 15). The to denervation, the fiber synthesizes new ACh- small-molecule transmitters include (a) acetyl- sensitive channels and inserts them into its choline, (b) the four amino acids glutamate, plasma membrane. In a sense, this is a rever- aspartate, GABA, and glycine, and (c) the four sion to its early development when newly dif- monoamines comprising the catecholamines ferentiated muscle fibers have ACh-sensitive dopamine, norepinephrine and epinephrine, channels scattered over their entire surface. and the indolamine serotonin. The neuroactive Upon reinnervation, the membrane’s ACh sen- peptides include at least 50 different pharmaco- sitivity again becomes restricted to the region logically active peptides such as the hypothala- of the NMJ. mic peptide somatostatin, the pituitary peptide vasopressin, the digestive system peptide substance P and such peptides as enkephalins. SYNAPSES AND CHEMICAL TRANSMISSION IN THE Synthesis of the Transmitters CENTRAL NERVOUS SYSTEM The transmitters are synthesized within the presynaptic neuron. The small-molecule trans- The primary means of communication mitters are generated in all regions of the neuron, between neurons is via chemical transmission including the nerve terminals. Its macromolecu- at synapses. Within the CNS, this process con- lar components are synthesized in the cell body

(Figure 3.10 continued) can presumably occur in less than 3 min. This ensures the maintenance of the population of about 200 vesicles in a single nerve ending. (Refer to the text.) B. Chemical synapse—indirect gating of an ion channel via a second messenger. The neuromodulator (transmitter) released from a synaptic vesicle into the synaptic cleft binds with a receptor on the postsynaptic membrane. The receptor activates a G-protein and an intracellular enzyme such as adenylate cyclase. This enzyme converts adenosine triphosphate (ATP) to the second messenger cyclic adenosine monophosphate (cAMP). In turn, cAMP activates other enzymes, called kinases (cAMP-dependent kinases), and phospho- rylates ion channels to modulate their function (also to influence activity in the nucleus and the cytosol). Second messengers frequently act through protein phosphorylation to open and close ion channels. The indirect gating of an ion channel is mediated by a second messenger that couples to the receptor of an ion channel. Neuromodulators can also bind with autoreceptors located on the presynaptic terminal membrane. These receptors activate the second-messenger system in the axonal terminal to modulate transmitter release. Neurotransmitter transporters are glycoproteins in the cell membrane that are active in reuptake systems conveying neurotransmitters from the synaptic cleft to the axon terminal for recycling. (Refer to the text.) Chapter 3 Basic Neurophysiology 59 and rapidly delivered by fast transport to the ter can coexist in the same mature neuron. The nerve terminals, where the synaptic vesicles are corelease of several transmitters from the assembled. Some are derived from released presynaptic neuron and the presence of appro- transmitters in the synaptic cleft and recycled priate receptors on the postsynaptic neuron is back into the terminal. The neuropeptides are one expression of the combination of diverse generated in the cell body. information transfer. Storage and Release of the Transmitters Interaction of Transmitter With Receptors Once formed, these transmitters are immedi- The released transmitters diffuse quickly ately sequestered within the vesicles and teth- across the synaptic cleft, are attracted by and ered to the cytoskeleton in the reserve pool bind to specific receptor proteins on the postsy- (storage or cytoskeletal anchored compart- naptic membrane, and initiate changes in the ment) of the nerve terminal. If left free in the membrane. There are two general groups of cytoplasm, the transmitter is vulnerable to transmitter: neurotransmitters and neuromodu- intracellular digestion. Vesicle stores constitute lators. a reserve of transmitters, protected from intra- Neurotransmitters are substances that act cellular enzymes. Thus, only an appropriate directly on the postsynaptic membrane chan- level of transmitter is available within the cyto- nels and, by altering their permeability, allow plasm. The small transmitters are stored in ions to pass through the channel mediated by small, clear vesicles about 50 nm in diameter. the transmitter receptor that is an integral part Vesicles are then transported to docking sites of the channel. The neurotransmitters include near the sites of release, called active zones, ACh and the amino acids glutamate, aspartate, where they are docked to fusion pore com- GABA, and glycine. They are involved with the plexes in the presynaptic plasma membrane. generation of fast EPSPs and IPSPs. These The entry of calcium into the nerve terminal local potentials commence within a fraction of through voltage-gated channels triggers the a millisecond after the release of the transmitter opening of the fusion pore complex and trans- and seldom persist longer than 100 ms. Gluta- mitter release into the synaptic cleft. The cal- mate and aspartate are excitatory neurotrans- cium also mobilizes cytoskeletally anchored mitters and GABA and glycine are inhibitory vesicles and makes them available for docking neurotransmitters. Depending on the nature of with the fusion pore complex. the receptor, ACh can act either as an excitatory In contrast to small-molecule vesicle trans- or inhibitory transmitter. mitters, the precursors of the neuroactive pep- Some substances released at synapses mod- tides are synthesized and packaged into ify or modulate neural activity rather than initi- secretory granules and synaptic vesicles in the ate it and are called neuromodulators. Their cell body. They are then transported by fast effects are of slow onset, but can last for sec- transport via neurotubules to the terminals. In onds to hours or longer. They operate in the this respect, they are unlike the small-molecule postsynaptic neuron through other molecules transmitters. The neuropeptides are stored in called second messengers (see later). These large (with an electron dense core) vesicles long-term changes can be involved with such about 120 nm in diameter. phenomena as memory and learning. Neuro- A transmitter is a substance that is released modulators include the monoamines dopamine, at a synapse by a neuron and affects another norepinephrine, epinephrine, and serotonin and neuron or effector cell (muscle fiber or glandu- the neuroactive peptides. Of the many neu- lar cell) in a specific manner. A mature neuron ropeptides in the brain, most act as neuromod- makes use of the same transmitter (or transmit- ulators. ters) at all of its synapses. A small-molecule The receptor protein to which a transmitter transmitter and a neuroactive peptide transmit- binds determines whether it will act as a neuro- 60 The Human Nervous System transmitter or a neuromodulator. A substance roactive transmitters such as serotonin, glu- such as ACh can, depending on the specific tamate, aspartate, glycine, GABA, and the cat- receptors, act as both (see Second Messenger echolamines dopamine and norepinephrine. System). Transporters are implicated as sites for drug action. Drugs that block neurotransmitter reup- Removal and Recycling of the take exert powerful physiologic effects. The Synaptic Vesicles and Transmitters action of many antidepressant drugs, such as Vesicle Membrane. In order to release its Prozac, result from the blocking of the sero- transmitters into the synaptic cleft, a vesicle tonin transporter. Thereby, the amount of sero- containing the transmitters initially fuses with tonin in the synaptic cleft is increased the presynaptic membrane. Following the (Chap. 15). release by a process known as exocytosis, the The neurotransmitter ACh released from vesicle membrane becomes incorporated in the cholinergic endings (e.g., motor end plate) is presynaptic membrane and coated on its inner not taken up into the axon terminal as ACh. surface by a dense layer of the protein clathrin. Rather it is degraded into choline and acetate A coated “pothole” is then retrieved as a vesi- by the enzyme cholinesterase located in the cle by the reverse process of endocytosis (Fig. basal membrane of the synaptic cleft. The 3.10). The budding off of the new vesicle, choline is taken up into the axon terminal to be which is energetically unfavorable, is aided by used in the synthesis of new ACh. The choline the clathrin, which remains as a temporary coat is combined with acetyl coenzyme A (an acti- around the vesicle. After being pinched off vated form of acetate) by the enzyme choline from the plasma membrane, the clathrin-coated acetyltransferase, as the catalyst, to become vesicles are enzymatically uncoated within a ACh, which is then concentrated in new synap- few seconds. Most of the recycled membranes tic vesicles. form intermediary structures called cisternae before forming vesicles that become filled with Life Cycle of a Synaptic Vesicle: A Sum- newly synthesized or reuptake transmitters. mary. The cycle commences with the synthesis Thus, the vesicle membrane and transmitters of vesicle-associated proteins in the cell body, are recycled. Some exocytosed vesicle mem- followed by assemblage of the synaptic vesicle branes can be returned by retrograde transport in the axon terminal. Within the terminal, the to the cell body where they are degraded by vesicle undergoes a maturation process involv- lysosomes. ing membrane formation, an endocytosis of transmitter, and the joining to a pool of vesicles Removal and Reuptake of Transmitters (Fig. tethered to the cytoskeleton. Mobilization from 3.10). Following their release from the nerve the cytoskeleton is followed by vesicle docking terminals, most transmitters are rapidly consisting of the approach of the vesicle toward removed from the synaptic cleft by a sodium- an active zone plasma membrane and the for- dependent cotransport reuptake system into the mation of protein complexes linking the vesicle axon terminal (or into glial cells). By cotrans- membrane to the plasma membrane. Exocyto- porting the transmitter with sodium, the energy sis requires an ATP-dependent priming reaction stored in the transmembrane electrochemical as a prerequisite for Ca2+-triggered membrane gradients can be used to drive the transmitter fusion. Following the release of the transmitter back into the axon terminal through the glyco- by exocytosis, the vesicle membrane, protein protein transporters in the plasma membrane. constituents, and excess transmitter are recy- Once inside the axon terminal, the transmitter cled by endocytosis, mediated, in part, by a is incorporated into a new synaptic vesicle. clathrin coat, The recycling vesicle sheds this Transmembrane transporters, each of which is coat and then can directly reuptake transmitter linked to a specific transmitter, take up neu- before undergoing the next round of exocytosis. Chapter 3 Basic Neurophysiology 61

Activity at the Synapse potential. These two events can be broken Following release, the neurotransmitter mol- down into eight steps: (1) the arrival of the nerve impulse results in presynaptic depolar- ecules diffuse across the synaptic cleft, result- ization, which (2) triggers the opening of cal- ing in a synaptic delay of about 1 ms. cium channels with an inrush of Ca2+ ions Depending on the chemical structure of the through the presynaptic membrane, which (3) transmitter and of the receptor sites on the triggers transmitter release from presynaptic postsynaptic membrane, the resulting perme- vesicles, followed by (4) diffusion of the trans- ability changes at the receptor channels lead mitter across the synaptic cleft and (5) the either to excitation or inhibition. The response binding of the transmitter to the receptor sites of the postsynaptic membrane (excitation or on the postsynaptic membrane, after which inhibition) cannot be attributed exclusively to there are (6) molecular events in the postsynap- the transmitter; the properties of the receptor tic membrane resulting in (7) the opening of are also critical. Stimulation of excitatory ion channels and (8) the generation of graded receptors results in excitatory responses on the postsynaptic potentials. Each of the receptor postsynaptic membrane, whereas the stimula- sites is a complex of proteins with an active tion of inhibitory receptors results in inhibitory binding portion facing the synaptic cleft and responses. For example, the transmitter ACh channel through the postsynaptic membrane. In stimulates excitatory activity in voluntary mus- effect, the transmitter binds to the receptive site cle and inhibitory activity in cardiac muscle. and opens the channel through which the ions Neurons generally exert either excitatory or flow. inhibitory influences, but there are other exceptions. As a rule, such transmitters as glutamate, aspartate, and ACh produce excitatory FIRST- AND SECOND-MESSENGER responses, whereas glycine and GABA pro- SYSTEMS duce inhibitory responses. Hormones and drugs can also bind to recep- Communication between two neurons tor sites of the plasma membrane. The mole- across a synapse involves first messengers cules of neurotransmitters, hormones, or drugs (e.g., neurotransmitters or hormones) released do not just bind to their receptors; each is in a from the presynaptic neuron that interact with process of binding and unbinding that results in two types of receptor on the plasma membrane a state of dynamic equilibrium. In this continu- of the postsynaptic neuron: (1) ionotropic ous process, each molecule–receptor combina- receptors, which directly gate (open or close) tion has its own dynamic steady state and rate the ion channels and (2) metabotropic recep- of binding and unbinding between free and tors, which activate second-messenger sys- bound molecules and between free and bound tems. Two exceptions to this generalization receptors. In addition, molecular pumps act include (a) gap junctions where ions pass quickly to remove the transmitter from the directly between neurons and (b) gaseous mes- receptor sites. sengers (e.g., nitric oxide) that do not act on In summary, two physiologic events occur at membrane-bound receptors. a synapse between a transmissive segment and The two main categories of neural first mes- a receptive segment: (1) The nerve impulse by sengers ( hormones act as first messengers) are depolarizing the presynaptic membrane brings based on their mode of action on postsynaptic about Ca2+ entry followed by transmitter cells. (1) Neurotransmitters interact directly release into the synaptic cleft and (2) there is a with the receptors of postsynaptic ligand-gated response at the postsynaptic membrane initi- (transmission-gated) ion channels (also called ated by the transmitter–receptor protein inter- ionotropic receptors). A ligand is a substance action followed by the generation of a graded such as a transmitter, hormone, or drug that 62 The Human Nervous System binds to a postsynaptic receptor of a channel. neuropeptides such as enkephalin, vasoactive (2) Neuromodulators interact with postsynaptic intestinal peptide, and oxytocin (Chap. 15). G-protein-coupled receptor membrane-span- The transmitters acting on the synaptic ning proteins that are also called metabotropic receptor sites of ligand-gated channels are the receptors. They do not directly open ion chan- hallmarks of fast neurotransmission. They are nels, but, rather, are linked to second-messen- fast-acting (millisecond timescale) with point- ger systems by membrane-spanning proteins. to-point (neuron to neuron) accuracy and pro- These are distinct intracellular biochemical voke either simple excitatory (EPSP) or signaling pathways that stimulate or inhibit inhibitory (IPSP) responses (Fig. 3.5). These intracellular responses. Second messenger for- expressions by postsynaptic cells do not mation typically is triggered by a first-messen- depend on the chemical properties of the trans- ger (transmitter or hormone) acting on a mitters but, rather, in the response properties of G-protein-coupled cell surface receptor. A sec- the receptors. The bulk of specific information ond messenger such as cyclic AMP (cAMP) processed by the nervous system is associated generates a short-lived chemical signal in the with synapses that are fast transmission-gated cytosol that can trigger a biochemical response channels opened by first messengers. They are that routes its signal via a distinct intracellular active in most motor actions and perceptual signaling pathway (cascade) within the postsy- processing within the nervous system. naptic neuron (Fig. 3.10B). The modulators are first messengers that An extensive diversity of signaling path- bind with receptors linked to a membrane- ways is present in all neurons. The activation of spanning protein unit (e.g., G-protein-coupled these pathways is typically initiated by such receptor; Fig. 3.10B) that activates (or chemical first-messenger molecular signals as inhibits), for example, an intracellular enzyme neurotransmitters and hormones. These mole- sequence of adenylyl cyclase and the cyclic cules bind to receptors such as ligand-gated ion adenosine monophosphate (cAMP) kinase channels and G-protein-coupled receptors. The phase of a second-messenger cascade. The outcome of the activation of these receptors is cAMP cascade is a multistep process that cou- commonly the production of second messen- ples the activation of the neurotransmitter gers, including cAMP, that activate intracellular receptor by the first messenger, leading to the signaling pathways. In turn, these intracellular activation of intracellular enzyme signaling signaling pathways convey secondary messen- pathways. The G-protein-coupled receptors are gers to the ion channels (with channel pores members of a large genetic suprafamily. They facing the cytosol), that are directly gated chan- act through G-proteins (guanine nucleotide- nels at chemical synapses (Fig. 3.10B). The binding proteins) that activate second-messen- result is that signaling pathways generate a vast ger intracellular pathways. array of responses over a wide range of times Modulation describes the actions of neuro- and distances, significantly augmenting and transmitters that do not directly evoke postsy- fine-tuning the information-processing ability naptic potentials, but, rather, modify or adjust of neuronal circuits. the neuronal responses generated by other Most first messengers can act both as trans- synapses (Fig. 3.10B). Modulation can alter the mitters and modulators, although some act properties of the membrane channel proteins exclusively as one or the other. In common through modifying the activity of the ion chan- usage, the term “neurotransmitter” (transmit- nels by changing their electrical properties in ter) often applies to both transmitter and mod- response to intracellular biochemical changes ulator. The transmitters include acetylcholine resulting from synaptic (or hormonal) stimula- and small amino acid molecules such as gluta- tion. The intrinsic properties of modulation are mate, GABA, and glycine. The modulators expressed as slow synaptic transmission (1) include monoamines (biogenic amines) and neither rapid, nor point-to-point, and not sim- Chapter 3 Basic Neurophysiology 63 ply excitatory or inhibitory and (2) achieve changes to activate protein kinases that phos- effects as typically having a slow onset, usually phorylate (energy-rich phosphate group) such in seconds, that last for long periods of time cellular constituents as target proteins. Kinase (hundreds of milliseconds to minutes, hours, or is an enzyme that uses ATP as a donor of phos- even longer). Second messengers do not medi- phate groups. The concept of phosphorylation ate rapid behaviors, but, rather, serve to modu- mediated by protein kinase is central to the late the strength and efficiency of the understanding of the second-messenger signal- ionotropic receptors or the external excitability ing pathways. The second-messenger system of the postsynaptic neurons. such as cyclic AMP affects cells through the Modulation is the term that describes the action of protein kinases. Virtually all known actions of neurotransmitters that do not directly cell membrane receptors are linked to intracel- evoke PSPs but can modify the neuronal lular signaling systems that interact first with response to EPSPs and IPSPs. This is accom- G-proteins. These include neuromodulatory plished as follows. In a different channel of the receptors on neurons, the light-sensitive mole- neuron, a second messenger is produced when cules in photoreceptors, and the odor-sensitive another first messenger binds to a receptor fam- proteins of olfactory neurons. A number of G- ily. It includes a cascade of certain proteins proteins that can activate (or inhibit) a variety (e.g., G-proteins) that release a second messen- of intracellular enzymes are known. There are ger that, in turn, can trigger a cascade in the many sequences of first messengers, receptor cytosol that modifies (e.g., enhances or lowers) G-proteins, second messengers, protein quality of the PSPs generated at other channels. kinases, and protein phosphatases that activate or inhibit many cascades of intracellular Modulatory Systems enzyme systems. These systems act through The modulatory form of neurotransmission subtle, complex, and highly integrated bio- offers an almost limitless number of ways that chemical reactions that operate throughout the neural information encoded by presynaptic neuron, including the nucleus (e.g., regulation impulse activity and conveyed by first-messen- of gene expression), plasma membrane (e.g., ger modulators is transformed and used by the subunits of ion channels), and protein sequences postsynaptic neuron. The released modulator within the networks of the cytoskeleton. Phos- interacts with receptors located at the synaptic phorylation, a reaction in which a phosphate is sites of the postsynaptic membrane to trigger transferred from ATP into another molecule, of the processing by the modulatory system of the proteins by protein kinases changes their bio- intracellular sequences within the neuronal logical activity. Second-messenger-activated cytosol The phenomena associated with neuro- kinases catalyze by phosphorylating cellular modulation occur when the neurotransmitter constituents by activating or inactivating bio- released by a neuron alters the synaptic and cel- chemical mechanisms. These sequences can lular properties of another neuron. The effects utilize the monorail neurotubules by transport- of neuromodulation are contingent on the activ- ing essential ingredients to their proper locale ity of the responding neurons. The following for functional integration into the sequence. are some basic features of how such a system Phosphorylation of ion channels, which alters functions (Fig. 3.10B). The first-messenger their conformation slightly, can significantly modulator binds to a receptor of a plasma influence the probability that they will open or membrane spanning complex to activate a tran- close. If the activated kinases are allowed to suding intermediate G-protein bound to an phosphorylate without some means of revers- effector enzyme system that activates adenylyl ing the process, the proteins would become cyclase, an enzyme that catalyzes the conver- fully saturated with phosphate and, thus, regu- sion of ATP to the quick diffusing small- lation would be impossible. Enzymes, called molecule C-AMP. In turn, C-AMP initiates protein phosphatases, can rapidly remove the 64 The Human Nervous System phosphate groups. As a consequence the degree cate balancing act of signaling networks, of channel phosphorylation at any moment is shifting its effects dynamically to the ongoing dependent on the phosphorylation by kinases demands of the (a) neuron or (b) the CNS that and dephosphorylation by phosphatases. vary and are synchronized with alterations of Neuromodulators can exert presynaptic as the ever-changing demands of the organism. well as postsynaptic effects. Presynaptic termi- 3. Learning produces changes in behaviors and nals have their own receptors, called autorecep- motor skills that do not occur by altering the tors (Fig. 3.10B), which are presynaptic circuitry in the brain, but, rather, by adjust- receptors able to recognize and bind with a neu- ing the strength of synaptic connections ron’s own transmitter that has been released. In between neurons largely via biochemical Fig. 3.10B, the autoreceptor is activated to inte- changes in the neuromodulatory system. grate a cAMP cascade to modulate the synthesis 4. Alterations in the modulation of synaptic of neuroactive agents in the axon terminal. The transmission are involved in neuromodulator released by the terminal can reg- a. the alterations in mental states caused by ulate, through a feedback sequence, the forma- drugs such as amphetamines and LSD tion of neuroactive agents in the axon terminal. (lysergic acid diethylamide) and b. in afflictions such as schizophrenia. General Comments 5. Several second-messenger systems, as well 1. Chemical synapses are the major structure in as variations within each of these systems, the brain that allows for the richness of inter- are known to exist in neurons. Complexities actions among neurons. Synaptic transmis- of these systems result from the myriads of sion resulting from the activation of ion-gated linkages involving different types of recep- channels is simple and fast. Synaptic modulator, G-protein, second messenger, and pro- tion resulting from activating G-protein tein kinase. One estimate suggests that 100 receptors is relatively complex and slow. In neurons have 1 or more receptor types that essence, the G-proteins are signal transducers communicate with 20 or so G-proteins. The that communicate signals from many neuro- G-proteins are considered to be a key com- transmitters and hormones. These extracellu- ponent within the plasma membrane of the lar signals are received by G-protein-coupled complex messenger network within the neu- receptors that activate G-proteins. The G-pro- ron. The biochemical networks and path- tein pathways route signals from a second ways of enzyme systems within the neuron can expand the neuronal information capac- messenger (i.e., cAMP) via a number of dis- ity beyond the currently recognized voltage tinct intracellular signaling G-protein path- signals. Thus, these biochemical systems ways within the neuron. These pathways might be potential conduits for information interact with one another to form a network in addition to their current roles of modulat- that regulates ion channels, metabolic ing the flow of information. enzymes, transporters, and other components 6. “When one thinks of fast synaptic transmis- of the cellular machinery. They control a sion as being the hardware of the brain and broad range of cellular processes including slow synaptic transmission as being the soft- transcription, mobility, contractility, and ware that controls fast transmission, the secretion. These processes, in turn, regulate molecular basis by which the cells commu- systems such as embryonic development, nicate with each other makes sense” (Green- homeostasis, learning, and memory. gard, 2001). 2. The dynamic networks of second-messenger intracellular enzyme sequences within the dendritic arbors, axon, and cell body of each ELECTRIC (ELECTRONIC) SYNAPSES neuron resemble the complex networks of the brain and spinal cord. Synaptic inputs to the Another type of synapse, the electric (elec- neuron and those to the CNS produce an intri- tronic) synapse, is relatively rare in the mam- Chapter 3 Basic Neurophysiology 65 malian nervous system. In these synapses, tion of the IPSPs, the initial segment of the there is cytoplasmic continuity between two axon might be excited to initiate the production adjacent neurons through 1.5-nm channels. of an action potential (Fig. 3.5). If the algebraic Because of this continuity, ions can flow summation of these potentials (EPSPs and between cells at these junctions; these low- IPSPs) is not sufficient to stimulate the initial resistance “gap junctions” result in “electri- segment, an action potential is not generated in cally coupled” neurons. In these synapses, no the axon. The depolarization of the initial seg- transmitter is involved. There is essentially no ment to the critical voltage is a prerequisite to synaptic delay, because the electrical activity the generation of an action potential. Thus, readily spreads from neuron to neuron. each dendrite–cell body complex of a neuron is Because these synapses cannot be modulated, a miniature integration center; it will respond they are not compatible with most neural func- with an action potential according to the net tions. However, they are occasionally found effect of the excitatory and inhibitory synaptic where activity must be tightly synchronized, activity on the receptive membrane of the neu- as, for example, in the circuits involved with ron. The axon is the vehicle for signaling coded stereotypic saccadic eye movements (Chap. information, via action potentials, from the 16), in the junctions (nexus) between smooth dendrite–cell body complex to other neurons or muscle cells involved in peristalsis of the gut, effectors (muscles or gland cells). and between cardiac muscle fibers (intercalated Each postsynaptic membrane of the signaled disks) in synchronizing the heart beat (Fig. 2.3). neurons and effectors contains hundreds or Because the current can flow across gap even thousands of receptor sites. Each receptor junctions in either direction, it might be diffi- site, which is composed of macromolecular cult to decide which is the presynaptic and proteins acting as specialized decoders, which is the postsynaptic side of the junction. responds to a given stimulus in its own, proba- They can be either, especially when the electric bly predetermined way. For example, acetyl- synapse adjoins two dendrites, two cell bodies, choline is an excitatory agent at a motor end or two axons. Evidence suggests that, at some plate (contraction of voluntary muscle) and an gap junctions, there is only a unidirectional inhibitory agent at the synapses of the vagus transport of ions. nerve with heart tissue (decrease in heart rate). A neuron can, in turn, be influenced by its own activity through a negative feedback loop NEURON AS AN INTEGRATOR involving an interneuron (Fig. 3.11). For example, an interneuron called a Renshaw cell is Each neuron is an integrator of stimuli (neu- intercalated between an axon collateral branch rotransmitters) streaming into its dendritic field of a lower motoneuron of the spinal cord and and onto its cell body (Fig. 3.11). Some of the the dendrite–cell body region of the same receptive patches (subsynaptic membranes) on motoneuron, and other motoneurons. The axon the dendrites and cell body are excitatory; oth- collateral terminates at an excitatory synapse ers are inhibitory. In addition, as will be on the Renshaw cell; the axons of this cell described, presynaptic inhibitory activity could have, in turn, inhibitory synaptic connections indirectly affect some excitatory receptive with the parent lower motoneuron (Chap. 10). sites. At any one moment, a neuron might Neurons in the CNS may be classified into receive hundreds or even thousands of stimuli two major types: (1) projection neurons and (2) on its excitatory and inhibitory membrane sites. local circuit neurons. Projection neurons have Most neurons are under constant synaptic long axons coursing from one region of the bombardment. In this battleground of activity, central nervous system to another. Local circuit the neuron reacts and might respond. If the neurons have axons passing and interacting summation of the EPSPs exceeds the summa- with neurons in the immediate vicinity. 66 The Human Nervous System

Figure 3.11: The neuron as an integrator. The interrupted line represents the boundary between the central nervous system and the peripheral nervous system. Arrows indicate the direction in which nerve impulses are propagated. Neurons from many sources in the brain, spinal cord, and body convey influences to each lower motor neuron (see Chap. 10), which, in turn, innervates some voluntary muscle fibers. The axon collateral of the lower motoneuron excites the interneuron (Ren- shaw cell), which feeds back inhibitory influences to the lower motoneuron.

There are three types of synapses: Fig. 3.8(A) ultrastructural and functional roles are essen- neuromuscular junction (NMJ); Fig. 3.8(B) tially similar. They contain pretransmitter- asymmetric central synapse (Gray type 1) and laden vesicles in their presynaptic terminals. Fig. 3.8(C) symmetric central synapse (gray Each synapse is capped by glial (astrocyte) or type 2). The asymmetric and symmetric Schwann cell processes. A synaptic cleft sepa- synapses of the CNS collectively are called rates neurons from each another at a synapse. central synapses. Three features are common Several significant differences do exist to both central synapses and NMJs. All origi- between these synaptic types. The quantity and nate developmentally as unspecialized contacts distribution of the synapses on the target cells between growth cones and the targets cells (neurons or muscle cells) are critical. Each (Chap. 6). Both types of synapse are functional postsynaptic neuron is the target and recipient at birth, but undergo postnatal alterations. Their of multiple small synaptic inputs from other Chapter 3 Basic Neurophysiology 67 neurons that converge on its dendrites and cell body. In contrast, each postsynaptic striated PRESYNAPTIC INHIBITION AND muscle cell is the target and recipient of a sin- PRESYNAPTIC FACILITATION gle massive input from only one NMJ of a motor neuron. The synapses are markedly dif- Presynaptic inhibition is the phenomenon ferent between the two synaptic types. The that occurs when a presynaptic neuron (neuron NMJs are characterized by having a basal lam- A) exerts inhibitory influences through transmit- ina located within the synaptic cleft that ters at an axoaxonic synapse with the axon ter- extends as a continuum to envelop both the minal of a postsynaptic neuron (neuron B) (Fig. nerve terminal and the Schwann cell (Figs. 2.5 3.11). In turn, this presynaptic inhibition of neu- and 3.9). In contrast, the central neuron’s ron B depresses the release of excitatory trans- synaptic cleft does not have a basal lamina, but mitter at the synapse of neuron B with neuron C. might have a slight amount of extracellular In Fig. 11, note that the axon terminal of neuron matrix. These differences suggest that the func- A synapses with the axon terminal of axon B. tional roles of cell adhesion molecules associ- When terminal B is stimulated alone, EPSPs are ated with the matrix of the extracellular clefts evoked in the postsynaptic neuron C. When ter- differ in these synaptic types. In the NMJs, minal A is stimulated alone, no response occurs such molecules as laminins, integrins, and oth- in the terminal B. When A and B are stimulated ers mediate the cell membrane–matrix simultaneously, the generation of EPSPs in the interactions. In central synapses, where the postsynaptic neuron C is decreased. extracellular space lacks a basal lamina, cell- The explanation for this phenomenon to-cell adhesion molecules are mediated by involves the Cl–,K+, and Ca2+ channels on ter- cadherins and others. minal B. The release of inhibitory transmitter The central synapses, functionally desig- from terminal A opens Cl– and K+ channels on nated as excitatory or inhibitory synapses, dif- terminal B. In turn, this reduces the influx of fer morphologically by the relative thickness Ca2+ through the voltage-gated channels on ter- between their presynaptic and postsynaptic minal A. This reduction of Ca2+ influx membranes. The asymmetric synapse has a depresses the release or excitatory transmitter postsynaptic membrane that is thicker than the by terminal B at its synapse with the postsy- presynaptic membrane; functionally, this is naptic neuron C. usually an excitatory synapse (Gray’s type 1; Presynaptic facilitation (presynaptic excita- Fig. 3.8). The symmetric synapse with its tion) is the phenomenon that occurs when a presynaptic and postsynaptic membranes presynaptic neuron (A) exerts excitatory influ- essentially equal in thickness is functionally ences through transmitters at an axoaxonic usually inhibitory Gray’s type 2. synapse upon the axon terminal of a postsy- The target cells functionally express the naptic neuron (B). The presynaptic release of nature of the multiple inputs to the central the transmitter is presumed to close the K+ synapses, as contrasted to the solitary input to a channels, resulting in a prolongation of the muscle cell. The multisynaptic inputs to CNS action potential (because of a slower repolar- neurons are essential for the critical role of pro- ization phase). This acts to increase calcium cessing excitatory and inhibitory synaptic influx into the postsynaptic axon terminal (neu- inputs. The unitary synaptic input to the NMJ ron B) and thereby enhances excitatory trans- of each voluntary muscle cell acts as a “fail- mitter release by neuron B at its synapse with safe” synapse that ensures a muscle contrac- the postsynaptic neuron C. tion, but lacks the critical qualities of the The mediation of presynaptic inhibition and integrated multisynaptic synaptic inputs that is presynaptic facilitation through axoaxonic characteristic of the innervation of each CNS synapses contributes to the elegant neural neuron. processing that takes place in the CNS. Of 68 The Human Nervous System significance is that axoaxonic synapses can (Shepherd, 1996). They possess the principal control and alter the Ca2+ influx into the axon receptors and neural processing complexes terminals. As a consequence, presynaptic activ- (“machines”) of each neuron (Fig. 3.12). Their ity makes it possible to influence selectively roles are in part expressed by their characteris- the signal transmission from one neuron to tic morphological differences in the various another, without affecting the general excitabil- regions of the brain and spinal cord. These are ity of the postsynaptic neuron and, thus, its features of the diversity and richness of den- responsiveness to other synaptic inputs. dritic arborization patterns coupled with the many varieties of spines on their branches (Fig. Importance of Inhibition 2.2). Dendritic spines, each usually not more Inhibition is a most significant neural activ- than 1 μm3 in volume, are diverse in shape and ity. It is as important as excitation. The size. However, in vivo imaging observations inhibitory neurons and their neural circuits act have demonstrated that spines can form, col- as governors that prevent, shape, and control the lapse, reform, and change size and shape rap- excitatory neurons and their neural circuits from idly in response to a diverse array of stimuli, firing to excess. In a simplistic explanation, and thereby exhibit activity-dependent plastic- imagine the consequences of excitatory influ- ity (Elhers, 2002). ences without braking (as the brakes in a car) to Of the estimated 1014 synapses on the 1011 keep these influences from getting out of hand. neurons in the human cerebral cortex, over Inhibitory influences function to channel and 90% are excitatory axo-dendritic synapses. modulate the effects of excitation and to direct Excitatory glutamate receptors are present pri- activity to attain a desired end. In learning the marily on the dendritic spines and inhibitory intricate movements of writing, a child initially GABA receptors are mainly on the dendritic has control difficulties because, in part, too shafts, cell body, and the axon’s initial seg- many unnecessary movements are made. Dur- ment. The processing resulting from the stimu- ing the learning process, these movements are lation of the ionotropic receptors of the gradually eliminated through inhibition. The transmission system and the metabotropic desired excitatory channels are sustained to pro- receptors of the modulation systems is more duce the focal movements. In this case, the inhi- complex than that involved in postulated alge- bition of the nonessential movements is braic summation of EPSPs and IPSPs that gen- significant to the learning process. The erates the action potentials of the axon. Some inhibitory circuits prevent an excess of neural evidence indicates that dendritic synaptic activ- timing and, in addition, time the specific ities are critical in the biochemical mechanisms responsiveness of the excitatory networks. This for regulating the synthesis of synaptic-specific also applies to neural networks (pathways) that proteins. Some of these proteins are presum- convey and interpret information about the ably involved in such phenomena as learning external and internal world. Inhibition, includ- and memory (processes by which knowledge of ing lateral inhibition, is presumably involved to facts, experiences, and skills are acquired and shape the excitatory activity in the neural path- stored). ways that form the basis of the experience of Dendrites throughout the CNS have roles in sensation and feeling (sentience) as distin- processing the neural inputs derived from the guished from perception and thought. sensory receptors. They are integrated and converted into patterns expressed as exquisitely coordinated motor movements. Dendrites con- FUNCTIONAL ROLES OF DENDRITES tain significant morphologic and functional entities (e.g., spines, postsynaptic densities, “Dendrites are the brains of the neurons” and ribosomes) to fulfill their roles within this and “the spines are their multifunctional units” neurobiologic organization by (1) genetic Chapter 3 Basic Neurophysiology 69

Figure 3.12: The production of synaptic-specific proteins within the multifunctional dendritic spines. Environmental stimuli derived from sources both external to and within the body are monitored by, and the response conveyed by, sensory neurons via an axon to an axon terminal (left side of figure). (1) At the axon terminal, neurotransmitters are released from synaptic vesicles that activate the excitatory asymmetric synapse of a dendritic spine with its postsynaptic density and spine apparatus. Molecular messengers generated by this synaptic complex are involved in messages from the spine via a retrograde intracellular signaling pathway to transcription regulatory proteins that activate gene expression within the nucleus of the neuron. The responses are the synthesis by transcription of mRNA, and its passage by nucleocytoplasmic transport through nuclear pore complexes to the cytoplasm. Following binding to ribosomes, the mRNA is transported via neurotubules within the shaft of the dendrite to selected designated “outposts” at the base of dendritic spines. From an “outpost”, the mRNA passes into the dendritic spine, where the translation of synaptic-specific protein is thought to occur. (2) At other terminals, the axons of the sensory neurons usually activate inhibitory symmetrical synapses with the dendritic shafts and cell bodies. Within axons (lower right), the synaptic vesicles migrate by anterograde transport from the Golgi apparatus via neurotubules to the axon terminals. Commencing in the axon terminal, degraded macromolecules are transported as vesicles by retrograde transport via neurotubules of the axon to the lysosomes in the cell body for disposal. Arrows within the neurons designates the direction of transport of ribosomes or vesicles via the neurotubules. Arrows outside of neurons designate the direction of nerve impulses. 70 The Human Nervous System

(genomic) influences and (2) environmental The scaffolding proteins embedded in the (epigenetic) influences (Chap. 6). The con- PSDs act as linkages for the stimuli from the struction of the basic neuronal networks and plasma membrane glutamate receptors (via their synaptic connections are guided by genet- interaction domains) to the receptors of the ically coded rules, followed by the subsequent smooth endoplasmic reticulum (ER) to recep- fine-honing of these connections from responses tors of the cytoskeletal actin filaments with to the ongoing environmental influences that their morphogens (types of induction signals) translate into a variety of neural adjustments that influence spine shape and size. Each spine such as plasticity (Chaps. 2 and 6). The effec- has a framework of dense actin filaments, tiveness of synaptic transmission, of the modi- called the spine apparatus, that serves as a (1) fication of existing proteins, of the synthesis of support and framework for localizing func- new proteins, and of plasticity are among the tional molecules, (2) means for propelling neural phenomena occurring in dendrites con- ingredients from the shaft of the dendrite to the tinuously being modified with changes in activ- PSD and in spine motility (Fig. 3.12), and (3) ity and experience (Chap. 25). source of spine morphogens that influence The major excitatory transmitter released synaptic function during development and plas- from the presynaptic terminals of synapses in ticity. Powered by actin filaments, the spines the CNS is the amino acid L-glutamate. This exhibit considerable motility. transmitter excites (1) mainly postsynaptic ion- The DNA of each neuron’s nucleus provides otropic glutamate receptors that directly gate genetically coded information to form messen- ion channels and (2) metabotropic receptors ger RNA (mRNA) that conveys the genetic that indirectly gate channels linked to second message through the nuclear pores to the cyto- messengers. Most glutamate receptors are plasm. The mRNAs attached to ribosomes (the located on the spines and relatively few on the genetic message can then be translated into the shafts of dendrites. The fact that each dendritic primary structure of a specific protein by the spine usually accommodates a single synapse molecular factories of the ribosomes) migrate suggests that the significance of a spine relates via neurotubules (acting like a monorail) to and to the creation of a local synapse-specific com- within the dendritic arbor to locate near the partment, rather than as a mere expansion of base of and within a spine (Fig. 3.12). Molecu- the postsynaptic surface area (Shepherd, 1996). lar triggers activate mRNAs located within the The consensus is that spines function as micro- spine for translation to synaptic-specific pro- compartments of chemical signals and regula- teins. Messengers synthesized at the synapse tory proteins that segregate as well as integrate could be involved in an active feedback with synaptic signals. An increase in the number of the nucleus of the neuron’s cell body in modu- compartments can enhance the informational lating DNA transcription. The activity level of processing power of dendrites. Some evidence the synapses may have a role in regulating the indicates that retrograde neural signals from a formation of mRNAs, the transport of ribo- spine to the presynaptic axon terminal acts to somes on the neurotubules, and the selection of enhance presynaptic function. certain ribosomes to localize adjacent to the The spines have postsynaptic densities appropriate base of spines where the mRNA (PSDs) that are attached to the cytosolic sur- translation to synaptic-specific proteins is sus- face of the postsynaptic membrane (Figs. 3.8 tained and regulated (alternate terms include and 3.12). The PSDs are large protein signaling ribopolysomes or synapse-associated polyribo- machines (biochemical signaling pathways) somes that are mRNAs with added ribosomes with roles (1) in regulating the strength of engaged in protein production). Biologists tra- synaptic transmission (Kennedy, 2000), (2) in ditionally view the nucleus as the command modifying spine morphology, and (3) influenc- center supplying mRNAs translation into pro- ing the synthesis of synaptic-specific proteins. tein. Neurons might have slightly modified this Chapter 3 Basic Neurophysiology 71 strategy by the synthesis of proteins in spines, Relation of the Morphological and and thereby exert influences on synapse-spe- Functional Parameters of Dendritic Spines cific protein production in consort with other Spines are dynamic morphological special- related synapses. This effect by a synapse izations that receive experience-derived synaptic might be another factor that enables the nerv- input, and following molecular microprocess- ous system to utilize the neural information ing with DNA derived ribosomes, they (mRNA received for strengthening specific synapses polyribosomal complexes) generate synaptic- with fresh proteins for a variety of neuronal specific proteins. The vast variety of forms and activities. It is even possible that certain pro- shapes of spines (Fiala and Harris, 1999; Fig. teins are uniquely involved in learning and 2.2) are presumably expressions of the many memory. In essence, the functional activities of multifunctional units within the spines (Shep- the synapses, PSD signaling machines, mRNA herd, 1996). For example, the volume of the production, and synapse-specific proteins are spine head is directly proportional (1) to the integrated by homeostatic integration with the number of postsynaptic receptors and (2) to the neuron’s nucleus, by which intraneuronal sig- number of docked synaptic vesicles in the naling cytoskeletal pathways from the spine presynaptic terminals (Yeste and Bonhoeffer, communicate with the nucleus (Fig. 3.12). 2001). This association of structure (form) and Indications are that active synapses of the spine function can be correlated with changes in the have a significant role in the regulation of lengthening, shortening or widening of the translation and in the direction of transport of a neck adjacent to the dendritic shaft, with ribosome to a spine. Although the synapse- changes in the size and shape of the head of the specific proteins produced might contribute to spine, and with changes in the formation of learning and memory; the linkage between new spines. Many changes have been associ- dendritic protein synthesis and learning and ated with synaptic plasticity. memory, as yet, has not been established. Synapses that undergo long-lasting changes in strength are likely to contribute to learning and memory. Thus, the dendritic spines function as SOME GENERAL CONCEPTS the recipients of (1) neural information via ASSOCIATED WITH CODING their synapses from both the external environ- AND NEURONAL PROCESSING ment and from the internal environment of the IN THE NERVOUS SYSTEM body and (2) genomic information from the neuron’s nucleus, This is consistent with the Neural Signals: Label Line Codes and role of the spines as multifunctional units of the Pattern Codes (Fig. 3.13) dendrites as the brains of the neurons. In neu- The body responds to external and internal rons, gene expression involves a distributed environmental stimuli through receptors that network of translating machines in a functional are associated with modalities of the sensory group of neurons. The polyribosomes are posi- systems. The recognized receptors are mech- tioned near synapses and translate populations anoreceptors, nociceptors, thermoreceptors, of mRNAs within selected spines. The local- photoreceptors, and chemoreceptors. The ization of translation machinery and mRNA at modalities comprise general somatic senses, synapses endows individual synapses with the balance, audition, vision, taste, and smell. Most capability of independently controlling synap- sensory receptors are sensitive to specific stim- tic strength through the local synthesis of ulus energies, called receptor specificity that proteins. The newly synthesized protein pre- results in generating a neural signal as a signal- sumably has roles in replacing degraded pro- line code in a first-order neuron. The code of teins, increasing the levels of existing proteins specific modalities associated with, for exam- or even in creating novel proteins. ple, touch (Chap. 10) is conveyed via specific 72 The Human Nervous System lines though a series of neurons and neural cen- tions among neurons. The numerous signals ters of the CNS where they are processed to arriving at each processing center and interac- evoke the perception of the sensation. Each tion with the local interneurons act to bias, sensory receptor responds when it is ade- enhance or dampen signals and their transmis- quately stimulated, in a specific manner regard- sion. In effect, each center acts as an editor. A less of the stimulus. Whether activated by a major role in the processing is performed by natural or an artificial (e.g., electrical) stimulus, the local inhibitory interneurons in (1) feed- the same sensation is elicited. Chemoreceptors back inhibition, (2) feed-forward inhibition, lack the specificity of responding to a single and (3) reflected inhibition. stimulus signal and, thus, do not project their information along signal lines. Rather, the Feedback (or Recurrent) Inhibition (Fig. 3.13) modalities associated with taste and smell use a In feedback inhibition, the most actively fir- pattern code signal in which several receptors ing relay neurons, utilizing inhibitory interneu- are activated. The resulting discharge pattern of rons, depress the activity of the adjacent, less signals formed by a group of neurons is the actively firing relay neurons. Thus, the more basis for the perception of a given flavor or active neurons enhance and amplify the con- odor. trast between the actively firing relay neurons and their less active neighbors. This leads to a Transformation of the Neural Signals at selective emphasis of one stimulus over Processing Centers of Pathways another. Stated differently, the signal is Neural processing occurs within the neural enhanced and the adjacent noise of the less centers (laminae, nuclei, and cortices) of each active neurons suppressed. It is called feedback pathway system. Neurons within these centers or recurrent inhibition because the recurrent process the patterns of incoming signals and collateral branches of the axon of the relay neu- transform them so that the relay neurons proj- ron feed back to excite inhibitory interneurons ect a different pattern of signals to other cen- causing inhibition of the adjacent relay neurons. ters. Each center performs a transformation function. Each center consists of (1) relay neu- Feed-Forward (or Reciprocal) Inhibition rons whose axons project to other centers, (2) (Fig. 3.13) interneurons with processes located wholly In feed-forward inhibition, the activity of within the center, and (3) terminations of axons one or more neurons inhibits another neuron or from other sources. group of neurons. This acts in what is called the singleness of action in which only a limited Processing Within the Nervous System number of competing responses are expressed The ascending (and descending) pathways and others are suppressed. The feed-forward function both as processors and as transmitters neuronal circuits consist of the branches of the of coded information. The processing within a axons of relay neurons entering a nucleus and center of a pathway is information linked, not terminating by synapsing with local circuit energy linked. For example, stimulation of the interneurons. In turn, these neurons exert optic system evokes sensations related to inhibitory influences upon relay neurons via vision, regardless of whether the stimulus is either presynaptic or postsynaptic inhibition. light, an electrical shock, or a blow to the eye. Presynaptic inhibition occurs when the axons The sensory inputs to the relay neurons entering a relay nucleus synapse with excita- within a center are examples of convergence tory local circuit interneurons that, in turn, (input of axons from many neurons to one relay synapse with the terminals of neighboring neuron) and divergence (input of an axon to entering axons. Postsynaptic inhibition occurs more than one relay neuron). These inputs form when the axons entering the nucleus synapse a basis for some of the complexities of interac- with local interneurons that, in turn, synapse Chapter 3 Basic Neurophysiology 73

Figure 3.13: Diagram illustrating three types of neural processing involving inhibition. The neurons represent relay (R) neurons and local inhibitory neurons (X, Y, and Z) associated with the nuclei gracilis and cuneatus of the posterior column–medial lemniscus pathway (Chap. 10). The relay neurons (R) project to the ventral posterior lateral nucleus (VPL) of the thalamus. 1. Feed-forward inhibition. Relay neuron A of a dorsal root ganglion has an axon that ascends to and diverges within the nuclei gracilis and cuneatus into branches that have excitatory synapses with several neurons (shaded area). These feed-forward to excite the relay neurons (R) and, in addition, local inhibitory interneurons (X). The latter inhibit adjacent relay neurons. 2. Feedback inhibition. Relay neuron (B) has recurrent branches that feedback to excite local inhibitory interneurons (Y). The latter inhibit the adjacent relay neurons. 3. Reflected inhibition. Neurons (C) of the somatic sensory areas 3, 1, 2, and 5 of the cerebral cortex (C) have long axons that excite local inhibitory interneurons (Z). The latter modulate the relay neurons by both presynaptic and postsynaptic inhibition. (Adapted from Kandel, Schwartz, and Jessell). 74 The Human Nervous System with the cell bodies of adjacent relay neurons. Reflected (or Distal) Inhibition A feed-forward inhibitory circuit is character- (or Excitation) (Fig. 3.13) ized by having one or more inhibitory interneu- This type of feedback involves descending rons within the circuit. These interneurons centrifugal fibers (reflected descending fibers) convey influences in a forward direction from the rostrally located cerebral cortex and toward the more distal levels of the pathway. brainstem nuclei to the more caudally located Because these inhibitory circuits utilize nuclei of the ascending pathways. Some influ- ascending or afferent relay neurons, their activ- ences might be projected from the brainstem and ity is referred to as afferent inhibition. spinal cord via fibers known as efferents to some Feed-forward inhibition is utilized by the sensory receptors. These descending fibers gen- influences of muscle spindles in the stretch erally form excitatory synapses with inhibitory reflex (Chap. 8). The afferent fibers from neu- interneurons. Cortical and brainstem neurons romuscular spindles excite inhibitory interneu- can regulate, through inhibition, the information rons that exert inhibitory influences upon the flow into the relay nuclei. This so-called distal alpha motoneurons innervating voluntary inhibition can express itself by exciting interneu- muscles. rons that modulate the relay neurons through An expression of feed-forward inhibition is both inhibitory presynaptic and postsynaptic known as lateral or surround inhibition. This synapses. By this means, the higher centers of physiologic activity is utilized by all sensory the brain can control the sensory input from the systems in processing neural information. For peripheral receptors to the relay nuclei (Chap. example, to discriminate between two points 10). Efferent neurons, with their cell bodies in close together (see Two-Point Discrimination, the brainstem and spinal cord, which send axons Chap. 10) the two signal lines for the two points to sensory receptors, can facilitate or inhibit and are each maintained in order for the perception thus alter the receptivity of the receptors. The to occur. Each signal line enhances its signal gamma efferent fibers to the neuromuscular and suppresses the surrounding relay neurons in spindles (Chap. 8) and the cochlear efferent order to maintain its identity. Inhibitory fibers to the organ of Corti (Chap. 16) are exam- interneurons interact with adjacent relay neu- ples of such feedback neurons. rons with the result that the signal-to-noise is enhanced. In effect, the excitatory neurons of the circuit or pathway convey the signal and SUGGESTED READINGS also stimulate the inhibitory interneurons in adjacent (lateral) locales to suppress the circuits Araque A, Carmignoto G, Haydon PG. Dynamic conveying the noise within the sensory path- signaling between astrocytes and neurons. Annu. way. This emphasis on the signal and suppres- Rev. Physiol. 2001;63:795–813. sion of the noise is also known as the focusing Chen YA, Scales SJ, Scheller RH. Sequential effect or sharpening effect. For example, back- SNARE assembly underlies priming and trigger- ground noise such as potential sound generated ing of exocytosis. Neuron 2001;30:161–170. by blood flow through the inner ear is not nor- Cline HT. Dendritic arbor development and synapto- mally heard because it is filtered out by lateral genesis. Curr. Opin. Neurobiol. 2001;11:118–126. inhibition within the auditory pathways, and the De Camilli P, Takei K. Molecular mechanisms in neural activity associated with the sound to be synaptic vesicle endocytosis and recycling. Neu- ron 1996;16:481–486. perceived is increased. In the visual system, Dowling J. Neurons and Networks: An Introduction inhibitory interneurons have a role in enhancing to Neuroscience. Cambridge, MA: Harvard Uni- information to heighten the contrast, to make versity Press, 1993. borders and contours more pronounced to the Eccles JC. The synapse: from electrical to chemi- viewer and in the generation of the center- cal transmission. Annu. Rev. Neurosci. 1982; surround receptor fields (Chap. 19). 5:325–339. Chapter 3 Basic Neurophysiology 75

Eccles JC. Developing concepts of the synapses. J. Kennedy MB. Signal-processing machines at Neurosci. 1990;10:3769–3781. the postsynaptic density. Science 2000;290: Ehlers MD. Molecular morphogens for dendritic 750–754. spines. Trends Neurosci. 2002;25:64–67. Li Z, Sheng M. Some assembly required: the devel- Ehlers MD. Eppendorf 2003 prize-winning essay. opment of neuronal synapses. Natl. Rev. Mol. Ubiquitin and the deconstruction of synapses. Cell Biol. 2003;4:833–841. Science. 2003;302:800–801. Lin RC, Scheller RH. Mechanisms of synaptic vesi- Farsad K, De Camilli P. Neurotransmission and the cle exocytosis. Annu. Rev. Cell Dev. Biol. synaptic vesicle cycle. Yale J. Biol. Med. 2002; 2000;16:19–49. 75:261–284. Littleton JT, Sheng M. Neurobiology: synapses Fenstermaker V, Chen Y, Ghosh A, Yuste R. Regula- unplugged. Nature 2003;424:931–932. tion of dendritic length and branching by sema- Maletic-Savatic M, Malinow R, Svoboda K. Rapid phorin 3A. J. Neurobiol. 2004;58:403–412. dendritic morphogenesis in CA1 hippocampal Fiala JC, Harris KM. Dendritic structures. In: Stuart dendrites induced by synaptic activity. Science G, Sprutson N, Hausser M, eds. Dendrites. New 1999;283:1923–1927. York: Oxford University Press; 1999. Mattson M. Neuroprotective signal transduction. Fields RD, Stevens-Graham B. New insights into Totowa, N.J: Humana Press. neuron–glia communication. Science 2002;298: Murthy VN, De Camilli P. 2003. Cell biology of the 556–562. presynaptic terminal. Annu. Rev. Neurosci. Gorlich D, Kutay U. Transport between the cell 1998;26:701–728. nucleus and the cytoplasm. Annu. Rev. Cell Dev. Nimchinsky EA, Sabatini BL, Svoboda K. Structure Biol. 1999;15:607–660. and function of dendritic spines. Annu. Rev. Greengard P. The neurobiology of slow synaptic Physiol. 2002;64:313–353. transmission. Science. 2001;294:1024–1030. Reith MEA ed. Cerebral Aignal Transduction: Hannah MJ, Schmidt AA, Huttner WB. Synaptic From First to Fourth Messengers. Totowa, NJ: vesicle biogenesis. Annu. Rev. Cell Dev. Biol. Humana; 2000. 1999;15:733–798. Reith MEA, ed. Neurotransmitter Transporters: Hering H, Sheng M. Activity-dependent redistribu- Structure, Function, and Regulation. Totowa, NJ: tion and essential role of cortactin in dendritic Humana; 2002. spine morphogenesis. J. Neurosci. 2003;23: Sheng M, Kim MJ. Postsynaptic signaling and 11,759–11,769. plasticity mechanisms. Science 2002;298: Ingolia NT, Murray AW. Signal transduction. His- 776–780. tory matters. Science 2002;297:948–949. Shepherd GM. The dendritic spine: a multifunc- Jan LY, Stevens CF. Signalling mechanisms: a tional integrative unit. J. Neurophysiol. 1996; decade of signalling. Curr. Opin. Neurobiol. 75:2197–2210. 2000;10:625–630. Song H, Stevens CF, Gage FH. Astroglia induce Kandel ER. The molecular biology of memory stor- neurogenesis from adult neural stem cells. age: a dialogue between genes and synapses. Sci- Nature 2002;417:39–44. ence 2001;294:1030–1038. Yasuda R, Sabatini BL, Svoboda K. Plasticity of Kandel E, Schwartz J, Jessell T, editors. Principles calcium channels in dendritic spines. Nature of Neural Science. 4th ed. New York, NY: Neurosci. 2003;6:948–955. McGraw Hill; 2000. Yuste R, Bonhoeffer T. Genesis of dendritic spines: Katz PS, Clemens S. Biochemical networks in nerv- insights from ultrastructural and imaging studies. ous systems: expanding neuronal information Natl. Rev. Neurosci. 2004;5:24–34. capacity beyond voltage signals. Trends Neu- Zucker RS, Regehr WG. Short-term synaptic plas- rosci. 2001;24:18–25. ticity. Annu. Rev. Physiol. 2002;64:355–405. 4 Blood Circulation

Arterial Supply Venous Drainage Functional Considerations Blood–Brain Barrier

Although the brain accounts for only 2% of taining the radioactive molecules, labeled glu- the body weight of a 175-lb human, its survival cose, following the injection of the radioactive and functioning depend on continuously glucose injected into an arm vein and moni- receiving 20% of the arterial blood flow from tored by the scanning of the head to map the the heart, metabolizing 20% of the available distribution of the glucose in the brain. Rapid oxygen, and generating 20% of the bodily repetition allows differences between brain energy. This level of energy consumption is structures to be detected and related to the type sustained by the high and privileged rate of the of “work” each portion of the brain is doing at flow of blood with its glucose and oxygen to that time. Labeled glucose accumulates in neu- the brain as compared to other organs. The high rons doing the “brain” work. Roughly 800 mL metabolic activity and high oxygen consump- of blood flows through the brain each minute, tion are characteristic of cerebral metabolism with 75 mL present within the brain at any that derives its energy largely from glucose, the moment. Each day, the brain utilizes about 400 basic energy substrate of the brain. Glucose is kcal, or about one-fifth of a 2000-kcal diet. It metabolized through glycolysis, Krebs’ citric takes about 7 seconds for a drop of blood to acid cycle, and the respiratory (electron trans- flow through the brain from the internal carotid port) chain. In aerobic respiration, the combi- artery to the internal jugular vein. The neces- nation of glucose and oxygen produces energy, sity for this continuous flow is because the

CO2, and H2O. Mitochondria carry out aerobic brain stores only minute amounts of glucose respiration that generates ATP (adenosine and oxygen and derives its energy almost triphosphate), which serves as the cell’s power- exclusively from the aerobic metabolism of house. The chemical energy stored as high- glucose delivered by the blood. Paradoxically, energy phosphate bonds in ATP is the constant this blood circulation is the minimum required; source of energy obtained from the conversion consciousness is lost if the blood supply is cut of ATP to ADP (adenosine diphosphate). off for less than 10 seconds. The demand for The energy utilized that is derived from glu- blood is the same whether one is resting, sleep- cose in the blood and changes in its consump- ing, thinking, or exercising. tion can be measured using the method of Neurons differ from cells of other organs in positron-emission tomography (PET, Chap. their requirements for oxygen. Deprived of 26). This technique depends on the detection of oxygen, neurons almost always die within a radiation, mainly positrons, released from few minutes. Neurons cannot build an oxygen short-lived radioactive atoms by an array of debt, as can muscle and other body cells, that radiation detectors positioned around the sub- is, they cannot survive anaerobically. This con- ject’s head. The procedure involves the rapid straint has enormous medical implications. synthesis of marker molecules of glucose con- When the oxygen supply is cut off following a

77 78 The Human Nervous System heart attack or suffocation, the brain dies first. vertebral arteries and (2) the internal carotid Only if oxygen is restored to the brain in a few arteries (Figs. 4.1 and 4.2). minutes will the brain retain its functional viability. Vertebral Circulation Blood is supplied to the brain by the internal The paired vertebral arteries enter the cra- carotid arteries and the vertebral arteries. It is nial cavity through the foramen magnum and drained from the brain largely by the internal become located on the anterolateral aspect of jugular vein. The cerebral arteries, venules, and the medulla (Fig. 4.1). They unite at the mid- veins do not differ structurally from vessels of line at the pontomedullary junction to form similar size and function in other organs. How- the basilar artery, which continues to the ever, the capillaries of the central nervous midbrain level, where it bifurcates to form the system (CNS) do differ significantly in ultra- paired posterior cerebral arteries. The structure and physiology from capillaries of the branches of the vertebral and basilar arteries general circulation (see Blood–Brain Barrier). supply the medulla, pons, cerebellum, midbrain, and caudal diencephalon. Each posterior cerebral artery supplies part of the caudal ARTERIAL SUPPLY diencephalon and the medial aspect (and adjacent lateral aspect) of the occipital lobe The arterial blood supply to the brain is including the primary visual cortex (area 17) derived from two pair of trunk arteries: (1) the and the inferior posterior temporal lobe. The

Figure 4.1: Major arterial supply to the brain. The vertebral–basilar–posterior cerebral arterial tree is indicated as solid black vessels and the paired middle and anterior cerebral tree is indicated as white vessels. Note the circle of Willis, which comprises the single anterior communicating artery and the paired anterior cerebral, internal carotid, posterior communicating, and posterior cerebral arteries. The last paired arteries are formed by the bifurcation of the basilar artery. The circle of Willis is located beneath the hypothalamus and surrounds the stalk of the hypophysis and optic chiasm. Chapter 4 Blood Circulation 79 branches of the vertebral and basilar arteries that supply the medial aspect of the brainstem adjacent to the midsagittal plane are called paramedian arteries (anterior spinal artery, paramedian branches of the basilar artery); those that supply the anterolateral aspect of the brainstem are called short circumferential arteries (branches of the vertebral artery, short pontine circumferential branches of the basilar artery); and those that supply the posterolateral and posterior aspect of the brainstem and cerebellum (Figs. 17.1 and 17.2) are the long circumferential branches (posterior spinal artery, posterior inferior cerebellar artery, anterior inferior cerebellar artery, superior cerebellar artery). Internal Carotid Circulation Each internal carotid artery passes through the cavernous sinus as the S-shaped carotid siphon and then divides, level with and lateral to the optic chiasm, into two terminal branches: (1) the anterior cerebral artery, which supplies the orbital and medial aspect of the frontal lobe and medial aspect of the parietal lobe, and (2) Figure 4.2: Cerebral arterial circle (circle of the middle cerebral artery, which passes later- Willis). The cerebral arterial circle consists of ally through the lateral fissure between the tem- the following: (1) the proximal part of three poral lobe and insula and divides into a number major paired arteries: anterior, middle and posterior cerebral; (2) the short, single anterior of branches supplying the lateral portions of communicating artery that connects the ante- the orbital gyri and the frontal, parietal, and rior cerebral arteries; and (3) the longer, paired temporal lobes (Figs. 4.1 and 4.3). Peripheral posterior communicating arteries that go branches of the middle cerebral arteries anasto- between the middle and posterior cerebral mose on the lateral surface of the cerebrum arteries. The circle of Willis is supplied by two with peripheral branches of the anterior and pairs of arteries (a) the vertebrals—branches posterior cerebral arteries. Branches of the of the subclavian arteries and (b) the internal middle cerebral artery and the choroidal arter- carotids—branches of the common carotid ies penetrate the cerebrum to supply the basal arteries. Each internal carotid artery divides ganglia, most of the diencephalon, internal cap- into an anterior cerebral artery and a larger sule, and adjacent structures; these central or middle cerebral artery. The arrows point to common sites of atherosclerosis and occlusion. ganglionic branches (e.g., striate arteries) and the choroidal arteries are variable in their extent and in their anastomotic connections. Other branches of the internal carotid arteries Circle of Willis include the ophthalmic artery (to the orbit), the Although the vertebral–basilar arterial tree anterior choroidal artery (to the arc structures and the internal carotid arterial tree are essen- adjacent to the choroidal fissure; Chap. 5), and tially independent, there are some anastomotic the posterior communicating artery (joins pos- connections between the two systems (e.g., terior cerebral artery). between the terminal branches of posterior 80 The Human Nervous System

Figure 4.3: Distribution of the arteries on the surface of the brain. (A) lateral surface; (B) medial surface. Superior cerebellar artery. cerebral arteries and those of the anterior and those of the basilar artery. Thus, (1) the ante- middle cerebral arteries). The cerebral arterial rior, middle, and posterior cerebral arteries are circle of Willis (Figs. 4.1 and 4.2) is an arterial actually long circumferential arteries, (2) the ring in which the two systems are connected by subbranches (e.g., striate arteries; Fig. 4.1) of the small posterior communicating arteries. these three major cerebral arteries close to the The anterior communicating artery that connects circle of Willis are short circumferential the two anterior cerebral arteries completes the branches, and (3) the small medial arteries aris- circle. There is actually little exchange of blood ing from the circle of Willis are paramedian through these communicating arteries; the cir- branches. cle of Willis can act as a safety valve when Anastomotic connections within the verte- differential pressures are present among these bral and internal carotid systems are extensive arteries. in the brain. Those that occur among the large The arteries meeting at the cerebral arterial branches of the superficial arteries on the sur- circle of Willis form branches comparable to face are usually physiologically effective, so Chapter 4 Blood Circulation 81 that occlusion need not result in impairment of along the midline within the tentorium, which blood supply to the neural tissues. Rich anasto- is dura mater lying between the cerebellum and moses do exist among the capillary beds of occipital lobe), transverse sinus,andsigmoid adjacent arteries within the substance of the sinus before draining into the internal jugular brain, but occlusions of these arteries most vein (Figs. 4.4 and 5.1). The straight sinus also often are followed by neural damage. The anas- receives venous blood from the inferior sagittal tomotic connections might not be sufficient to sinus located along the inferior margin of the allow adequate blood to reach the deprived falx cerebri just above the corpus callosum. region rapidly enough to meet its high meta- Some blood from the base of the cerebrum bolic requirements. drains into the superior and inferior petrosal sinuses and then flows into either the sigmoid sinus or the cavernous sinus in the region of the VENOUS DRAINAGE hypothalamus (on the sides of the sphenoid bone). The cavernous sinus is connected via the The veins draining the brainstem and cere- superior petrosal sinus with the transverse bellum roughly follow the arteries to these sinus, via the inferior petrosal sinus with the structures. On the other hand, the veins drain- jugular vein, and via the basilar venous plexus ing the cerebrum do not usually form patterns with the venous plexus of the vertebral canal that parallel its arterial trees. In general, the (Fig. 4.4). venous trees in this region have short stocky branches that come off at right angles, resem- Emissary Veins bling the silhouette of an oak tree. Some dural sinuses connect with the veins superficial to the skull by emissary veins. Dural Sinuses These veins act as pressure valves when Venous anastomoses are extensive and intracranial pressure is raised and are also effective between deep veins within the brain routes for spread of infection into the brain and superficial surface veins (Fig. 4.4). The case (infection in the nose could spread via an veins of the brain drain into superficial venous emissary vein high in the nose into the plexuses and dural sinuses. The dural (venous) meninges and could result in meningitis). The sinuses are valveless channels located between cavernous sinus is connected with emissary two layers of the dura mater. Most venous veins, including the ophthalmic vein, which blood ultimately drains into the internal jugu- extends into the orbit. lar veins at the base of the skull. The blood from the cortex on the upper, lateral, and medial aspects of the cerebrum drains FUNCTIONAL CONSIDERATIONS into the superior sagittal (dural) sinus to the occipital region. From there, it flows to the The mean blood flow in the normal brain is transverse (lateral) and sigmoid sinuses into 50 mL/100 g of brain tissue per minute. It takes the internal jugular vein. All dural sinuses about 7 seconds for a drop of blood to flow receive blood from veins in the immediate through the brain. At any given moment, how- vicinity. ever, the flow through a specific region could The deep cerebral drainage is to the region be greater, the same, or less than the mean flow of the foramina of Monro, where the paired through the CNS. The brain is similar to other internal cerebral veins (posterior to the choroid tissues of the body where the amount of blood plexus of the third ventricle) extend to the flow varies with the level of metabolic and region of the pineal body. There, they join to functional activity. For example, dynamic vol- form the great vein of Galen. Blood then flows, untary movements of the hand are associated successively, through the straight sinus (located with an increase in the blood flow within the 82 The Human Nervous System

Figure 4.4: Venous drainage from the brain. (A) lateral view of the brain (*Location of emissary veins); (B) medial view of the brain. Chapter 4 Blood Circulation 83 cerebral cortical motor areas associated with of the brain, but an occlusion of the supplying hand movements and with sensory areas arteries is often followed by neural damage, receiving signals from skin, joints, and muscles causing symptoms and signs correlated with associated with these movements (Chap. 25). the site (Chaps. 17 and 25). This occurs because Anastomotic connections within the verte- the anastomotic connections are not suffi- bral and internal carotid arterial systems form ciently rich to allow adequate blood flow to extensive patterns of collateral circulation in reach the deprived areas rapidly enough to the brain. A sudden deprivation of the blood meet the high metabolic requirements. supply to a region of the brain could, if the vas- An occlusion of the anterior cerebral artery cular insufficiency lasts for more than a few results in a lesion of the paracentral lobule that minutes, result in the necrosis (infarct) of brain has the general sensory and motor cortical tissue. The inadequate oxygen and glucose sup- areas for the contralateral lower extremity ply at the lesion (infarct) site is the essential (Chap. 25). A lesion in this area results in con- cause of a “stroke” (sudden appearance of focal tralateral paresis as a motor sign coupled with neurologic deficits). This could result from the diminished sensitivity (hypoaesthesia) of the sudden occlusion by a thrombus (blood clot general senses in this extremity (Chap. 12). formed within the blood vessel), or an Blockage of the calcarine branch of the poste- embolism (a portion of clot transported along in rior cerebral artery (which supplies the pri- the blood stream) to the occlusion site, or the mary visual cortex of one side) results in a rupture of an artery often the result of arte- contralateral hemianopsia (Chap. 19). Occlu- riosclerosis or hypertension; this is called a sion of small branches of the posterior cerebral cerebrovascular accident (CVA). A stroke is artery (which supplies the posterior thalamus often preceded by a significant warning sign and adjacent tissues) produces the thalamic known as a ministroke or transient ischemic syndrome (Chap. 23). Strokes following the attack (TIA). These temporary spells are the rupture and bleeding of the striate arteries, result of impaired neural function caused by a branches of the middle cerebral artery (which brief but definite reduction in blood flow to the supply portions of the internal capsule and brain. Depending on the location that is adjacent structures), result in signs that include deprived of oxygen and glucose, the symptoms an upper motoneuron paralysis of the face and might include difficulty in talking, temporary upper and lower limbs on the opposite side as weakness or paralysis on one side, dizziness, well as sensory disturbances (Chaps. 12 and blurred vision, loss of hearing, and so forth. 25). Signs associated with vascular lesions of Interconnections among the large branches branches of the vertebral artery supplying the of the superficial arteries are usually physio- brain stem are outlined in Chapter 17. logically effective, so that an occlusion of one Although collateral circulation provides cer- need not result in a marked impairment of the tain regions of the CNS with a margin of safety blood supply to the neural tissues. For example, during arterial occlusion, the anastomotic net- following an occlusion within the circle of work also allows for a degree of vulnerability. Willis, or its proximal branches, the collateral With a reduction in the systemic blood pres- circulation is often adequate, especially if the sure, a region supplied by an anastomotic net- involved artery becomes occluded slowly work is susceptible to ischemia; such an before the stroke. In contrast, anastomoses anastomosis occurs at the terminal ends of two among the distal arterial branches of the circle or more arterial trees, a border region where of Willis are variable; consequently, the collat- perfusion pressure is lowest. These border eral circulation might not be adequate and regions, which are supplied by major arteries, occlusion of a vessel might result in an infarct. are called border zones or watershed zones. An Rich anastomoses exist among the capillary infarction occurring in such a region is called a beds of adjacent arteries within the substance border zone or watershed zone infarct. 84 The Human Nervous System

excess is conveyed by transporters from brain BLOOD–BRAIN BARRIER to blood (Fig. 4.5). The combination of the specialized cell The blood–brain barrier (BBB) is a special- membrane of the endothelial cells linked by ized functionally dynamic structure that main- intercellular tight junctions is the hallmark of tains the microenvironment, thus enabling the BBB (Fig. 4.5). This duo effectively neurons to function effectively. Anatomically, excludes by blocking the passage of many sub- the barrier consists of endothelial cells of the stances across the capillary wall. The perme- brain capillaries and their tight junctions (Fig. ability property can be enhanced by the state of 4.5). The BBB’s role is accomplished by activ- phosphorylation of the proteins of the cell–cell ities that regulate the movement of various adherens junctions. The cadherin proteins of metabolites and other chemical substances the adherens junctions also act as a signaling between the blood and the brain by (1) exclu- component between endothelial cells through sion, (2) selective passage, and/or (3) removal. linkages with the cytoskeletal protein filaments The capillary bed is comprised of endothelial of the endothelial cells. The presence of so few cells with adjacent smooth-muscle-like peri- pinocytotic vesicles within the endothelial cells cytes and end-feet of astrocytes that ensheathe is indicative that the transcellular movement by the endothelial cells (Fig. 4.5). The contractile vesicles across the BBB (transendocytosis) is property of endothelial cells and the pericytes both relatively deficient and slow. However, the can alter the shape and size of a capillary selective passage of substances is related to lumen. Exclusion of blood-borne substances is the presence of high concentrations of carrier- largely regulated by the properties of the cell mediated transport systems that act as transmembrane of the brain’s endothelial cells. For porters for glucose, essential amino acids, other example, this membrane limits the passive dif- required nutrients, and macromolecules. These fusion of H2O and certain aqueous substances ensure the passage of essential substances from from the blood. Selective passage of metabo- the blood to the CNS. The perivascular astro- lites and chemical substances essential for the cytes with end-feet that ensheathe about 95% growth and function of the brain are conveyed of the capillary surface are not considered to be (1) by the diffusion of some lipid-soluble sub- a component of the BBB. Some evidence sug- stances by ion channels and transport proteins gests that the early proliferating perineural (transporters) and (2) by facilitative and energy- blood vessels, composed of primordial fenes- dependent receptors that mediate the transport trated endothelial cells with no BBB, might be of water-soluble substances. These include the induced by brain-derived molecular signals transport from blood to brain of amino acids, from early perivascular astroglia to develop peptides, and the energy substrate glucose. into endothelial cells lacking fenestrations and, Removal of metabolites that accumulate in thus, express BBB properties.

Figure 4.5: Ultrastructural features of the specialized capillary endothelial cells of the brain compared to a general capillary. A,B: Brain capillary. The endothelial cells (ECs) have several anatomic features that contribute to the so-called blood–brain barrier (BBB). Transcellular passage of substances across the BBB from the blood to brain is regulated, in part, by the combination of restrictions, including specialized cell membranes of the ECs adjacent to the bloodstream, tight junctions between ECs, a scarcity of pinocytotic vesicles, and selective transport of water-soluble compounds by transendocytosis. The presence of abundant mitochondria supplies the energy- dependent transport system delivering substances required by the brain. The cell-to-cell adherens junctions contribute minimally to the BBB. The foot processes of the astrocytes that almost completely ensheath the brain capillaries are not functional components of the BBB, but could influence “barrier-specific endothelial cell differentiation.” Note the smooth muscle-like pericyte Chapter 4 Blood Circulation 85

adjacent to the capillary. C: General (systemic) capillary. In contrast, the relatively unselective diffusion across endothelial cells of other organs is enhanced by the presence of fenestra, interen- dothelial cleft passage of fluid, numerous pinocytotic vesicles, and few mitochondria and the absence of tight junctions. 86 The Human Nervous System

The selective passage of essential sub- An astrocyte might have processes with sev- stances that must cross the BBB in sufficient eral end-feet that come in close contact with a quantities is primarily accomplished by the dif- capillary, with a neuron, and with the pia–glial fusion of lipid-soluble solutes and by facilita- membrane (Fig. 5.5). Thus, an astrocyte might tive and carrier-mediated transport of have a transport function of transferring water-soluble substances. The great concentra- metabolites bidirectionally among the endothe- tions of mitochondria within the endothelial lial cells, neurons, and cerebrospinal fluid. . cells are indicative of high oxidative metabolic Astrocytes can (1) take up from the extracellu- activity required by the carrier-mediated trans- lar fluid the excess potassium ions generated port systems. This explains, in part, why small during intense neuronal activity and (2) regu- molecules pass through the barrier more rap- late the extraneural concentrations of neuro- idly than medium-sized molecules and why transmitters by an uptake process and store large molecules such as serum proteins and them. penicillin do not pass through the BBB. Activated lymphocytes, macrophages, and certain types of metastatic cell can cross the Diffusion BBB barrier. These cells can recognize and

Lipid-soluble solutes such as O2,CO2, and bind to endothelial cells and then activate sig- some drugs pass rapidly from the blood naling systems that initiate transmigration through the barrier into the brain. Facilitated junctional-opening mechanisms. Another per- diffusion occurs “downhill” down a concentra- meability barrier, called the blood–cere- tion gradient because it is not energy depend- brospinal fluid barrier, is present between the ent. Systems that move molecules rapidly capillaries of the choroid plexus and the cere- without consuming energy act bidirectionally brospinal fluid (Chap. 5). from the brain and cerebrospinal fluid to blood The ependymal cells and subjacent astro- and vice versa, thereby influencing the passage cytes (i.e., subependymal glial membrane) of to and from blood plasma and brain. the ventricles constitute a brain–cerebrospinal fluid interface (Fig. 5.6). The lateral cell sur- Carrier-Mediated Transport Systems faces of the ependymal cells are comparatively Most substances that must cross the BBB simple without elaborate folds or interdigita- are not lipid soluble. They cross by facilitated tions. This structural arrangement forms the diffusion and energy-dependent carrier-medi- brain-cerebrospinal fluid interface. Neither ated active transporters (membrane-spanning the ependymal surfaces of the ventricles nor the proteins that facilitate the passage of small pia–glial membrane on the surface of the brain molecules), which are the conveyers of the impede the exchanges of substances of between numerous essential water-soluble substances the cerebrospinal fluid and the capillaries of the such as glucose, amino acids, lactate, ribonu- brain. Thus, the brain–cerebrospinal fluid inter- cleosides, and several vitamins that cross the face does not constitute a BBB. BBB. In these forms of transport, the solute Homeostasis of the neuronal environment is (e.g., 99% of the glucose) combines with a spe- vital for the proper functioning of each neuron. cific membrane carrier on one side of the bar- In turn, barriers are essential for the preserva- rier and then “shuttles” the solute across the tion of homeostasis by maintaining the ionic barrier for release. These systems are efficient constancy of the extraneuronal interstitial fluid for transporting the glucose and other critical (fluid surrounding the neurons, glial cells, and nutrients that must be supplied continuously capillaries) by promoting the entry of required and in a large quantity. Should the brain be molecules, by preventing the entry of unwanted inadequately supplied with sufficient glucose substances. and by removing unwanted sub- or oxygen, loss of consciousness and even stances. Following infections, stroke, tumors, or death can occur within minutes. trauma, the blood–brain barrier can be breached. Chapter 4 Blood Circulation 87

Isobe I, Watanabe T, Yotsuyanagi T, et al. Astrocytic SUGGESTED READINGS contributions to blood–brain barrier (BBB) formation by endothelial cells: a possible use of aor- Bevan RD, Bevan JA. The Human Brain Circula- tic endothelial cell for in vitro BBB model. tion: Cunctional Changes in Disease. Totowa, Neurochem Int. 1996;28:523–533. NJ: Humana; 1994. McAllister MS, Krizanac-Bengez L, Macchia F, Brightman M. Implication of astroglia in the blood- et al. Mechanisms of glucose transport at the brain barrier. Ann. NY Acad. Sci. 1991;633: blood–brain barrier: an in vitro study. Brain Res. 343–347. 2001; 904:20–30. Brightman MW, Kadota Y. Nonpermeable and per- Pardridge W. The Blood–Brain-Barrier. Cellular meable vessels of the brain. NIDA Res. Monogr. and Molecular Biology. New York, NY: Raven 1992;120:87–107. Press; 1993. Brightman MW, Ishihara S, Chang L. Penetration Pardridge WM. Blood–brain barrier genomics and of solutes, viruses, and cells across the blood- the use of endogenous transporters to cause drug brain barrier. Curr. Topics Microbiol. Immunol. penetration into the brain. Curr. Opin. Drug Dis- 1995;202:63–78. cov. Dev. 2003;6:683–691. Brust J. Circulation of the brain. In: Kandel WR, Schwartz JH, Jessel T., eds. Principles of Neural Pardridge WM. Molecular biology of the blood– Science, 4th ed. New York: McGraw-Hill, 2002; brain barrier. Methods Mol. Med. 2003;89: 1303–1316. 385–399. Cassella JP, Lawrenson JG, Firth JA. Development Purves MJ. The Physiology of the Cerebral Circula- of endothelial paracellular clefts and their tight tion. Monographs of the Physiological Society No. junctions in the pial microvessels of the rat. J. 28. Cambridge: Cambridge University Press; 1972. Neurocytol. 1997;26:567–575. Reese TS, Feder N, Brightman MW. Electron Cassella JP, Lawrenson JG, Allt G, Firth JA. microscopic study of the blood–brain and blood– Ontogeny of four blood–brain barrier markers: cerebrospinal fluid barriers with microperoxi- an immunocytochemical comparison of pial dase. J. Neuropathol. Exp. Neurol. 1971;30: and cerebral cortical microvessels. J. Anat. 137–138. 1996;189(Pt 2):407–415. Rubin LL, Staddon JM. The cell biology of the Cucullo L, McAllister MS, Kight K, et al. A new blood–brain barrier. Annu. Rev. Neurosci. dynamic in vitro model for the multidimensional 1999;22:11–28. study of astrocyte-endothelial cell interactions at Stanness KA, Westrum LE, Fornaciari E, et al. Mor- the blood–brain barrier. Brain Res. 2002;951: phological and functional characterization of an 243–254. in vitro blood–brain barrier model. Brain Res. Harik SI, Kalaria RN. Blood–brain barrier abnor- 1997;771:329–342. malities in Alzheimer’s disease. Ann. NY Acad. Tao-Cheng JH, Nagy Z, Brightman MW. Tight junc- Sci. 1991;640:47–52. tions of brain endothelium in vitro are enhanced Harik SI, Gravina SA, Kalaria RN. Glucose trans- by astroglia. J. Neurosci. 1987;7:3293–3299. porter of the blood–brain barrier and brain in Walz W. The Neuronal Environment: Brain Home- chronic hyperglycemia. J. Neurochem. 1988;51: ostasis in Health and Disease. Totowa, NJ: 1930–1934. Humana, 2002. 5 Meninges, Ventricles and Cerebrospinal Fluid

Meninges Ventricles Fluid Environment of the Brain Circumventricular (Periventricular) Organs Hydrocephalus Clinical Aspects of Cerebrospinal Fluid

The meninges are three layers of connective cerebellum. The pontine and interpeduncular tissue that surround and protect the soft brain cisterns are located on the anterior brainstem, and spinal cord. Cerebrospinal fluid (CSF) and the superior cistern is located posterior to passes between two of the layers of the the midbrain. The spinal (lumbar) cistern is meninges and, thus, slowly circulates over the located caudal to the spinal cord (lumbar-2 to entire perimeter of the central nervous system sacral-2 vertebral levels). Large cisterns at the (CNS). CSF also flows through the ventricles, base of the brain are traversed by arteries. which are the cavities within the brain derived In the head, the tough nonstretchable dura from the central canal of the embryonic neural mater consists of two layers: the outer and tube (Fig. 5.1). inner dura mater. The skull and dura mater form an inelastic envelope enclosing the CNS, CSF, and blood vessels. This inelasticity per- MENINGES mits only a slight increase in the cranial contents; the concept that the volume of the Each of the meningeal layers—pia mater, intracranial contents cannot change is the basis arachnoid and dura mater—is a separate, con- of the Monro–Kellie doctrine (see “CSF Pres- tinuous sheet: thin strands of connective tissue sure”). The outer dura mater is really the perios- called trabeculae extend from the arachnoid to teum of the skull. The inner dura mater is a the pia mater (Fig. 5.2). thick membrane, which extends (1) between The pia mater is intimately attached to the the two cerebral hemispheres in the midsagittal brain and spinal cord, dipping into every sulcus plane as the falx cerebri and (2) between the and fissure. It is a vascular layer containing occipital lobes and the cerebellum as the tento- blood vessels whose branches nourish the rium cerebelli. The subdural space is a poten- underlying neural tissue. tial thin space located between the inner dura The arachnoid is a thin, avascular, delicate mater and the arachnoid. The film of fluid in layer, which does not follow each indentation the subdural space is not CSF. of the brain, but, rather, skips from crest to The dura mater is also called the pachy- crest. The subarachnoid space, between the pia meninx and the arachnoid and pia mater com- mater and the arachnoid, contains CSF and prise the leptomeninges. large blood vessels. In several places, the sub- In head injuries, bleeding could occur into arachnoid space is enlarged into cisterns. The the subarachnoid space (subarachnoid hemor- cisterna magna (cerebellomedullary cistern) is rhage), into the subdural space (subdural hem- located dorsal to the medulla and inferior to the orrhage), and between the outer dura mater and

89 90 The Human Nervous System

Figure 5.1: Midsagittal view of the meninges, ventricles, subarachnoid spaces, and cisternae. Arrows indicate the normal direction of CSF flow.

the skull (extradural hemorrhage). An extra- aneurysm; bloody CSF obtained from a lumbar dural hemorrhage could result from the bleed- puncture is confirmatory. ing of meningeal vessels after a fracture of the skull. A subdural hemorrhage could be caused by the tearing of veins crossing the subdural VENTRICLES space, which might follow after the sudden movement of the cerebral hemispheres relative The ventricular system is a series of cavities to the dura and skull. A subarachnoid hemor- within the brain, lined by ependyma and filled rhage could result from the rupture of an with CSF. The ependyma is a simple cuboidal Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 91 epithelial layer of glial cells. Paired lateral temporal lobe, and posterior horn in the ventricles, within the substance of the cerebral occipital lobe. hemispheres, communicate with the midline Each ventricle contains a choroid plexus,a third ventricle via the interventricular foram- rich network of blood vessels of the pia mater ina of Monro (Figs. 5.3 and 5.4). The third that is intimately related to the ependymal lin- ventricle is continuous with the tubelike cere- ing of the ventricles. The membrane formed by bral aqueduct of Sylvius (iter) in the midbrain, the pia mater, its vascular network, connective and the latter with the fourth ventricle in the tissue, and ependyma is called the tela pons and medulla (Fig. 5.1). The fourth ven- choroidea. The choroid plexus of each lateral tricle, in turn, is continuous with the central ventricle is located in the body and inferior canal that extends from the caudal medulla horn; it is continuous through the foramen of almost to the lower tip of the spinal cord, Monro with the unpaired choroid plexus of the where it terminates without outlet. The central roof of the third ventricle (Fig. 5.3). The canal has a small diameter and is, for the most choroid plexus of the fourth ventricle is located part, occluded. Each lateral ventricle is subdi- in the roof of the medulla, in which there are vided into four parts: anterior horn in the three foramina through which CSF escapes frontal lobe (rostral to foramen of Monro), from the fourth ventricle into the cisterna body in the parietal lobe, inferior horn in the magna. The two lateral openings are the lateral

Figure 5.2: Coronal section through the superior sagittal sinus and associated structures. Vac- uole transport within the villi of the arachnoid granulations (arrows on left side of midline) appears to occur via one-way bulk-flow of CSF via giant vacuoles from the subarachnoid space into the venous blood of the dural sinus. The collapsed villus lacking vacuoles (on the right side) is indicative of a markedly reduced bulk flow of CSF via vacuoles. The one-way flow is called bulk flow within each villus because all constituents of the CSF, including small molecules, micro-organisms, and even erythrocytes, are transported with the vacuoles. The dura mater represents the combined inner dura mater and outer dura mater. 92 The Human Nervous System apertures (foramina of Luschka) and the choroid plexus-produced CSF within the sub- medial opening is the medial aperture (fora- arachnoid space. This CSF is constantly being men of Magendie) (Fig. 5.4). renewed by production and resorption so that the total volume is replaced several times a day. Two structures have critical roles in the FLUID ENVIRONMENT formation and maintenance of this environ- OF THE BRAIN ment: (1) the brain capillaries and (2) choroid plexuses. They act as selective barriers and The brain and spinal cord can only function major transfer sites of certain substances that in a chemically stable homeostatic fluid envi- constitute these fluids. ronment. This comprises (1) the interstitial Tight junctions between endothelial cells of fluid bathing the neurons, glia, and blood ves- the cerebral capillaries form the so-called sels within the central nervous system and (2) blood–brain barrier between the blood and the the CSF. These two fluids are essentially simi- interstitial fluid. The capillaries and the lar in composition. ependymal epithelial cells of the choroid The extracellular fluid occupies a space of plexus form the blood–cerebrospinal fluid bar- about 15–20% of the volume of the brain. This rier between the blood and CSF (Figs. 5.5 and interstitial space is greater in the gray matter 5.6). In addition, the arachnoid is essentially than in the white matter. The former has higher impermeable to water-soluble substances and water content than the latter. This fluid joins the its role is largely passive.

Figure 5.3: Lateral view of the ventricles of the brain. Note in the small drawing that the choroid plexus of the lateral ventricle, the hippocampus–fornix complex, and the caudate nucleus parallel the curvature of the lateral ventricle. The caudate nucleus is cut off just behind its head in this view. Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 93

Figure 5.4: Frontal (A) and lateral (B) views of the ventricles of the brain.

Cerebrospinal Fluid drain by diffusion from extracellular fluids Cerebrospinal fluid is a crystal clear, color- of the brain to the ventricles and subarach- less solution that looks like water and is found noid space. Other products of brain metabo- in the ventricular system and the subarachnoid lism are removed to the blood flowing space. It consists of water, small amounts of through the capillaries. The CSF and capil- protein, gases in solution (oxygen and carbon laries act as substitutes for the lack of a lym- dioxide), sodium, potassium, magnesium, and phatic system in the brain and spinal cord. chloride ions, glucose, and a few white cells The CSF along with extracellular fluids sur- (mostly lymphocytes). rounding the neurons are the “expressions” The CSF, formed primarily by a combina- of state of chemical equilibrium of the neu- tion of capillary filtration and active epithelial ral environment, called homeostasis, essen- secretion, serves two major functional roles: tial for the normal functioning of the central nervous system. 1. Physical Support. By acting as a “water jacket” surrounding the brain and by provid- The brain and spinal cord actually float in ing buoyancy for it, the CSF protects, sup- the CSF; the 1400-g brain has a net weight of ports, and keeps the brain afloat in a sea of about 25 g while suspended in the CSF fluid. (reduces brain weight 60-fold). The brain is 2. Homeostasis. The CSF of the ventricles and “shock mounted” in the CSF and, thus, is able the subarachnoid space comprises a pool to to withstand the stress during sudden move- which some of the endogenous water-soluble ments of the head. Illustrative of its buoyancy, products, including unwanted substances, removal of the CSF as was done in pneumoen- 94 The Human Nervous System

Figure 5.5: Relations of the leptomeninges, subarachnoid, choroid plexus, ventricle, astroglia, and neurons of the CNS. The subarachnoid space is located between the arachnoid and pia mater. The choroid plexus is composed of an ependymal layer and a highly vascularized connective tissue core. Subarachnoid blood vessels and subarachnoid space are continuous with the core of the choroid plexus. The astrocyte has several processes: One extends to a blood capillary and terminates as a perivascular foot, another process extends to and contacts the pyramidal neuron, and another extends to the pia mater. The pia mater and arachnoid constitute the leptomeninges. The dura mater is called the pachymeninx. cephalography caused intense pain and head- nial blood vessels. Headaches rarely occur aches with each movement of the head, which when a small sample of CSF is removed for persisted until the fluid was naturally replen- chemical analysis. The volume of CSF in an ished. adult is about 150 mL (60 mL in the ventricles The headaches were attributed to irritation and 90 mL in the subarachnoid space, includ- of nerve endings in the meninges and intracra- ing the lumbar cistern; Chap. 7). CSF is formed Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 95

Figure 5.6: Ultrastructural features in the brain, choroid plexus, pia– arachnoid layer, and ventricle. The continuous extracellular space is located among the glia (G), neurons or their processes (N), and the capillary. The basement lamina (also surrounds the capillary) is a porous structure. Note the tight junctions between capillary endothelial cells and choroid plexus ependymal cells, and the gap junctions between pial cells and ependymal cells lining the ventricle. 96 The Human Nervous System at a rate of approximately 500 mL/day; that is, ity. Both of these transfers are thought to be the total volume is replaced every 3-4 hours. dependent on ion pumps. The details of the The interstitial fluid within the brain is read- means for the transfer of molecules from the ily exchanged with CSF. As the CSF flows ventricular CSF to the capillaries have not been through the ventricles and the subarachnoid fully resolved. space around the spinal cord and brain, the The choroid plexuses of the four ventricles exchange between the two fluids occurs (1) at where the blood–cerebrospinal fluid barrier is the leaky spaces (gap junctions; Fig. 5.6) of the located continuously secrete most of the CSF. ependymal layer within the ventricles and (2) at Impermeable tight junctions join the endothe- the perivascular spaces on the pial surface of lial cells and also the cuboidal ependymal cells the CNS. of the choroid plexus (Fig. 5.6). These junctional barriers prevent the serum proteins from Choroid Plexus and the Blood–Cerebrospinal entering the CNS and inhibit the free diffusion Fluid Barrier of water-soluble molecules. The formation of The choroid plexus comprises a single row the CSF by the choroid plexus involves capil- of choroidal epithelium, arranged as villi lary filtration and active transport by the around a core of blood vessels derived from the ependymal cells. Flow of molecules across the pia mater and connective tissue Figs. 5.5 and cells of the choroid plexus occurs via active 5.6). The choroidal epithelium is continuous transport (energy required), facilitated diffu- with the ependyma of the ventricles. The extension (no energy required), and facilitated sive vascular network of the plexus is an exchanges of ions (e.g., sodium, potassium, expression of its active metabolic activity. The and chloride ions). Although the CSF is char- ventricular surface of each choroidal cell has a acterized as a cell-free, low-protein ultrafiltrate brush border comprised of microvilli, a feature of blood and that the CSF and blood plasma are of epithelial cells noted for fluid transport. in osmotic equilibrium, some small but signifi- These cells contain many oxidative enzymes, cant differences do exist between the two flu- which are indicative of their role in the active ids. As compared to the blood plasma, CSF transport of electrolytes and other solutes. contains less potassium, bicarbonate, calcium, Tight junctions join adjacent endothelial cells and glucose and more magnesium and chlo- of the brain and the choroid plexus, adjacent ride; its pH is lower. choroidal epithelial cells, and adjacent cells of The choroid plexus acts as a “kidney” of the the arachnoid membrane. These tight junctions brain that maintains the chemical stability of are a barrier to the passage of macromolecules the CSF in a similar fashion as the kidney (1) from the blood to the ventricular CSF (CSF maintains the chemical stability of the blood. A secretion) and (2) from the CSF to the capillary key difference in this comparison is that the blood (absorption by the choroid plexus). The kidney removes waste products from the blood, mechanism of CSF secretion and absorption whereas the choroid plexus pumps some from the CSF can be summarized as follows. “waste products” (byproducts of metabolic The hydrostatic pressure within the choroidal activity) from the CNS into the blood. capillaries initiates the passage of water and These barriers consist of permeability barri- ions across the endothelial cells to the intersti- ers that comprise systems whose primary roles tial connective tissue and then to the choroidal are to preserve homeostasis in the central nerv- epithelium. The completion of the transfer to ous system. They facilitate the entry of essen- the CSF takes two routes; (1) transcellular tial substances and metabolites and they block movement through the epithelial choroidal cells the entry or facilitate the removal of toxic sub- and across the plasma membrane into the ven- stances and unnecessary metabolites. In many tricular cavity and (2) paracellular movement neurologic diseases, the blood–brain barrier across the tight junction to the ventricular cav- breaks down and does not function as usual, Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 97 with some substances normally excluded pass- bulk flow via vacuole (some of giant size) ing through the barrier. This occurs in some transport from the subarachnoid space through infections, strokes, brain tumors, and trauma. the cells of the arachnoid villi (pacchionian granulations) into the dural venous sinuses Flow of CSF (Fig. 5.2). This one-way passage is called bulk After its formation at the choroid plexuses flow because all constituents leave with the and in the ventricular surfaces, there is bulk CSF including small molecules, micro-organ- flow of CSF through the ventricular system, the isms, and even, at times, erythrocytes. These subarachnoid spaces, and cisterns surrounding villi are grossly visible spongelike herniations the CNS before it enters the systemic blood cir- of the arachnoid that penetrate into the lumen culation. The CSF travels from the lateral ven- of the superior sagittal sinus. CSF also extends tricles through the foramina of Monro into the into and fills the tubular extensions of the third ventricle, through the narrow cerebral arachnoid and subarachnoid space that form aqueduct into the fourth ventricle, through the the sleeves around the roots of the spinal nerves paired apertures of Luschka and the median (Fig. 5.7). These numerous microscopically aperture of Magendie within the tela choroidea visible arachnoid villi associated with spinal in the roof of the fourth ventricle into the cis- veins of the spinal roots absorb some CSF. terna magna, and then slowly circulates rostrally through the subarachnoid space to the CSF Pressure region of the superior sagittal venous sinus at Cerebrospinal fluid pressure is lower than the top of the skull (Fig. 5.1). Most of the CSF blood pressure. In an individual lying side- appears to enter the venous blood by a one-way ways, the pressure varies from 65 to 195 mm of

Figure 5.7: Dorsal view of a dorsal root ganglion and dorsal root illustrating an arachnoid villus adjacent to the dorsal root (spinal cord to the right of figure). The arachnoid, CSF, and subarachnoid space of the spinal canal extend as sleeves that surround the ganglion and roots of each spinal nerve. The arachnoid of this sleeve protrudes into a spinal root (radicular) vein to form an arachnoid villus from which some CSF can pass into a vein. (Adapted from Fishman., 1992) 98 The Human Nervous System water throughout the subarachnoid space. In a subcommissural organ, organum vasculosum seated subject, the pressure may rise to of the lamina terminalis, subfornical organ, between 200 and 300 mm of water in the lum- and area postrema (Chap. 21). The functional bar cistern, reach zero in the cisterna magna, roles of the latter group are largely unknown. and go below atmospheric pressure in the ven- The area postrema is a chemoreceptive struc- tricles. Fluctuations in the pressure occur in ture activated by blood-borne substances that response to phases of the heartbeat and the res- elicit vomiting and its removal causes refrac- piratory cycle. These shifts occur because the toriness to some but not all forms of emetic rigid box of dura and skull does not yield, so stimuli. that the intracranial pressure changes if additions or subtractions to the intracranial contents occur (Monro–Kellie doctrine). HYDROCEPHALUS An obstruction to the normal passage of CSF results in a backup of CSF and an increase An increase in the volume of CSF within the in intracranial pressure. Because the CSF skull is known as hydrocephalus. Several types extends to the optic disk (optic nerve head, exist. In compensating hydrocephalus, there is blind spot) of the subarachnoid space within no increase in pressure; this usually occurs the dural sleeve along the optic nerve, an ele- when cerebral atrophy associated with a pri- vated CSF pressure results in dilated retinal mary CNS disease is compensated with an veins and forward thrust of the optic disk increase in CSF volume. In obstructive hydro- beyond the level of the retina. This cephalus and communicating hydrocephalus, papilledema, or so-called “choked disk”, can be there is both an increase in volume and in pres- observed during an inspection of the fundus of sure of the CSF. Obstructive hydrocephalus the eye with an ophthalmoscope. A persistent occurs when there is an obstruction to the flow papilledema could result in damaged optic of CSF within the ventricles, cerebral aque- nerve fibers. duc,t or the apertures in the roof of the fourth ventricle. The blockage results in an increase in the volume of CSF above the obstruction, CIRCUMVENTRICULAR which might be caused by a tumor, develop- (PERIVENTRICULAR) ORGANS mental anomaly, or some inflammatory process. In communicating hydrocephalus, the Adjacent to the median ventricular cavities ventricular CSF can readily flow into the sub- (third ventricle, cerebral aqueduct, and fourth arachnoid space; the hydrocephalus results ventricle) are several specialized regions of either from an obstruction to its flow within the ependymal origin called circumventricular subarachnoid space or from an alteration in the organs (Fig. 21.5). The common vascular, rate of formation and absorption of the CSF. ependymal, and neural organization of these structures differs from that found in typical brain tissue. They are referred to as “being in CLINICAL ASPECTS OF the brain, but not of it,” in part because their CEREBROSPINAL FLUID capillaries are lined by fenestrated endothelial cells indicative of a defective blood–brain bar- Cerebrospinal fluid is used for diagnostic rier to macromolecules. In humans, these testing. Samples of CSF for examination are anatomically well-defined organs include (1) usually obtained by a lumbar puncture (spinal the median eminence of the tuber cinereum tap) into the spinal cistern; this is done by (hypothalamus), the neurohypophysis, and the inserting a long needle in the midline between pineal body, all of which have a role in neu- the spines of vertebrae L3 and L4, or L4 and roendocrine regulation (Chap. 21), and (2) the L5, with the patient lying curled up on one side. Chapter 5 Meninges, Ventricles, and Cerebrospinal Fluid 99

There is no risk to injuring the spinal cord because it terminates above these levels. The SUGGESTED READINGS nerve roots of the cauda equina are usually Blaas HG, Eik-Nes SH, Kiserud T, Berg S, Angelsen deflected by the needle and, thus, rarely injured. B, Olstad B. Three-dimensional imaging of the With the relaxed patient lying sideways, the brain cavities in human embryos. Ultrasound normal pressure as indicated ranges from 65 to Obstet. Gynecol. 1995;5:228–232. 195 mm of water. The pulsations of the cere- Davson H. Formation and drainage of the cerebral arteries are registered as small oscillations brospinal fluid. In Shapiro K, Marmarou A, Port- on the manometer. Compression on the internal noy H, eds. Hydrocephalus. New York, NY: jugular veins draining blood from the brain Raven; 1984:p 1–40. results in a brisk rise in the CSF pressure. A Davson H, Segal MB. Physiology of the CSF and lumbar puncture is contraindicated in the pres- Blood–Brain Barriers. Boca Raton, FL: CRC; ence of an elevated intracranial pressure or an 1996. Davson H, Welch K, Segal MB. Physiology and obstruction in the subarachnoid space. In such Pathophysiology of the Cerebrospinal Fluid. cases, removal of CSF from the lumbar cistern New York, NY: Churchill Livingstone; 1987. would lower pressure below blockage, with Fishman RA. Cerebrospinal Fluid in Diseases of the several possible results: herniation of (1) uncus Nervous System. 2nd ed. Philadelphia, PA: Saun- of temporal lobe through the tentorium or (2) ders; 1992. cerebellar tonsils into the foramen magnum. Laterra J, Goldstein G. Ventricular organization of The former, through pressure on the midbrain, the cerebrospinal fluid, blood-brain barrier, brain can result in coma and the latter, through pres- edema, and hydrocephalus. In: Kandel ER, sure on the medulla, can cause death from Schwartz JH, Jessel T., eds. Principles of Neural malfunctioning of the cardiac and respiratory Science, 4th ed. New York: McGraw-Hill, 2002; centers. 1288–1301. McConnell H, Bianchine JR. Cerebrospinal Fluid in The removed CSF is examined for the pres- Neurology and Psychiatry. New York, NY: Chap- ence of cells (lymphocytes and erythrocytes), man & Hall; 1994. plasma protein, gamma globulins, and glucose. Walz W. The Neuronal Environment: Brain Home- Special tests are carried out for specific dis- ostasis in Health and Disease. Totowa, NJ: eases. Humana; 2002. 6 Development and Growth of the Nervous System

Origin of the Nervous System Establishing Patterns and Regions of the Brain and Spinal Cord Differentiation of Neurons and Glial Cells Neural Stem Cells The Neuron: Early Development Through Maturity Development of the Cerebellum Neural Plasticity Intraneuronal Transport of Signals Reciprocal Schwann Cell–Axon Interactions Apoptosis or Naturally Occurring Neuronal Death Aging of the Brain Spinal Cord and Peripheral Nervous System Brain Critical Periods: Effects of Genetic and Environmental Factors on Development

Individuals are as old as their neurons in the an avoidance reflex withdrawal of the head. A sense that almost all neurons are generated by mother might feel life as early as the 12th pre- early postnatal life and are not generally natal week. replaced by new ones during a lifetime. The From a relatively few primordial cells pres- genetically driven development of the complex ent several weeks after fertilization of the circuitry of the nervous system continues ovum, the nervous system undergoes a remark- throughout life, tempered and honed by a com- able change to attain its complex and intricate bination of constraints readjustments and organization. Once a neuroblast leaves the ven- responses to the influences and demands from tricular layer of the neural tube, not only is it both the internal and external environments. committed to differentiate into a neuron but The cardiovascular system and the nervous also it will never divide again. To generate the system are the first organ systems to function estimated 100–200 billion neurons in the during embryonic life. In humans, the heart mature brain requires a calculated production begins to beat late in the third week after fertil- of more than 2500 neurons per minute during ization. Before the heart begins to beat, the the entire prenatal period. The brain of a nervous system commences to differentiate and 1-year-old child has as many neurons as it will change in shape. Growth in size occurs after ever have. Throughout life, cells are continu- the heart commences to pulsate and blood ously lost at an estimated rate of 200,000 per slowly circulates to bring oxygen and essential day in humans. The estimate is based on the nutrients to the developing nervous system. observation of the 5 to 10% loss of brain tissue During the second month, when stimuli are with age. Assuming that there is a 7% loss of applied to the upper lip of the embryo, there is neurons over a life-span of 100 years and with

101 102 The Human Nervous System

100 billion neurons at 1 year of age, 200,000 for survival) factors are molecules secreted by neurons will be lost per day. Because the brain their targets (target-derived neurotrophic fac- has so many neurons, most individuals get tors) and are essential for the differentiation, through life without losing so many that they- growth, and survival of neurons. Neurons in become mentally disabled. part depend on one another for trophic factors, The central goal of developmental neurobi- which affect their signaling efficiency and even ology is to gain an understanding of the inter- their survival. actions and resolution of the forces of “nature” The neurotrophic concept states that during versus “nurture”. Nature is the cell’s intrinsic development, neurons are critically dependent potential contained in the genetic pool to mas- for their survival on these target-derived fac- termind the neuroblast to attain the full reper- tors. The presence of limited amounts of these toire of cellular processes and features of the factors ensures that only a select proportion of mature neurons. Nurture refers to the extrinsic neurons survives and do not succumb to natu- epigenetic extracellular factors, both tropic and rally occurring cell death (see Apoptosis or trophic, that shape the development of the neu- Naturally Occurring Neuronal Death) and, ron and continue to operate even on the mature thus, the appropriate innervation density of the neuron. target is attained. The scenario during develop- Differentiation and growth continue postna- ment can be categorized as a competitive, yet tally, attaining the organized complexity of the regulated “battleground” among many influ- entire nervous system. It continues throughout ences: life as the nervous system is remodeled through plasticity. The totality of events occurring dur- 1. The genetic impetus is to produce, during ing the development of the brain is not the early development, an oversupply of neu- exclusive property of rigid genetic codes. For rons, axons, and dendrites (including their example, the human brain probably contains terminal branches) and synapses. more than one trillion synapses, and there sim- 2. The growth of the axons to their target is ply is not enough genes, to account for this usually attained by a specific route; how- complexity. ever, alternate routes are possible. The normal development of a neuron and its 3. The projections of the axons from several subsequent integration into neuronal circuits sources to a specific target neuron or struc- result from activities at both (1) the genetic ture (e.g., muscle) is generally diffuse and level and (2) the epigenetic level. The former intermingled in the vicinity of their defini- (genetic) comprises (a) transcription or the tive target. transfer of information from DNA molecules 4. Competition occurs among the oversupply into RNA molecules and (b) translation or the of axonal terminals for appropriate targets transfer of information from the RNA mole- (neuron or synapses) with the elimination of cules into polypeptides. The latter (epigenetic) supernumerary neurons, axons, and synaptic includes many environmental and extracellular terminals. factors that can modify, regulate, or channel subsequent development. Epigenesis involves Experimental evidence indicates that devel- neurotropic and neurotrophic molecules that opmental changes continue to occur even in old have critical roles in the structural changes age. Dendrites and axons of neurons of the occurring during ontogeny of the nervous sys- cerebral cortex of old rats (equivalent in human tem. Tropic (having affinity for and turning terms of roughly 75 years) respond to an toward) factors are molecules to which, for enriched environment by forming new axon example, growth cones are attracted (see con- terminals and synaptic connections. Investiga- tract guidance in Neuronal Navigation and tions reveal that the structure and chemistry of Development). Trophic (relating to nutrition the brain can be affected by experiences Chapter 6 Development and Growth of the Nervous System 103 throughout life, indicating that there is more thicken in the head region to form placodes, flexibility and plasticity in neuronal connectiv- which are progenitors of the organs of special ity in old age than previously thought. Thus, sense such as the eyes (optic placode), ears the debate over nature or nurture with regard to (otic placode), and nose (nasal placode). In the brain and behavior is essentially over. fact, the neural plate is a giant placode. The Although many details remain to be resolved, neural plate elongates, and its lateral edges are both are involved. raised to form the neural folds or keyhole stage (see Fig. 6.1). The anterior end of the neural plate enlarges and will develop into the brain. ORIGIN OF THE NERVOUS SYSTEM The lateral edges, or lips, continue to rise and grow medially until they meet and unite in the When the human embryo is but 1.5 mm long midline, to form the neural tube. This midline (18 days old), the ectoderm (outer germ layer) union commences in the cervical region and differentiates and thickens along the future progresses both cephalically and caudally until, midline of the back to form the neural plate in 25 days, the entire plate is converted into the (see Fig. 6.1). With the transfer of certain neural tube (see Fig. 6.1). The tube becomes chemical substances from the underlying detached from the skin and sinks beneath the mesoderm, the induction of this ectoderm surface (see Fig. 6.2). The cavity of the neural occurs so it is now irreversibly committed to tube persists in the adult as the ventricular sys- form neural tissue. The neural plate is exposed tem of the brain and the central canal of the to the surface and to the amniotic fluid; it is spinal cord. continuous laterally with the future skin. Cer- The cephalic end of the neural tube differen- tain portions of the ectoderm differentiate and tiates and enlarges into three dilations called

Figure 6.1: Dorsal aspect of human embryo: (A) Primitive-streak plate stage of a 16-day presomite embryo; (B) two-somite keyhole stage of an approximately 20-day embryo (note the first somites, neural fold, and neural groove); (C) seven-somite stage of an approximately 22-day embryo; (D) 10-somite neural tube stage of an approximately 23-day embryo. 104 The Human Nervous System

Figure 6.2: Development of the spinal cord, neural crest, somite, and spinal nerve (transverse sections) in a human embryo of the following ages: (A) approximately 19 days; (B)approximately 20 days; (C) approximately 26 days; (D) after 1 month. The alar plate gives rise to sensory (afferent) neurons and the basal plate gives rise to motor (efferent) neurons. The sulcus limitans is the boundary between alar and basal plates. Chapter 6 Development and Growth of the Nervous System 105 the “primary brain vesicles.” Rostrally to (AP axis, rostrocaudal axis) of the CNS. Dur- caudally, the three divisions are the prosen- ing early development, there is an induction cephalon or forebrain, the mesencephalon or pathway linked to a program of transcription midbrain, and the rhombencephalon or hind- factors that establishes the neuroectoderm and brain. A bilateral column of cells differentiates its neuroregulation, or leads to the differentia- from the neural ectoderm at the original junction of the neural tube and the CNS. The tran- tion of the skin ectoderm and the rolled edges scription factor program is a determinant of the neural plate. These two columns of cells resulting in the dominant AP axis pattern of become the neural crests (see Fig. 6.2). forebrain, midbrain-cerebellum, hindbrain and The neural tube is the primordial structure spinal cord. The dorsal-ventral axis pattern is for the central nervous system (CNS) (brain established as the expression of other transcrip- and spinal cord), including all neurons in the tion factors. The dorsalization of specific neu- CNS, oligodendroglia, and astroglia. The neural cells types occurs following their induction ral crest gives rise to a number of neural and by locally acting peptide growth factors, non-neural derivatives. The neural derivatives whereas the ventralization of other cell types include (1) neurons in all the sensory, auto- following their induction is by signal regula- nomic, and enteric ganglia, (2) cells of the pia tory sonic hedgehog factors. mater and arachnoid and the sclera and choroid coats of the eye, (3) neurolemma (Schwann) Spinal Cord cells and satellite cells of the ganglia, (4) adre- The spinal cord comprises 31 segments nal medullary cells, and (5) receptor cells of the arranged in an AP axis. The development of the carotid body. Some neurons of sensory ganglia neural tube into these spinal segments is deter- of cranial nerves V, VII, IX, and X are derived mined by the AP axis and the influences of the from cells of the otic placode. AP sequences of mesodermal somites (see Fig. Several mesodermally derived elements are 6.1). Thus, the basic AP-axis segmentation is associated with the nervous system, including derived from an immediate source, namely the the meninges. Those that secondarily invade dermatome. In turn, each somite and its associ- the CNS include the blood vessels and micro- ated spinal cord segment is integrated into a glial cells. structural and functional unit consisting of a spinal nerve together with its dorsal and ventral roots, the combination of neural crest and dor- ESTABLISHING PATTERNS AND sal root ganglion, its sensory dermatomal dis- REGIONS OF THE BRAIN tribution, and its motor neurons and myotome AND SPINAL CORD (see Figs. 7.1–7.3 and 8.1).

The ectoderm of the presomite stage is Regional Patterning of the Neural Tube induced by trophic factors derived from the and the Brain underlying mesoderm and notochord to differ- The regionalization of the neural tube into entiate into neuroectoderm and the neural plate the brain is a gene expression patterning result- that will develop into the CNS. Molecular ing in an AP-axis segmentation. However, other genetic studies indicate that the development of multiple gene expression patterns can modify the early CNS progresses within a program in the basic pattern (Rubenstein, 1998). Thus some which genomic transcription factors are genes may encode protein factors that regulate involved with neural induction. Furthermore, the transcription of other downstream genes these studies are revealing the role of genes in that, in turn, control cellular differentiation. establishing the patterns and regions within the nervous system (Hatten, 1999) that activate the 1. In the hindbrain and spinal cord, HOX genes genesis of the anterior–posterior axis pattern (a subset of homeobox genes) appear to 106 The Human Nervous System

control the identity of cells in the hindbrain ventricular, intermediate (mantle), and mar- as well as the overlapping segmental pat- ginal (see Fig. 6.3). The adult nervous system terns of the spinal cord and spinal ganglia. is derived from these basic zones, none of The spatial order of the gene expression pat- which corresponds precisely to any adult com- terns in the neural tissue is reflected in an ponents. orderly distribution of the genes on specific The ventricular zone consists of dividing chromosomes. This segmentation is noted in cells. The nucleus of each ventricular cell the roots of the spinal nerves (see Fig. 7.1) migrates to the luminal end of the cell (adjacent and in the brainstem (see Fig. 22.1). to the central canal), rounds up, and undergoes 2. Evidence of this basic axial gene is a mitotic division; after dividing, the nuclei of expressed patterns in the neural plate and the daughter cells migrate to the apical portions early- to mid-gestational developing prosen- of their respective cells, where the replication cephalon (forebrain) Thus, gene expression of its deoxyribonucleoproteins occurs. Thus, patterns of the forebrain reflect the simpler the ventricular zone is known as the lamina of AP-axial sequences of the neural plate. The the to-and-fro nuclear movement. The mitotic complexity of forebrain reorganization and nuclear migration cycle lasts from 5 to 24 apparently results from multiple distinct pat- hours. Ventricular cells are the progenitors of terning mechanisms. This indicates that neurons and macroglia (astroglia and oligoden- there are several forebrain (prosencephalic) droglia) of the CNS. gene expression patterns. The precursor cells of glial cells can be distinguished from those of neurons by the presence of glial fibrillary acidic protein (GFAP) in DIFFERENTIATION OF NEURONS dividing glial precursor cells of the ventricular AND GLIAL CELLS zone. The first glial cells to be formed appear at about the same time as the first neurons. As The embryonic neural tube eventually com- previously stated, most, but not all, neurons in prises four concentric zones: ventricular, sub- humans are generated during prenatal life. In

Figure 6.3. The four zones of the embryonic CNS (neural tube). The ventricular cells (stem cells) are derived from neuroectodermal cells of the neural plate. The ventricular stem cells divide into new stem cells that remain within the ventricular zone and others that migrate into the subventricular zone. Within the subventricular zone, the stem cells differentiate either into glioblasts, neuroblasts, or ependymal cells. Some glioblasts differentiate into radial glia cells that extend from the ventricular zone and as a glial fiber to the pial surface of the neural tube. The arrows within the stem (ventricular) cells indicate the direction in which the nucleus migrates to and fro during a mitotic cycle. Arrows outside the cells indicate the direction of the migration of neuroblasts and glioblasts (progenitors of astrocytes and oligodendroglia). The neuroblasts are guided in their migration by the radial glial fibers. Chapter 6 Development and Growth of the Nervous System 107 contrast, the precursors of the glial cells retain some capacity for proliferation throughout life. NEURAL STEM CELLS The subventricular zone in time differentiates from the ventricular zone. It is composed Stem cells are “persistent embryonic” cells of small cells that proliferate by mitosis but do present even in adults. They have the several not exhibit the to-and-fro nuclear movements potentials of being able to (1) replicate them- during the mitotic cycles. This zone persists selves as self-renewal precursors, (2) prolifer- only a few days in the spinal cord, but many ate large numbers of progeny by neurogenesis, months and even years in the cerebrum. It gen- and (3) retain multilineage potential over an erates certain classes of neurons and macroglia extended time. The inner cell mass of the blas- of the CNS. It gives rise to (1) the rhombic lips tocyst consists of embryonic stem cells, which located on the lateral margins of the medulla are totipotential stem cells with the capability, and (2) the ganglionic eminence located in the under proper conditions, to develop into almost floor of each lateral ventricle. The rhombic lips any cell type. The germinative zones of the generate certain brainstem and cerebellar neu- neural tube and the neural crest are comprised rons, including the billions of interneurons of of neural stem cells, called multipotential stem the cerebellar cortex (Chap. 18). The gan- cells (derivative, progenitor or persistent stem glionic eminence generates many of the small cells (see Fig. 6.3). neurons of the basal ganglia (Chap. 23) and of Multipotential neural stem cells (NSC) are some other deep structures of the cerebrum. progenitor cells of the nervous system with the After these newly differentiated neurons capability of developing into neurons and neu- have apparently lost their capacity to synthesize roglia (oligodendrocytes and astrocytes) of the DNA, the mitotic cycle ceases and the cells are CNS and into neurons, Schwann, cells and triggered to migrate from both the ventricular satellite cells of the peripheral nervous system and subventricular zones into the intermediate (PNS). Note that microglial are mesodermal zone or even farther to form the cortical plates derivatives. Some NSCs persist and exhibit (see below). Never again will these postmitotic activity throughout life. . A stem cell is charac- cells divide. Those cells that migrate into the terized by the combination of both its morpho- rhombic lips and ganglionic eminences, as logical fate and its functional role. Although noted earlier, retain their capacity to undergo NSCs have a high capability for self-renewal in mitosis. As a rule, the large neurons differenti- the developing and immature nervous system, ate before the small neurons. The large neurons they remain quiescent and divide much less fre- are primarily those whose axons extend long quently in the mature nervous system, but they distances, and small neurons (local circuit neu- can resume activity on demand. Thus, NSCs rons) are those whose fibers are confined to the exhibit an impressive power of renewal. region immediately surrounding the cell body. In consort with general biological phenom- The intermediate (mantle) zone evolves into ena, the numbers and activity of the NSCs and the gray matter of the CNS, with its complex their progeny are homeostatically regulated. In neural organization. The neurons that migrate adults, persistent neurogenesis of new progeni- and collect to form the cortical plates differen- tor neurons from NSCs occurs in the olfactory tiate into neurons of the cerebral cortex and neuroepithelium (olfactory mucosa), olfactory cerebellar cortex. Most cerebellar cortical neu- bulb, dentate gyrus of the hippocampus, and in rons are derived from the rhombic lips. the prefrontal, posterior parietal, and inferior The marginal zone is the cell-sparse layer temporal gyri of the cerebral cortex (Chapter with no primary cells of its own. Eventually, it 25). Other locations where NSCs in the adult is invaded by axons, both myelinated and give rise to derivative cells remain to be uncov- unmyelinated, and macroglia to form much of ered; their capabilities have been questioned the white matter. and, at best, are markedly reduced. Typically, 108 The Human Nervous System many potential NSCs remain quiescent and of the symptoms, including slowness of move- unrecognized unless activated to supply a need. ment and rigidity. This indicates that survival The fate of the genetic potential of the multipo- of transplanted fetal cells into the brain does tential NSCs to become neurons or glial cells is occur and they have the capacity to express rel- expressed in a sequential progression of restric- evant functional activity. tion stages: (1) differentiation into neuroblasts or glioblasts, followed by (2) differentiation into committed neuronal or glial progenitor THE NEURON: EARLY DEVELOPMENT cells, and, ultimately in adults, into specific THROUGH MATURITY neurons or glia. The precise roles of a variety of molecular Neuronal Navigation and Docking During factors that regulate and influence the develop- Early Development ment and ultimate fate of each NSC are incom- The stages involved in the creation of the pletely understood. The following are some of neuronal network of the brain and spinal cord the types of molecular factors involved in the and its integration with the peripheral nerves potential resident NSCs expression of their during prenatal development are precise and genetic potential in the sequence of differentia- apparently predetermined to a considerable tion and restriction stages leading to their fates degree. The first two stages are pathway selec- as committed functional stem cells: (1) trans- tion and target selection. In humans, they are formation (growth) factors that modulate dur- instrumental in establishing the basic ground- ing the restriction stages as each cell passes through its development; (2) signal factors that work of the neuronal networks and pathway act as guideposts during each cell’s migration systems during prenatal life. The third, the to its destination; and (3) induction factors that activity-dependent and experience-dependent are involved in the modifications associated stage, continues throughout life. with interactions and adjustments to the spe- Evidence is available that identifies some of cific environment of the NSCs. the factors involved in assembling, integrating, and maintaining the 100 billion neurons of the Stem Cell Therapies human nervous system. Because there are more The developmental potentials of NSCs can neurons than genes, each neuron cannot possi- have significance in regenerative and reparative bly have its own gene to regulate the naviga- (cell replacement) therapies. Transplantation of tional system controlling (1) pathway selection NSCs as donor cells from embryonic and fetal or cell migration from the ventricular layer of sources into the brain and spinal cord is being the neural tube and (2) target selection or the evaluated for roles in regenerative therapy and guidance of the growth of axons at their tips reparative therapy for several neurologic disor- (growth cones) as their endings “hone in” to ders such as Parkinson’s disease, Huntington’s make synaptic connections with their target disease and Alzheimer’s disease, as well as for neurons. The development of the nervous sys- traumatic injuries resulting in, for example, tem from the neural plate and neural crest stage paraplegia. The symptoms of parkinsonism are to the mature nervous system is synchronized associated with the degeneration of dopaminer- by genetic influences and epigenetic factors. In gic neurons in the basal ganglia (Chap. 24). essence, each neuroblast differentiates into a Neurons obtained from selected sites of neuron with its axon terminals, which must aborted fetuses were grafted into the basal gan- migrate to and dock in its designated site, and glia of patients with Parkinson’s disease be there at the right time to be integrated into a (Bjorklund, in Barinaga, 2000). In many cases, prescribed circuitry. the transplanted fetal tissues (containing either At the time a neuroblast commences to stem or fetal cells) significantly relieved some migrate from the ventricular zone of the neural Chapter 6 Development and Growth of the Nervous System 109 plate, it becomes a postmitotic cell that is (1) sentinels. Powered by actin microfilaments, the incapable of dividing and (2) is branded to cones actively explore and probe the tissue become a neuron. The kinetics of cell migra- environment. Filopodia protrude randomly tion commences as each neuroblast (and from the leading edge of the growth cone. glioblast) leaves the ventricular zone at a defi- Those that extend in the “intended” new direc- nite time to navigate to its port of call in the tion of growth become stabilized, whereas the brain and spinal cord. The differentiation of others are retracted. Stabilization involves the each immature neuron, and the specific path it concentration of actin in the filopodia and a takes to reach its destination, is determined (1) local consolidation of the microtubules in the by the activation of specific sets of genes com- growth cone. This establishes the new direction bined (2) with a variety of epigenetic external in which the axis cylinder continues to elon- signals from other cells in the environment. Ini- gate. Receptor molecules on the cone’s plasma tially, the neuroblasts of the brain contact the membrane, acting as sensors, are responsive to fibers of the radial glial cells. These are spe- the diffusible molecules in the vicinity. cialized cells, each with a process extending to Chemotrophic factors furnish guidance cues the ventricular surface and another to the pial leading to the precision of pathfinding as the surface. The neuroblasts migrate along the axon elongates and sprouts collateral branches. scaffolds of these glial fibers by contact Some guidance cues can be inhibitory and, (mechanical) guidance (see Fig. 6.3). How- thus, modulate random collateral sprouting of ever, many neuroblasts migrate without the branches and prevent aberrant growth. The gly- guidance of the glial fibers. Both of these coproteins laminin and fibronectin are growth migratory patterns are apparently accom- factors present in the extracellular matrix of plished with the aid of tropic molecular cues or both the developing PNS and CNS. The cone markers, which attract the migrating neuroblast responds to molecular cues (chemoaffinity) and or its growing tip. This establishes the basic guidepost cells, which trigger radical turns structural matrix of the brain and spinal cord. (even right angle) in the trajectory of an axon In addition, there are neurotrophic factors, and also define the location of branching sites which are chemical substances released by the for the development of collateral branches (see targets of neurons. Such factors trigger chemi- Fig. 6.4). It has been established that growth cal changes in the neurons that are critical for cones follow cues and markers that are encoded the survival, differentiation, and growth of neu- by the cells with which they are in direct con- rons. Nerve growth factor (NGF) is the proto- tact or that diffuse from target cells. However, typical target-derived neurotrophic factor the molecular nature of these cues remains elu- (family of proteins called neurotrophins) sive. (Chap. 2). Other putative neurotrophins have One of the primary goals of developmental been proposed. The view that there is a single neurobiology is to identify the chemical signals target-derived neurotrophic factor for each neu- involved with the accurate guidance of growing ron is being modified; more than one factor can axons as they establish the basic circuitry of the presumably influence the development and sur- nervous system. Directing axons to their mark vival of some neurons. In addition, some neu- during development is presently conceived to rotrophic factors can be derived from sources involve, in part, diffusible chemotropic (neu- other than the target. Once the immature neurotropic) factors secreted by cells along the ron arrives at its destination, the outgrowth of designated pathways and target cells. These its axon begins. The terminal tip of the elongat- factors apparently affect the biochemical and ing axon is the growth cone characterized by functional properties of the receptor sites on the presence of finger like projections (filopo- the axonal growth cones. This is an expression dia) or flattened extensions called lamellipodia of epigenesis, in which chemotropic factors (see Fig. 6.4). The growth cones act as mobile contribute to the patterns associated with axon 110 The Human Nervous System

Figure 6.4: (A) Growth cone. The growth cone is a specialized sensory motor structure at the growing terminal of an axon (neurite). (A) Each growth cone is a structure comprised of a central core domain (C) and a peripheral domain (P) from which extends the leading edge of fingerlike protuberances called filopodia at the base of which are weblike veils called lamellipodia; these are shaped by actin filaments (one of the protein filaments of the cytoskeleton). Neurotubules are abundant in the organelle-rich central domain and the actin filaments predominate as tight bundles in the filapodia and as dense interwoven networks in the lamellipodia. (B) Directional responses of cones mediated by diffusing guidance molecules from a distant producer site, expressed as attractive or repellent, are called (1) chemo-attractive (Ch-A) or (2) chemo-repellent (Ch-R) responses, Directional growth responses of the growth cones mediated by direct contact with membrane- bound guidance molecules, expressed as either attractive or repellent, are called (3) contact- dependent (Co-D) or (4) contact-repellent responses (Co-R). Chapter 6 Development and Growth of the Nervous System 111 pathfinding and axon fasciculation (Jessel and roof-plate grow ventrally to the region near the Sanes, 2000). floor-plate (see Fig. 6.5). Netrins possess com- Early differentiation of the nervous system missural outgrowth-promoting activity signals is regulated by a series of chemical inductive that cause the growing axons to decussate signals, some derived from mesoderm. The (cross over) as commissural axons to the con- mesodermal notochord conveys local signals tralateral side. The floor-plate apparently that induce the formation of the floor-plate of releases these factors even when the human the neural tube (see Fig. 6.2). In turn, the cells embryo is as young as 1 mo old. Thus, they of the floor-plate secrete diffusible proteins have a role in the act of designating the sites of (axon-guidance factors) called netrin-1 and the decussation of various fiber systems in the netrin-2, named for the Sanskrit word for “one spinal cord and brainstem. Examples include who guides” (Kennedy et al., 1994). The axons the spinothalamic fibers in the anterior white originating dorsally in the neural tube near the commissure (see Fig. 9.2) and the internal

Figure 6.5: (A) In the neural tube, the cell bodies of commissural interneurons are located dorsally. The growth cones of their axons migrate toward the ventral midline in response to cues from attractant guidance molecules of the midline floor-plate. (B) In the hindbrain, the cell bodies of the commissural axons of the trochlear (IV) cranial nerve are located ventral to the central canal near the floor-plate before crossing the midline (decussating) dorsal to the floor-plate (see Fig. 13.14). The growth cones of their axons nerve migrate dorsally toward the midline as a presumed response to the repellent cues of guidance molecules of the floor-plate. (C) The decussation of the growth cones of axons of interneurons or of ascending tract fibers (e.g., spinothalamic) results from the attractant axon-guidance factor netrin (circles) released by cells in the floor-plate. During the crossing of the floor-plate, the netrin receptors of the axon’s growth cones are suddenly silenced by a guidance molecule called “slit”(triangles) that activates the “slit” receptor of the growth cone. By the “hierarchical organization of guidance molecules,” the activated “slit” receptor silences the netrin receptor to the attractant response netrin, but not the growth- stimulatory response to the netrin receptor (see text). This growth cone is able to continue its growth, decussation, and pathfinding migration as a postdecussated ascending fiber in the growth-permissive microenvironment with its molecular guidance factors within the developing CNS. 112 The Human Nervous System arcuate fibers from the dorsal column nuclei this differentiation. In turn, the postsynaptic that decussate in the medulla to form the cell is modified by influences from the presy- medial lemniscus (see Fig. 10.3). naptic membrane, which regulates the number The glycoproteins, called neural cell adhe- and distribution of transmitter receptors and sion molecules (NCAMs), contribute to the other molecules of the postsynaptic membrane. general adhesive properties of neurons that are The interaction of the axon terminal (growth important as identity sites enabling one neuron cone) with the plasma membrane of a myotube to recognize another. An NCAM molecule on (immature striated muscle fiber) at a neuro- one neuron can bind to a counterpart NCAM muscular junction (motor end plate) illustrates molecule on another neuron during develop- the influence of the presynaptic terminal on the ment of specific populations of neurons. How- postsynaptic membrane. Prior to the arrival of ever, NCAM molecules might not have a role the motor nerve terminal, the acetylcholine in promoting axonal growth. Rather, NCAMs (ACh) receptors are uniformly distributed over are requisite for anchoring the growth cone to a the surface of a muscle fiber. Following the surface, but not for the directed migration and arrival of the future synaptic site, the axon ter- guidance. The axons and dendrites grow out in minal induces the accumulation of a new clus- a predetermined manner during normal devel- ter of ACh receptors on the muscle membrane opment, with axonal outgrowth preceding den- at the point of ACh release. Some receptors are dritic outgrowth. Axons utilizing growth cones redistributed as they diffuse within the mem- as sensors can be conceived as navigating brane and become immobilized in the cluster. through an epigenetic landscape that guides Others are synthesized anew and inserted their growth through reactions to a variety of within the cluster. Thus, the presynaptic ending chemical factors and physical substrates. controls the synthesis and distribution of In summary, there are presumed to be a vari- receptors on the postsynaptic membrane. A dif- ety of (1) outgrowth-promoting protein mole- fusible protein, called acetylcholine receptor- cules that stimulate the increase in numbers inducing activity (ARIA), has a role in this and lengths of axons—these include such transformation. Following the clustering of the chemotropic factors as laminin and nitrins— receptor sites at the motor end plate, the recep- and (2) outgrowth-suppressing molecules that tors outside of the vicinity of the end plate dis- have the opposite effect. These chemotropic appear. factors combine to influence the directed In summary, the precision of the molecu- migration and guidance of the growing axons larly guided navigation during these two stages to their targets. The NCAMs have an anchoring is coupled by giving rise to the basic neuronal role to bind the axon to a surface. connections specified by recognition mole- The goal of each axon is to make functional cules. Thus, the basic connectivity of complex synaptic connections with such targets as other circuitry of the nervous system is established in neurons (dendrites, cell bodies, and axons) and the sensory systems such as the posterior effectors (muscles and glands). Complex inter- column–medial lemniscal pathways (Chap. actions between the nerve terminal and the 10), the motor systems such as the corticobul- postsynaptic cell are critical for the initially bar and corticospinal pathways (Chap, 11), and immature synapse to become stabilized and other integrating circuits such as those associ- functionally effective. The growth cone ated with the basal ganglia (Chap. 24). These matures into the presynaptic nerve terminal by are presumed to have developed independently honing its capability to store and release trans- of activity or experience. mitter spontaneously into a mature terminal Oligodendrocytes develop relatively late, with a coordinated response to action poten- always after the growth of the axon in the CNS. tials. The postsynaptic cell requires some of This timing is essential because these glia cells Chapter 6 Development and Growth of the Nervous System 113 exert inhibitory influences on axonal growth through NMDA receptors on postsynaptic neu- and regeneration. This results from the action rons (Chap. 15). of membrane-bound inhibitors of mature oligodendrocytes and CNS myelin. DEVELOPMENT OF THE CEREBELLUM Activity-Dependent and Experience-Dependent Stage The development of the cerebellum presents This stage is involved with refining the a dramatic example of the migration of germi- coarser features of the circuitry by fine-tuning nal cells (neuroblasts and glioblasts) from two the patterns of connectivity of the pathway sys- sources navigating along different routes to tems through activity and experience. The finally mesh into the intricate circuitry that impetus to accomplish this is through activity characterizes the cortex and deep nuclei of the and by the experience gained by responding cerebellum (see Figs. 6.6 and 18.3). Only a and adjusting to both external and internal few aspects of these precisely timed and inte- environmental stimuli. Many of these connec- grated sequences will be outlined. tions continue to be capable of modification The two sources are (1) the ventricular zone throughout life. The activity-dependent and of the neural (cerebellar) plate and (2) the experience-dependent plasticity of the ocular rhombic lip of the dorsolateral lower pons. The dominance columns of the visual cortex is routes are (1) direct migration from the ventric- expressed in anatomical and physiological ular zone to the primordial cerebellum (cere- changes during the critical period that results in bellar plate) and (2) migration from the amblyopia (Chap. 19). Activity- and experi- rhombic lip to the outer surface (external gran- ence-induced changes in the nervous system ular layer) of the cerebellar plate. are phenomena responding to and associated The neuroblasts of the ventricular zone with the continuous honing of the skills in pro- migrate into the cerebellar plate to form two ficient athletes and musicians. Structural plas- strata: Neuroblasts of the deep stratum differ- ticity, axonal sprouting, and the changes in entiate into the neurons of the deep cerebellar number of dendritic spines can be enhanced (or nuclei (dentate, emboliform, globose and fasti- suppressed) in appropriate neurons through an gial nuclei), whereas those of the superficial increase (or decrease) in activity. Engaged stratum differentiate into the Purkinje cells and exposure to sensory stimulation (e.g., touch or Golgi cells (neurons of the cerebellar cortex). visual) during development can lead to signifi- Neuroblasts from the rhombic lip migrate over cant increases in the number of dendritic spines the surface of the cerebellar plate to form the and synapses in neocortical neurons of the pri- external granular layer. This layer gives rise to mary sensory areas (Chap. 25). Even the corti- the granule cells, basket cells, and stellate cells cal map of the primary sensory cortex can be (neurons of the cerebellar cortex). Glial cells modified by activity and experience (Chap. are derived from the same sites as the neurons. 25). The ability of axons to regenerate in the The results of these migrations from dual adult is an expression of the neuron’s retention sources to the right places and arrivals at the of an embryonic potential throughout life right times lead to the formation of the complex (Chap. 2). A physiological expression of motor integrated circuitry involving the neurons of learning and skills by the activity of inhibitory the cerebellum (see Fig. 6.6). synapses is noted in the “importance of inhibi- The Purkinje cells form their dendritic trees tion” (Chap. 3). Changes at the molecular level within the molecular layer. At the same time, that are associated with memory presumably the granule cells migrate from the external involve the second-messenger system and granular layer through the molecular layer to modulatory glutamate transmitters acting the granular layer (deep to the cell bodies of the 114 The Human Nervous System

Figure 6.6: The two routes (arrows) of neuroblast migration during histogenesis of the cerebellum.

Purkinje cells). These cells are guided (contact morphologic components and their functional guidance) along the processes of radial glial roles. As a concept, plasticity involves certain cells (Bergmann glial cells). Neurotrophic fac- changes occurring in both differentiating and tors and interactions among the differentiating mature neurons, synapses, and networks. Purkinje cells and granule cells contribute to Broadly defined, neural plasticity is the poten- the events within the molecular layer. Among tial of both the developing and mature nervous these are the formation and orientation of the system to change the neural phenotype based parallel fibers of the granule cells and the com- on altered patterns of circuits, connections, or plete differentiation of the dendritic trees of the activity. Plasticity is operative as a factor in the Purkinje cells, as well as the specific connec- ability of an organism to alter its behavior in tions of these neurons with each other and with response to novel stimuli from the internal and other neurons. To these can be added the external environments. sequence involving the differentiation, growth, Plasticity is reflected in a neuron’s ability to and synaptic connections of the Golgi cells, change (1) innately (genetic), (2) in response to stellate cells, and basket cells and of the climb- stimuli from the environment (epigenetic), and ing fibers and mossy fibers. (3) in response to influences from neurotrophic factors. These plasticities are variously specified as developmental, chemical, neurotrophic, NEURAL PLASTICITY neuronal, synaptic (strength), and others (regenerative, adaptive, short or long term, Neural plasticity is the expression of the experience-dependent, representational [e.g. capability of the nervous system to modify its body parts], and behaviorally induced). Chapter 6 Development and Growth of the Nervous System 115

Developmental Plasticity the conversion of these adrenergic neurons to Plasticity is active during ontogeny as neu- cholinergic ones. This illustrates that neurons roanatomical and neurophysiological changes are not irrevocably genetically programmed to as neurons integrate and mature as components produce one transmitter. Rather, the choice of of circuits, pathways, and processing com- transmitter synthesized and released by a neu- plexes (e.g., nuclei and cortices of the sensory ron can be acquired at a late developmental and motor systems). Plasticity continues stage and can be changed to another transmitter throughout life. For example, neural changes by a neuron’s environment (MacAllister et al., occur within the mature cerebral cortex, whose 1999). input and output pathways are dynamically The differentiation of neurons during devel- altered in response to a continuous stream of opment can be dependent on and influenced by inputs from sensory, behavioral, and experien- multiple neurotrophic factors. This applies to tial activities. Some plasticity is expressed as a neuroblasts, which presumably have an unre- means of enhancing and focusing the precision stricted progenitor potential. Such an embry- of a neuron’s output along with modifications onic neuroblast (stem cell) is present in the of the neural circuitry, including by pruning inner layer of the optic cup. Evidence indicates surplus collateral branches by microglial that such a specific neuroblast is prompted by phagocytosis. diffusible factors to differentiate into any of the cells of the adult retina, namely rods, cones, bipolar, horizontal, amacrine, retinal ganglion Chemical Plasticity neurons, and also glial (Muller’s) cells (Chap. The dynamics of the chemistry of the brain 19). Those developing cells that can differenti- has a role in plasticity. For example, the brain ate into only one mature neuronal type are is continuously turning over its biochemical called highly restricted progenitor cells. constituents that might be involved in coping with changing demands. Radioactive isotope Neuronal Plasticity studies reveal the rapidity of biochemical Neurons possess the capability of generating turnover. On the basis of half-life, free amino new branches (axonal and dendritic sprouting), acids in the brain are incorporated into proteins to form new synapses (synaptic replacement), within 30 minutes. Depending on the particular to modify synapses (synaptic change), and, chemical substance, the rate ranges from a “fast thereby, to modify neuronal circuits. These turnover” of a few hours to a “slow turnover” features of neuronal plasticity are lifelong measured in days. In the case of myelin, the expressions. The broad concept of learning and half-life of one of its constituents, lecithin, is memory, including a vast array of coordinated about 15 days. Proteins, considered to be rather learned movements (e.g., dexterous movements stable, also turn over to a significant degree. A exhibited in music, athletic, and ordinary activ- rat replaces about 25% of its brain protein ities), involve synaptic plasticity. These adapta- every 30 days, so that by 6 months, only about tions occur at all levels, including sensory 1–2% of the original protein remains. inputs, processing centers (nuclei), pathways, cortical areas, and motor outputs. Neurotrophic-Derived Plasticity During early development, prior to innervat- Synaptic Plasticity ing the sweat glands, postganglionic sym- Electrical synapses do not exhibit plasticity. pathetic neurons are adrenergic (release They are involved with the rapid and essentially norepinephrine). Following innervation of the stereotyped responses that are the hallmark of sweat glands by these postganglonic neurons, electrical transmission. Because these synapses an interaction occurs with target-derived (i.e., are not readily modified and changed in sweat gland) neurotrophic factor that triggers effectiveness, they maintain a stable functional 116 The Human Nervous System structure that continuously communicates bidi- strated that spines can form, collapse, and rectionally via ionic currents and gap-junctions reform and also change in size and shape rap- channels. idly in response to a diverse array of stimuli In contrast, chemical synapses (those releas- and thereby exhibit activated-dependent plas- ing neurotransmitters) exhibit both short-term ticity (Chap. 3). and long-term plasticity. They mediate both A generalization is emerging that the more excitatory and inhibitory activities and, in addi- recently phylogenetically evolved parts of the tion, can produce more subtle and complex brain, those concerned with higher neural func- behavioral activities than the stereotyped tioning, are more flexible or plastic than the older responses of electrical synapses. Because these parts of the brain. This plasticity is reflected in synapses can undergo short or lasting changes the ability of certain parts of the brain to reor- in effectiveness, chemical synapses have an ganize itself after damage and to recover func- order of plasticity that is significant in such tion. Stated in cellular terms, neurons in some manifestations as from how we move, perceive, newer parts of the brain are more capable of and feel to such phenomena as learning mem- extending new branches and forming new ory and other higher functions of the nervous synapses than neurons in other parts of the brain system (learning and memory applies to non- (Dowlng, 1993). The capacity for functional cognitive motor skills as well as to cognition). plasticity is maintained throughout old age. Synaptic plasticity is expressed as the The biological expression of each person’s “strengthening or weakening of synapses,” individuality is based on a distinctive genetic which can be of short or long duration. Short- constitution combined with unique epigenetic term or transient changes (e.g., minutes to modifications involving a degree of plasticity. hours) in the influx or accumulation of calcium ions within the presynaptic terminal can affect the amount of transmitter released. The free- INTRANEURONAL TRANSPORT calcium-ion concentration in the presynaptic OF SIGNALS terminal can be the basis for a number of mechanisms that convey plasticity to chemical Anterograde and retrograde transport con- synapses. Short-term memory is associated vey macromolecules, including trophic factors, with transient synaptic plasticity changes and that are involved in such roles as general main- long-term memory with permanent changes. tenance of the neuron, axonal growth during An emerging view of synaptic plasticity sug- development, axonal remodeling as an expres- gests that local neurotrophic action and synap- sion of plasticity, and regeneration of injured tically associated protein synthesis promotes neurons (Chap. 2). These transport systems are synaptic remodeling. Evidence indicates that essential for coordinating the complex func- the addition of synapses (increase in synapses tional interrelations between the cell body and per neuron) as well as changes in synaptic the entire axon and dendrites, especially structure occur during learning and memory. because macromolecules are synthesized in the cell body. Some macromolecules are thought to Synaptic Plasticity and Dendritic Spines convey signals (signal peptides); that is, they Several features make dendrites, especially act as messengers with roles in influencing var- those with spines, basic to an understanding of ious aspects of the neuronal processes. Newly learning and memory. These features are as fol- synthesized macromolecules by each neuron lows: (1) About 90% of all synapses are with are delivered from the cell body, via the antero- dendrites; (2) plasticity changes result in grade transport pathway in the axon, to sites strengthening or weakening the synapses; (3) where these proteins are utilized by the neuron spines are characterized as multifunctional throughout its life history, from early develop- integrative units; in vivo imaging has demon- ment through maturity. Chapter 6 Development and Growth of the Nervous System 117

Indications are that neurons utilize the retro- specially regulated by contact with axons. This grade transport pathway to convey signal pep- relationship is essential for the conduction of tides generated by events (e.g., axon injury) in the nerve impulse. The Schwann cells play a the axon to the cell body and nucleus of the critical role in several aspects of axonal regen- neuron. Means of conveying information from eration in the PNS. The ability of these cells to the sites of axonal growth, reorganization, and promote the regenerative efforts of the CNS injury are essential because axons have a lim- (Chap. 2) has stimulated interest in using ited capacity for synthesizing macromolecules. Schwann cells as autographs for CNS repair. Retrograde communication can influence The neuron through its axons exerts, through activity, for example, in the gene transcription chemical factors, influences that can (1) stimu- essential for supplying macromolecules late differentiation of Schwann cells, (2) induce required for axonal repair, regeneration, and and repress the proliferation of Schwann cells, plasticity, and even learning (Ambron et al., and (3) modify the migration and growth of 1995). This rapid retrograde transport is a sys- Schwann cells. By these means, the appropriate tem by which the needs of each axon are con- placement in functionally relevant numbers of tinuously communicated to the biosynthetic Schwann cells is reached during development, centers of the neuron. Another role of signals is maintenance and regeneration. to inform the cell body of the neuropeptide The relation of Schwann cells and axons is transmitter stores in the axon terminals and to not stereotypic, as demonstrated in several adjust the activity of the biosynthetic centers of variants form the typical nerve with each fiber the cell body to maintain adequate supplies of ensheathed by its own Schwann cells. In transmitters in the terminals (Chap. 3). unmyelinated fibers, the usual pattern of ensheathment is for the Schwann cell to harbor a number of nerve fibers within individual RECIPROCAL SCHWANN channels continuous with the Schwann cell sur- CELL–AXON INTERACTIONS face (see Fig. 2.8A). A variant occurs in the olfactory nerve, where clusters of groups of From the early stages of development fine fibers are enclosed in troughs communally through old age, reciprocal Schwann cell–axon within the Schwann cell (see Fig. 2.8B). interactions occur with profound effects by one Another is in the enteric plexus of the gut on the other. The vehicles for these activities (autonomic nervous system; Chap. 20, Fig. are signal molecules (information carriers) that 20.4), where enteric glia cells (equivalent of are (1) generated by Schwann cells to and act Schwann cells) ensheathe both the cell bodies on neurons or (2) generated by neurons and and their processes. their axons to act on Schwann cells. Among these signal molecules are neurotrophic factors involved with growth and survival. Neurons APOPTOSIS OR NATURALLY and Schwann cells are critically dependent on OCCURRING NEURONAL DEATH signaling mechanisms of immense and subtle complexity. Although less well documented, The life cycle of neurons consists of mitosis, significant glial cell–axon interactions are also differentiation, migration, maturation, and presumed to occur. death. During development, massive numbers The Schwann cells influence the differentia- of neurons are lost as a result of a process tion and growth of axons. Their released solu- called apoptosis (programmed cell death, phys- ble factors have roles in guiding the growing iological cell death [PCD]). Apoptosis is con- axon, promoting its maintenance, and ensuring served throughout evolution, occurring in such its survival. The ensheathment and myelination forms as nematode worms, with which impor- of both unmyelinated and myelinated axons are tant insights were derived. The purpose of 118 The Human Nervous System apoptosis is the removal of surplus or damaged rotrophin class (NGF, neurotrophin 3, neu- cells. It is essential for development and tissue rotrophin 4/5, brain-derived neurotrophic fac- homeostasis, and when dysregulated, it can tor); (2) interleukin 6 class (e.g., ciliary result in cancer, neurodegenerative disease, or neurotrophic factor); (3) transforming growth autoimmunity. factor α class (e.g., glial-derived neurotrophic growth factor); (4) fibroblast growth factor Control of Survival or Death of Neurons class; and (5) hepatocyte growth factor class. During ontogeny, at least half of all neurons Genes encode neurotrophic factors and their do not survive; they die via programmed cell receptors on target cells. death. The morphologic features of apoptosis Apoptosis is orchestrated and tightly regu- are cell shrinkage, condensation and clumping lated by interconnected biochemical pathways of nuclear (DNA) chromatin, cellular fragmen- involving protein factors that act either as tation into discrete granular masses, and phago- “death” activators or as “death” inhibitors. The cytosis of cellular remnants by macrophages. potential role of apoptosis during development This contrasts with necrotic cell death following includes the reorganization of neuronal traumatic injury in which there is early dilata- branches, including synaptic connections, in tion of the nucleus with scattering of chromatin addition to removal of unnecessary neurons. against the nuclear membrane, rapid hydrolysis Early cell death is a possible destiny for any of the cell membrane, and dilatation and frag- neuron, but this fate can be circumvented by menting of cytoplasmic organelles. avoiding apoptotic signals or by receiving The nervous system sculpts excess neurons appropriate survival signals from neu- in order to maintain a precisely regulated rotrophins. Apoptosis has been characterized homeostasis for the steady-state preservation of as a default pathway for all cells, and only by neuronal organization and optimal functioning receiving the appropriate survival signals can of the nervous system during development. neurons or glia escape. Genes encode several This neuronal suicide is accomplished by acti- components of the biochemical machinery of vating intrinsic biochemical and molecular apoptosis. This cell death in the mammalian mechanisms. Astrocytes, oligodendroglia, and nervous system is activated by intracellular and Schwann cells also undergo programmed cell extracellular apoptotic signals that control bio- death. Apoptosis is essential in eliminating chemical pathways involving families of superfluous neurons and injured neurons asso- caspaces. In the living cell, caspaces exist as ciated with disease-related deterioration or inactive proteolytic enzymes (zymogens), and neuronal damage resulting from toxic expo- when activated, they can cleave substrate pro- sure, low oxygen, or traumatic injury. The teins by a proteolytic program that mediates debris is removed by the macrophages that act apoptosis. as scavengers of the immune system’s cleanup Originally, neurotrophic factors were crew. This suggests that neurons are initially believed, as noted by their name, to promote overproduced and then are required to compete the survival of neurons by stimulating their for the just normal amount of available target- metabolism in beneficial ways. However, gene- derived neurotrophins. Consequently, some targeted studies have demonstrated that the neurons succumb by apoptosis. survival of neurons also is dependent on neu- The differentiation and survival of neurons rotrophins, which act to suppress an endoge- and glia require trophic support, which appears nous cell death program. This is accomplished to be dependent and promoted by the critical by a biochemical linkage between a neurotro- action of multiple protein neurotrophic factors phic factor that inhibits the signaling cascade produced by target cells. Nerve growth factor activating caspaces. Elimination of neu- (NGF), the first described, is one of many that rotrophins and their receptors leads to neuronal have been divided into several classes: (1) neu- death by loss of trophic support. Chapter 6 Development and Growth of the Nervous System 119

From Genes to Survival or Apoptotic Death resulting in apoptosis. Insufficient neu- Genes encode the neurotrophic factors and rotrophins allows for the dominance of the their receptors to initiate the molecular basis “death genes.” for trophic support by the neurotrophins. The In addition, neurotrophins fine-tune and regulate axon growth, dendritic pruning, and pat- genetically mediated neurotrophins are integral terning of the innervation with other neurons to the assemblies of neurons that are dependent and effectors (i.e., muscle cells) and the expres- on the cell-to-cell interactions and, more sion of proteins in normal neuronal function specifically, by the neuron-to-target-cell inter- (neurotransmitters, channels, neurotubules, and actions, for neuron survival during develop- others). In the mature nervous system, neuro- ment. As such, the neurotrophins are regulators trophins are thought to have some control over of development, maintenance, and function of synapse function and neuronal plasticity. Simul- the nervous system. The “survival genes” are taneously, they modulate neuronal survival. dependent on neurotrophins to protect neurons from apoptotic death by inhibiting the activa- Apoptosis in Neurodegenerative Diseases tion of the caspace-generated biochemical cas- Degeneration occurring in Alzheimer’s dis- cades. The “death genes” promote the ease, Huntington’s disease, and amyotrophic programs that activate the families of proteases lateral sclerosis might be associated with apop- called caspaces, which are central to the death tosis. These diseases have the following in cell role. Activation of caspace enzymes leads common: (1) There is a familial form with to the proteolytic activity of substrate proteins Mendelian inheritance patterns, (2) there is within the neuron, leading to apoptosis. selective degeneration of particular neuronal During ontogeny, by limiting the quantity of types, and (3) all are associated with cellular or neurotrophins to an appropriate amount, the extracellular degeneration aggregates. neurotrophin can function in a survival mode to ensure a match between the viable number of surviving neurons and the requirement for AGING OF THE BRAIN appropriate target innervation to meet the functional demands of the neuron. The number of neurons tends to decrease Some basic elements relevant to the caspace with age, for as neurons die, they are not biochemical pathways associated with activa- replaced by new neurons. The consequences of tion or inhibition of apoptosis are outlined. The a slight loss are not necessarily noticeable caspaces comprise over a dozen members because the remaining neurons can functionally (caspaces are derived from pro-caspaces). They compensate for a small decrease in numbers. cleave numerous types of protein, producing The brain is said to decrease gradually in many products essential to neuronal viability. A weight over the years, losing as much as 10% number of stimuli can trigger apoptosis by between the ages of 20 and 90 years. This is activating caspaces to act as the “executioners” presumably related to the loss and atrophy of of neuronal death apoptosis. Neurotrophins neurons and glia and to the decrease of extra- suppress endogenous death programs. The cellular spaces. The loss of cells varies from binding of neurotrophins to tyrosine kinase region to region, with the brainstem exhibiting receptors is considered to trigger the activation only a slight decline and the cerebral cortex of a biochemical pathway leading to the phos- undergoing the greatest loss. Some evidence phorylation of protein substrates that inhibit indicates that the decrease in weight and the caspace activity to thereby avoid apoptosis. degree of cortical atrophy in healthy old indi- Neurotrophin deprivation triggers caspace acti- viduals who have no neuropathological condi- vation and a fate by apoptosis. Possibly this tion in the brain is relatively slight. Within the deprivation permits cleavage of pro-caspace, cerebral cortex, the loss of neurons is greatest 120 The Human Nervous System in the neocortex of the frontal pole, precen- than the vertebral column. This is accompanied tral gyrus, cingulate gyrus, and primary visual by an elongation of the roots of the spinal cortex. nerves between the spinal cord and the inter- Neurons undergo senescence. Aging of neu- vertebral foramina. rons is evidenced by a change in size (either At birth, the caudal end of the spinal cord is decrease or increase), by the accumulation of located at the level of the L3 vertebra, and at pigment, or by a decrease in amount of Nissl adolescence, as in the adult, the caudal end is at substance. In humans, the quantity of ribonu- the level approximately between the L1 and L2 cleoproteins in the alpha motoneurons of the vertebrae. As a result of this disparity in spinal cord increases significantly from birth to growth, the lumbar, sacral, and coccygeal roots 40 years of age, plateaus from 40 to 60 years, become directed caudally at an acute angle to and decreases thereafter. In elderly people, the the spinal cord. The subarachnoid space below decrease in the weight of the brain, increase in the first lumbar vertebra in the adult is occu- the size of the ventricles, and calcification in pied by dorsal and ventral roots of spinal the meninges are all signs of an aging nervous nerves (cauda equina) and by the filum termi- system. nale, not by the spinal cord (see Fig. 7.1). An indication of the degree of the aging Adjacent to the neural tube are 31 pairs of process after the prime of life is obtained by somites. These are embryonic structures that comparing several parameters in the 30-year- differentiate into muscles, skeleton (including old age group with those in the 75-year-old the vertebral column), and connective tissues group. In the older group, the reduction in brain (see Figs. 6.1 and 6.2). The somites are seg- weight is about 10%; in the blood flow to the mental (metameric) structures arranged in brain, about 20%; in the number of nerve fibers sequence from the first cervical through the in large nerves, about one-third; in the number coccygeal levels. By segmental is meant a of taste buds, about two-thirds; and in the repeating unit of similar composition. velocity of nerve conduction, about 10%. The Each pair of nerves develops in association last correlates with the observation that the rate with each pair of somites. The apparent seg- and magnitude of reflex responses to stimula- mentation of the spinal cord is dependent on tion decrease with age. the development of the paired segmental spinal nerves. The bilateral neural crest also becomes segmented into paired units, one pair for every SPINAL CORD AND PERIPHERAL future sensory (dorsal root) ganglion of each NERVOUS SYSTEM spinal nerve.

Up to about the third fetal month, the spinal cord extends throughout the entire length of the BRAIN developing vertebral column. At this time, the dorsal (sensory) roots and the ventral (motor) Prenatal Development roots of the spinal nerves extend laterally at Early in the second fetal month, the “three- right angles from the spinal cord. The roots vesicle brain” differentiates into a “five-vesicle unite in the intervertebral foramina to form brain” (see Fig. 6.7). The prosencephalic vesi- spinal nerves. The roots and spinal nerves are cle is subdivided into the telencephalon, or products of outgrowths from the spinal cord endbrain, and the diencephalon, or between and neural crests (see Fig. 6.2). Because the (twixt) brain. The mesencephalic vesicle growth in length of the bony vertebral column remains as the midbrain; the rhombencephalic exceeds that of the spinal cord during fetal and vesicle is subdivided into the metencephalon, early postnatal life, the spinal cord after the or afterbrain, and the myelencephalon, or third fetal month becomes relatively shorter spinal brain. Chapter 6 Development and Growth of the Nervous System 121

Figure 6.7: Human brain (lateral view): (A) 3-week embryo; (B) 4-week embryo; (C) 5-week embryo; (D) 7-week embryo; (E) 11-week fetus. (Adapted from Corliss.)

The development of the “contorted” brain develops into the cerebellum. The differential from the tubelike structure is the result of the enlargement is most pronounced in the cerebral complex integration of several processes: (1) and cerebellar hemispheres. The telencephalon three bends known as flexures, (2) differential during development surrounds most of the enlargement of the different regions, (3) growth diencephalon; there is an intussusception (tele- of portions of the cerebral hemispheres over the scoping) of the diencephalon into the telen- diencephalon, midbrain, and cerebellum, and cephalon (see Figs. 6.7 to 6.9). (4) the formation of sulci and gyri in the cere- At the end of the third fetal month the main bral and cerebellar cortices (see Figs. 6.7 to outlines of the form of the brain are recogniza- 6.9). The flexures are the mesencephalic (mid- ble and the external surface of the cerebrum is brain) flexure (forming an acute angle on the still smooth. Fissuration commences in the anterior surface of the brain), the pontine flex- fourth fetal month with the appearance of the ure (forming an acute angle on the posterior lateral sulcus of the cerebrum and posterolat- surface), and the cervical flexure at the lower eral sulcus of the cerebellum separating the medulla (forming an acute angle on the anterior nodulus and attached flocculi from the vermis surface). The posterolateral margin of the of the posterior lobe (see Fig. 18.1). The central rhombencephalon is the rhombic lip, which sulcus, calcarine sulcus, and parietooccipital 122 The Human Nervous System sulcus are indicated by the fifth fetal month; all insula, and by the presence of all primary and of the main gyri and sulci of the cerebral cortex secondary sulci and a few tertiary sulci. The are present by the seventh fetal month. The occipital lobe overrides the cerebellum. During external structure of the cerebral hemisphere of the last month of fetal life, the frontal and tem- the 8-month fetus is characterized by the poral lobes are stubby, the insula is still prominence of the precentral and postcentral exposed to the surface, and the occipital poles gyri, by a wide-open lateral sulcus exposing the are blunt. The cortical gyri are broad and plump,

Figure 6.8: Human brain (lateral view): (A) 4-month fetus; (B) 6.month fetus; (C) 8-month fetus; (D) newborn infant. (Adapted from Corliss.) Chapter 6 Development and Growth of the Nervous System 123

Figure 6.9: Human brain (midsagittal view): (A) 3-month fetus; (B) 4-month fetus; (C) 8-month fetus; (D) newborn infant. and the fissures are shallow. The patterns of the sions are essentially similar to those of the primary and secondary sulci are simple. adult brain. The brain is firmer. The gray cortex The cerebrum of the full-term neonate is is demarcated from the subcortical white mat- more fully developed in the regions posterior to ter, which is now myelinated. The superficial the central sulcus than in the anterior regions. cortical blood vessels are predominately tucked The frontal pole and the temporal pole are rel- into the fissures and sulci. After the end of the atively short, and the insula is almost com- second year, the tertiary sulci dominate the pletely covered by the adjacent lobes. The topographic pattern of the cerebral surface. number of tertiary sulci is still small. The pia These sulci are variable from brain to brain and mater is not completely adherent to the brain thereby put the stamp of individuality on each and does not dip into all the sulci. The superfi- brain. Tertiary sulcation can continue through- cial blood vessels are straight. The brain has a out life. gelatinous consistency. The cortex is poorly demarcated from the white matter. By the end Postnatal Growth of infancy, at 2 years of age, the relative size The large brain in the newborn infant and proportions of the brain and its subdivi- exceeds 10% of the entire body weight; in the 124 The Human Nervous System adult, the brain constitutes only approximately (chromosomal abnormalities or mutant genes) 2% of the total body weight. The postnatal and environmental factors. growth of the brain is rapid, especially during the first 2 years after birth. The brain weighs Genetic Factors about 350 g in the full-term infant and about Many cases of congenital mental deficiency 1000 g at the end of the first year. The rate of and retardation are the result of trisomy of growth slows down after this, and by puberty, autosomes (three chromosomes instead of the the brain weighs about 1250 g in girls and 1375 usual pair). Down syndrome (mongolism) is a g in boys. It appears that the brain of a girl genetic condition in which there are three grows more rapidly than that of a boy up to the copies of chromosome 21. third year, but the brains of boys grow more Another genetic disease, phenylketonuria rapidly after that. This brain size is reflected in (PKU), is a clinical syndrome of marked men- the growth of the cranial skeleton. In contrast to tal retardation associated with irritability and the adult, the young child has a large cranium abnormal electroencephalogram (EEG) pat- in relation to the face. Head circumference is a terns. This condition is the result of an inher- measure of the growth of the brain. The head ited inborn error of phenylalanine metabolism circumference is 34 cm at birth, 46 cm at the (transmitted by an autosomal recessive gene) end of the first year, 48 cm at the end of the sec- that results in an excessive accumulation of the ond year, 52 cm at 10 years, and only slightly amino acid phenylalanine and its metabolites. larger at puberty and in the adult. The basic defect is a deficiency of the enzyme phenylalanine hydroxylase in the liver; it is essential for the conversion of phenylalanine to CRITICAL PERIODS: EFFECTS OF tyrosine. Treatment consists of placing PKU GENETIC AND ENVIRONMENTAL patients on a low-phenylalanine diet commenc- FACTORS ON DEVELOPMENT ing in the first year of life; it must be done at this time because the brain damage caused by Of all the malformations and congenital this condition is the result of the accumulation defects in human beings, ranging from minor of excess phenylalanine, which reaches its peak observable variations from the norm to lethal between the second and third years of life. abnormalities, as many as one-half are estimated to involve the nervous system. Although Nutrition the entire nervous system develops as an inte- Malnutrition and undernutrition during fetal grated organ system, its various parts and sub- life, infancy, and childhood have an effect on parts maturate at different rates and tempos. the developing nervous system. Certain nutri- During ontogeny, each structure passes through tional deficiencies, especially those occurring one or more critical period, during which it is at the critical early rapid period of maturation, sensitive to various influences. These periods can result in permanent damage. In humans, are generally times of rapid biochemical differ- the critical period extends from the second entiation. At such a period, the proper influ- trimester of pregnancy through most of the first ences have a significant role in advancing year after birth. During this interval, many neu- normal development. When normal influences rons and macroglia are being replicated and are wanting or when abnormal influences are much of the brain growth is taking place. Evi- exerted at these critical times, subsequent nor- dence indicates that under severe protein mal- mal development is often impaired. When the nutrition, the rates of proliferation of new impaired development results in anatomic neurons and glial cells are reduced. This reduc- abnormalities that are present at birth, they are tion occurs during fetal life because even the called congenital malformations. These abnor- fetus is not protected from maternal malnutri- malities are usually caused by genetic factors tion. The developing brain is vulnerable during Chapter 6 Development and Growth of the Nervous System 125 the remainder of this critical period of postna- physical and mental handicaps. Thus, these tal life; the formation of glial cells is impaired, poverty (nongenetic) conditions are perpetu- and myelination is inefficient. Severe malnutri- ated through their children—to be passed down tion during this period in human infants is from one generation to the next. known as marasmus. If the child is fed a nutritionally adequate diet after this period, the Hormones damage is not completely repaired, even The mental retardation associated with cre- though normal appearance can be achieved in tinism in humans is the result of a thyroid hor- some subjects. Those who appear to be healthy mone deficiency at a critical period during the have brains, that could be damaged by the pro- late stages of in utero development (estimated tein deficiency. The functional abnormalities in to begin at the seventh fetal month). The cere- children reared on nutritionally inadequate bral cortex of cretinoid individuals is poorly diets could consist of transient apathy, lethargy, developed. There is a reduction in the number or hyperirritability, together with a lesser intel- and size of neuronal cell bodies, as well as lectual development as measured by a decrease hypoplasia of both their axons and dendrites. of some 10–20% of mental capacity. Mental retardation of the cretinoid human child Prolonged protein deficiency in children can be prevented or effectively remedied if ade- from 1 to 2 years of age can result in kwashior- quate doses of thyroid hormones are given dur- kor. In this condition, the number of neurons is ing the first year of life. not reduced, because the deficiency occurs after the full complement of neurons is formed; Amblyopia (Lazy Eye) however, the complete differentiation and con- Amblyopia, or lazy eye, is a condition of nectivity of cortical cells could be impaired. If, reduced visual acuity caused by inadequate after being subjected to prolonged, severe mal- stimulation of the macula of one eye by formed nutrition, children with kwashiorkor are fed a objects between the second and fourth years of normal diet, their IQ test scores still remain age. It results in a defect in the image viewed below those of other children in the same pop- by the macula of the affected eye. The slightly ulation, including siblings who were not sub- cross-eyed child favors one eye over the other jected to severe malnutrition. to avoid seeing double (diplopia). In response The timing of nutritional deprivation is a to the altered balance of visual output from the critical factor in determining whether or not two eyes, long-lasting anatomical and physio- subsequent recovery from the effects of such logical changes occur in the ocular dominance deficiencies is possible. In contrast to brains of columns of the visual cortex (Chap. 19). An fetuses and young children, the brains of ado- inadequate input to the visual cortex from the lescents and adults are more resistant to perma- macula of the abnormal eye was insufficient nent effects of malnutrition. The young and during the critical period to nurture the matura- mature adult victims of starvation during World tion of the experience-dependent synaptic plas- War II did not show any loss of intelligence ticity in the ocular dominance columns. This after their nutritional rehabilitation. failure during the critical period results in a The effects of malnutrition assume gigantic permanent amblyopia. Ocular dominance plas- proportions in the world today. Roughly 60% ticity is one of the best examples of synaptic of the world’s preschool population (over 500 plasticity in the neocortex. million children) are exposed to varying degrees The concept of critical period during child- of undernutrition. These children live primarily hood is the basis for the suggestion that young in underdeveloped lands on diets low in pro- children should be exposed to rich visual expe- teins and calories. Malnutrition is contributory riences, even more than they can handle intelli- to the early death of many of them. Survivors gently. This should help to ensure the optimal grow up in poverty and become adults with maturation of the child’s visual pathways. 126 The Human Nervous System

Figure 6.10: Some anomalies that can occur in the lumbosacral region. (A) Spina bifida occulta results from the failure of the neural arches of the vertebrae to fuse dorsally. (B) Spina bifida with meningocele is a defect with a subarachnoid fluid-filled meningeal cyst bulging through unfused neural arches. The cyst is covered with skin. (C) Spina bifida with myelomeningocele is a defect with a meningeal cyst containing spinal cord and nerve roots. (D) Spina bifida with myeloschisis is a defect in which the neural plate (having failed to close) is exposed to the surface.

Spina Bifida skin. In a minor form, only the bony neural Spina bifida is one of the more common arches might be defective and functional defects that occur at spinal cord levels. The impairment is absent. term is used to cover a wide range of closure defects, usually located in the lower lumbar region (see Fig. 6.10). The most extreme ver- SUGGESTED READINGS sion occurs when the neural plate in the lumbar region remains as a plate exposed to the Ambron RT, Dulin MF, Zhang XP, Schmied R, Wal- ters ET. Axoplasm enriched in a protein mobi- outside. An infant with this defect has bladder lized by nerve injury induces memory-like and bowel incontinence, sensory loss, and alterations in Aplysia neurons. J. Neurosci. motor paralysis of the lower extremities. In 1995;15:3440–3446. less severe cases, the meninges or the Bagri A, Marin O, Plump AS, et al. Slit proteins meninges along with the spinal cord, though prevent midline crossing and determine the displaced backward, are still covered by the dorsoventral position of major axonal pathways Chapter 6 Development and Growth of the Nervous System 127

in the mammalian forebrain. Neuron 2002;33: Kozorovitskiy Y, Gould E. Adult neurogenesis: a 233–248. mechanism for brain repair? J. Clin. Exp. Neu- Barinaga M. Fetal neuron grafts pave the way ropsychol. 2003;25:721–732. for stem cell therapies. Science. 2000;287: Lyuksyutova AI, Lu CC, Milanesio N, King LA, 1421–1422. Guo N, Wang Y, Nathans J, Tessier-Lavigne M, Barry MF, Ziff EB. Receptor trafficking and the Zou Y. Anterior–posterior guidance of commis- plasticity of excitatory synapses. Curr. Opin. sural axons by Wnt-frizzled signaling. Science Neurobiol. 2002;12:279–286. 2003;302:1984–1988. Brose K, Tessier-Lavigne M. Slit proteins: key McAllister AK, Katz LC, Lo DC. Neurotrophins regulators of axon guidance, axonal branching, and synaptic plasticity. Annu. Rev. Neurosci. and cell migration. Curr. Opin. Neurobiol. 2000; 1999;22:295–318. 10:95–102. Mueller BK. Growth cone guidance: first steps Cohen-Cory S. The developing synapse: construc- towards a deeper understanding. Annu. Rev. Neu- tion and modulation of synaptic structures and rosci. 1999;22:351–388. circuits. Science 2002;298:770–776. Nguyen-Ba-Charvet KT, Picard-Riera N, et al. Dickson BJ. Molecular mechanisms of axon guid- Multiple roles for slits in the control of cell ance. Science 2002;298:1959-1964. migration in the rostral migratory stream. J. Neu- Dowling J. Neurons and Networks: An Introduction rosci. 2004;24:1497–1506. to Neuroscience. Cambridge, MA: Harvard Uni- Nijhawan D, Honarpour N, Wang X. Apoptosis in versity Press, 1993. neural development and disease. Annu. Rev. Neu- Edgerton V, Bigbee L, deLeon R. Plasticity of the rosci. 2000;23:73–87. spinal neural circuitry. Ann. Rev. Neurosci. 2004; Rakic P. Adult neurogenesis in mammals: an iden- 27:145–167. tity crisis. J. Neurosci. 2002;22:614-618. Gottlieb DI. Large-scale sources of neural stem Rakic P. Neurogenesis in adult primates. Prog. cells. Annu. Rev. Neurosci. 2002;25:381–407. Brain Res. 2002;138:3–14. Gould E, Gross CG. Neurogenesis in adult mam- Rubenstein JL, Shimamura K, Martinez S, Puelles mals: some progress and problems. J. Neurosci. L. Regionalization of the prosencephalic neural 2002;22:619–623. plate. Annu. Rev. Neurosci. 1998;21:445–477. Gould E, Reeves AJ, Graziano MS, Gross CG. Neu- Sanes DH, Reh TA, Harris WA. Development of the rogenesis in the neocortex of adult primates. Nervous System. San Diego, CA: Academic; 2000. Science 1999;286:548–552. Schnorrer F, Dickson BJ. Axon guidance: morpho- Gould E, Vail N, Wagers M, Gross CG. Adult- gens show the way. Curr. Biol. 2004;14:R19–R21. generated hippocampal and neocortical neurons Shirasaki R, Pfaff SL. Transcriptional codes and the in macaques have a transient existence. control of neuronal identity. Annu. Rev. Neurosci. Proc. Natl. Acad. Sci. USA 2001;98:10,910– 2002;25:251–281. 10,917. Stein E, Tessier-Lavigne M. Hierarchical organiza- Hatten ME. Central nervous system neuronal migration of guidance receptors: silencing of netrin tion. Annu. Rev. Neurosci. 1999;22:511–539. attraction by slit through a Robo/DCC receptor Hatten ME. New directions in neuronal migration. complex. Science 2001;291:1928-1938. Science 2002;297:1660-1663. Tessier-Lavigne M, Goodman CS. The molecular Holden C. Stem cell research. Cells find destiny biology of axon guidance. Science 1996; though merger. Science 2003;300:35. 274:1123–1133. Irvine KD, Rauskolb C. Boundaries in development: Weissman IL, Anderson DJ, Gage F. Stem and pro- formation and function. Annu. Rev. Cell Dev. genitor cells: origins, phenotypes, lineage com- Biol. 2001;17:189–214. mitments, and transdifferentiations. Annu. Rev. Jessell TM, Sanes JR. Development. The decade of Cell Dev. Biol. 2001;17:387–403. the developing brain. Curr. Opin. Neurobiol. Zhang XP, Ambron RT. Positive injury signals 2000;10:599–611. induce growth and prolong survival in Aplysia Jones EG. Cortical and subcortical contributions to neurons. J. Neurobiol. 2000;45:84–94. activity-dependent plasticity in primate somato- Zigova T, Sanberg PR, Sanchez-Ramos J, eds. sensory cortex. Annu. Rev. Neurosci. 2000; Neural Stem Cells: Methods and Protocols. 23:1–37. Totowa, NJ: Humana; 2002. 128 The Human Nervous System

Zigova T, Snyder E, Sanberg P, eds. Neural Stem Zou Y, Stoeckli E, Chen H, Tessier-Lavigne M. Cells for Brain and Spinal Cord Repair. Totowa, Squeezing axons out of the gray matter: a role for NJ: Humana; 2003. slit and semaphorin proteins from midline and ventral spinal cord. Cell. 2000;102:363–375. 7 The Spinal Cord

Anatomic Organization Spinal Roots and Peripheral Nerves Laminae of the Spinal Cord Pathways and Tracts

The spinal cord is a slender cylindrical dally to the sacral-5 vertebral level, where they structure less than 2 cm in diameter composed merge with the filum terminale to form the of gray and white matter that is located in the coccygeal ligament or filum of the dura. The upper two-thirds of the vertebral canal and is subarachnoid space, which is filled with cere- surrounded by the bony vertebral column. It is brospinal fluid (CSF) and blood vessels sur- the central processing and relay station (1) rounds the spinal cord and is called the spinal receiving input via peripheral nerves from the or lumbar cistern between the conus medullaris body and via descending tracts from the brain and the sacral-2 level (see Fig. 5.1). The roots and (2) projecting output via the peripheral of the lumbar and sacral spinal nerves “float” nerves to the body and via the ascending tracts within the CSF of this cistern. To avoid injury to the brain. to the spinal cord during removal of CSF, spinal taps into the cistern are made in the lower lumbar region. ANATOMIC ORGANIZATION The dura mater and the capillary-thin subdural space (not containing CSF) surround the The spinal cord extends from the foramen arachnoid and merge with the filum terminale magnum at the base of the skull to a cone- at the sacral-2 level. The spinal cord is sus- shaped termination, the conus medullaris, usu- pended by a series of 20–22 paired lateral septa ally located at the caudal level of the first of pia mater surrounding the cord extending lumbar centrum. The nonneural filum terminale laterally as flanges through the arachnoid to the continues caudally as a filament from the conus dura mater, called the denticulate ligaments. medullaris to its attachment in the coccyx (see The pointed attachment to the dura mater is Fig. 5.1). between two successive spinal nerves. The ligaments are oriented rostrocaudally in a frontal Meningeal Coverings plane between the dorsal and ventral roots. The spinal cord is surrounded by three men- Between the dura mater (equivalent to inner inges, which are continuous with those encap- dura mater surrounding the brain) and the sulating the brain (Chap. 5). All three meninges periosteum of the vertebral column (equivalent invest the nerve roots emerging from the spinal to outer dura mater surrounding the brain) is cord and are continuous with the connective the epidural space containing venous plexuses tissue sheath of the peripheral nerves. and fat. The epidural space caudal to the sacral- The vascular pia mater is intimately 2 level is the site for injection of anesthetics attached to the spinal cord and its roots. The used to modify sensory input (e.g., saddle dura and nonvascular arachnoid extends cau- block for painless childbirth).

129 130 The Human Nervous System

Blood Supply rostral. Because the spinal cord is much shorter The variably sized spinal arteries are than the bony vertebral column, the lumbar and branches of the vertebral, cervical, thoracic, sacral nerves develop long roots, which extend and lumbar arteries. Each artery passes through as the cauda equina (horse’s tail) within the an intervertebral foramen and divides into an spinal cistern (see Figs. 5.1 and 7.1). anterior and a posterior spinal root (radicular The cord is enlarged in those segments that arteries), which form an anastomotic plexus on innervate the upper extremities (called the cer- the surface of the spinal cord (see Fig. 12.2). vical [brachial] enlargement, which extends Venous drainage is via a venous plexus, and from C5 to T1 spinal levels) and in those seg- veins roughly parallel the arterial tree. The ments that innervate the lower extremities large spinovertebral venous plexus is continu- (called the lumbosacral enlargement, which ous rostrally with that surrounding the brain. extends from L1 to S2). Venous pressure within these veins and CSF Functional Components of Spinal Nerves pressure can become elevated when the outflow of venous blood into the systemic circula- Each spinal nerve contains nerve fibers clas- tion is impeded, as happens when the pressure sified into one of four functional components, in the thoracic and abdominal cavities namely (1) general somatic afferent, (2) gen- increases while one is lifting a heavy object or eral visceral afferent, (3) general somatic coughing. efferent, and (4) general visceral efferent. Com- ponents that are distributed throughout the body are designated general, whereas those that innervate the body wall and extremities are SPINAL ROOTS AND somatic and those that innervate the viscera are PERIPHERAL NERVES visceral. Furthermore, sensory fibers are afferent and motor fibers are efferent. The spinal cord receives input and projects output via nerve fibers in the spinal rootlets and Dorsal Roots roots, spinal nerves, and their branches (see The dorsal (sensory) roots consist of affer- Figs. 7.1 and 7.2). Nerve fibers emerge from ent fibers that convey input via spinal nerves the spinal cord in an uninterrupted series of from the sensory receptors in the body to the dorsal and ventral rootlets that join to form 31 spinal cord (see Fig. 7.2). The cell bodies of pairs of dorsal and ventral roots. In the vicinity these neurons are located in the dorsal root of each intervertebral foramen, a dorsal root ganglia within the intervertebral foramina. and a ventral root join to form a spinal nerve, which supplies the innervation of a segment of the body. In all, there are 8 pairs of cervical (C), Table 7.1 12 pairs of thoracic (T), 5 pairs of lumbar (L), Interspace 5 pairs of sacral (S), and 1 pair of coccygeal Spinal between (Co) roots and nerves (see Fig. 7.1 and Table Process vertebral 7.1). Cervical-1 and coccygeal-1 usually have of vertebra bodiesa Spinal Cord Segment only ventral roots. C1 C1–2 Spinal cord segments and their nerves are C6 C6 T1 named after their corresponding vertebrae. Cer- T10 T10 L1 vical nerves C1 to C7 are numbered for the ver- T12 T12 S1 tebra just caudal to the foramen through which T12–L1All sacral and coccygeal levels they pass. In humans, because there are only S2 or S3Caudal terminations of subarachnoid space seven cervical vertebrae, C8 and all other CoccyxTermination of filum terminale spinal nerves are numbered for the vertebra just a Named from centrum of vertebra above interspace. Chapter 7 The Spinal Cord 131

Figure 7.1: Topographic relations of the spinal cord segments, spinous processes, and bodies of the vertebrae, intervertebral foramina, and spinal nerves. Refer to Table 7.1. Spinal nerves from cord segments C1–C7 emerge from the spinal canal through the intervertebral foramen immediately above their corresponding vertebrae. Because there are only seven cervical vertebrae, fibers from C8 and all other segments emerge below the corresponding vertebrae. 132 The Human Nervous System

Figure 7.2: Neurons of a reflex arc of the somatic nervous system on the left, and a visceral reflex arc of the sympathetic nervous system on the right. The spinal somatic reflex arcs are described in Chapter 8, and the spinal visceral arcs are described in Chapter 20.

Despite the term, these ganglia contain no tion of afferent fibers by conduction velocity synapses. The fibers of the dorsal root of each recognizes groups I, II, III, and IV fibers spinal nerve supply the sensory innervation to a (Chap. 8). Furthermore, group I is subdivided skin segment known as a dermatome (see Fig. into group Ia, for nerve impulses from the pri- 7.3 and Table 7.2). There is usually no C1 or mary sensory endings of muscle spindles, and Co1 dermatome. Adjacent dermatomes over- group Ib, for impulses from Golgi tendon lap, so that the loss of one dorsal root results in organs (see Table 7.4). Group II fibers transmit diminished sensation, not a complete loss, in impulses from encapsulated skin and joint that dermatome (Chap. 9). receptors (e.g., Meissner’s and Pacinian cor- The general afferent fibers are classified into puscles), monitoring touch, pressure, tempera- (1) general somatic afferent (GSA) fibers, con- ture, and joint movements, and secondary veying information from sensors in the extrem- sensory endings of muscle spindles. Groups III ities and body wall, and (2) general visceral and IV fibers transmit impulses arising from afferent (GVA) fibers, conveying information unencapsulated endings, mediating pain, touch, from the viscera (e.g., circulatory system). and pressure. In all cases, fibers of greater A classification of sensory receptors and diameter have a higher conduction velocity their probable functional roles are presented in than thinner fibers, and myelinated fibers are Table 7.3. Further details concerning sensa- faster than unmyelinated ones. tions, functional significance, reflexes, and A second classification of fibers by conduc- pathways associated with these receptors are tion velocity into A, B, and C is also employed, discussed in subsequent chapters. A classifica- for both sensory and motor fibers. The A and B Chapter 7 The Spinal Cord 133 A B

Figure 7.3: Dermatomal (segmental) innervation of the skin. Refer to Table 7.2. The trigeminal nerve has three dermatomes: ophthalmic division (V1), maxillary division (V2), and mandibular division (V3). fibers are myelinated and the C fibers are Table 7.2 unmyelinated. The A fibers are further divided Dorsal by conduction velocity (hence, fiber size) into spinal root Body region innervated a alpha, beta, gamma, and delta (see Table 7.4). C2 Occiput Ventral Roots C4 Neck and upper shoulder T1 Upper thorax and inner side of arm The ventral (motor) roots consist of efferent T4 Nipple zone fibers that convey output from the spinal cord. T10 Umbilical girdle zone There are two functional components: (1) gen- L1 Inguinal region eral somatic efferent (GSE) fibers, which inner- L4 Great toe, lateral thigh, and medial leg vate voluntary striated muscles, and (2) general S3 Medial thigh visceral efferent (GVE) fibers, which convey S5 Perianal region influences to the involuntary smooth muscles, a Dermatome and region to which radicular parts is cardiac muscle, and glands (see Table 7.4). referred. 134 The Human Nervous System

Table 7.3: Classification of Sensory These fibers are axons of (1) alpha moto- Receptors (Probable Functional Roles) neurons (lower motoneurons; Chap. 11) that I. Receptors of general sensibility (exteroceptive) convey impulses to the motor end plates of vol- A. Endings in epidermis untary muscle fibers, (2) gamma motoneurons 1. Free nerve endings (tactile, pain, thermal that convey impulses to the motor endings of sense) intrafusal fibers of muscle spindles (Chap. 8), 2. Terminal disks of Merkel (tactile) and (3) preganglionic (lightly myelinated) 3. Nerve (peritrichial) endings in hair follicle autonomic neurons that synapse with postgan- (tactile, movement detector) glionic (unmyelinated) neurons (Chap. 20). B. Endings in connective tissues (skin and Gamma motoneurons are also known as connective tissue throughout body) fusimotor neurons (innervate the muscles of the 1. Free nerve endings (pain, thermal sense) fusiform-shaped spindles). 2. Encapsulated nerve endings The muscles innervated by motoneurons a. End bulbs of Ruffini (touch-pressure, position sense, kinesthesia) from a single spinal cord segment constitute a b. Corpuscles of Meissner (tactile, flutter myotome. Like dermatomes, there is myotomal sense) overlap. The spinal cord innervation of a few c. Corpuscles of Pacini (vibratory sense, muscles and regions is shown in Table 7.5. A touch-pressure) single alpha motoneuron together with the C. Endings in muscles, tendons, and joints muscle fibers it innervates constitutes a motor (proprioceptive) unit. Such units vary widely in the number of 1. Neuromuscular spindles (stretch muscle fibers they contain, ranging from units receptors) innervating 3 to 8 muscle fibers in the small 2. Golgi tendon organs, neurotendinous finely controlled extraocular muscles of the eye endings (tension receptors) or those in the larynx important for speech, to 3. End bulbs of Ruffini in joint capsule (touch-pressure, position sense, units containing as many as 2000 muscle fibers kinesthesia) in postural muscles (e.g., soleus in the leg). 4. Corpuscles of Pacini (touch-pressure, Individual muscle fibers are innervated by one vibratory sense, kinesthesia) motor end plate, referred to as a neuromuscular 5. Free nerve endings (pain) junction, usually located near the middle of the II. Receptors of special senses cell. The muscle fibers of a motor unit inter- A. Bipolar neurons, of olfactory mucosa mingle with those from other motor units. (olfaction) In general, there is a continuum of attributes B. Taste buds (gustatory sense) that form three functional types of muscle fiber, C. Rods and cones in retina (vision) namely (1) slow-twitch fibers, (2) fast-fatigable- D. Hair cells in spiral organ of Corti (audition) twitch fibers, and (3) fast-fatigue-resistant E. Hair cells in semicircular canals, saccule, and utricle (equilibrium, vestibular sense) twitch fibers. Each motor unit comprises only III. Special receptors in viscera (interoceptive) one type. The slow-twitch fibers are the signa- A. Pressoreceptors in carotid sinus and aortic tures of “red meat” muscles that have (1) a rich arch (monitor arterial pressure) extracellular matrix of blood capillaries, (2) B. Chemoreceptors in carotid and aortic bodies numerous mitochondria with high levels of and in or on surface of medulla (monitor oxidative enzymes, and (3) a large amount of arterial oxygen and carbon dioxide levels) myoglobin that helps absorb and store oxygen C. Chemoreceptors probably located in from the blood. These are slow-twitch fibers supraoptic nucleus of hypothalamus (monitor because the force they produce in response to osmolarity of blood) an action potential rises and falls relatively D. Free nerve endings in viscera (pain, fullness) slowly. Their fatigue resistance results from a E. Receptors in lungs (respiratory and cough reflexes) reliance on oxidation catabolism, whereby glucose and oxygen from the blood is available to Chapter 7 The Spinal Cord 135

Table 7.4: Classification of Nerve Fibers Conduction Fibers Diameters velocity (m/s) Role/receptors innervated Sensorya Ia (A-α) 12–20 70–120 Primary afferents of muscle spindle Ib (A-α) 12–20 70–120 Golgi tendon organ Touch and pressure receptors II (A-β) 5–14 30–70 Secondary afferents of muscle spindle Touch, pressure, and pacinian vibratory sense receptors III (A-δ) 2–7 12–30 Touch and pressure receptors Pain and temperature receptors IV (C) 0.5–1 0.5–2 Pain and temperature receptors Unmyelinated fibers Motorb Alplia (A-α) 12–20 15–120 Alpha motoneurons innervating extrafusal muscle fibers in laminaa Gamma (A-γ) 2–10 10–45 Gamma motoneurons innervating intrafusal muscle fibers in laminaa Preganglionic autonomic >3 3–15 Lightly myelinated preganglionic autonomic fibers (B) fibers Postganglionic autonomic 1 2 Unmyelinated postganglionic autonomic fibers fibers (C) a The fibers of I, II, and III are myelinated and those of IV are unmyelinated. The fibers of I and II are associated with mechanoreceptors and those of III with mechanoreceptors in hair skin. b Cell bodies of alpha and gamma motoneurons are located in lamina IX. c A lower motoneuron (lower motor neuron, alpha motoneuron, gamma motoneuron) is a motor neuron with its cell body in the CNS and an axon that innervates voluntary (striated, skeletal) muscle fibers.

regenerate ATP, which fuels the contractile high jumpers, requiring quick starts and short process. The two subtypes of fast-twitch fibers bursts of speed, could have up to 85% fast- comprise most of the “white meat” muscles, twitch fibers in certain muscles. Fibers of the characterized by a more rapid rise and fall of slow motor units contract and relax relatively their force response. They also tend to have a slowly and tend to fatigue less rapidly. World- different form of myosin that possesses cross- class long-distance runners, especially mara- bridges and produce force more effectively in thoners, could have up to 90% slow-twitch rapid shortening velocities. One subtype of the fast-fatigable-twitch fibers relies almost exclu- Table 7.5 sively on anaerobic catabolism and has rela- Ventral tively large stores of glycogen. This provides spinal root Muscles innervated energy to rapidly rephosphorylate ADP, as C5–6 Biceps brachii (flexes elbow) glycogen is converted to lactic acid. This C6–8 Triceps brachii (extends elbow) source is depleted fairly quickly and full recov- T1–8 Thoracic musculature ery could take hours. The second subtype of T6–12 Abdominal musculature fast-fatigue-resistant fibers combines relatively L2–4 Quadriceps femoris (knee jerk, fast-twitch dynamics and contractile velocity patellar tendon reflex) with enough capability to resist fatigue for L5–S1–2 Gastrocnemius (ankle jerk, minutes to hours. World-class sprinters and Achilles tendon reflex) 136 The Human Nervous System fibers in certain muscles. They display a great are oriented in the longitudinal plane parallel to capacity for running through fatigue. the neuraxis. The gray matter has been parceled anatomically, primarily on the basis of the microscopic appearance, into nuclei that con- LAMINAE OF THE SPINAL CORD form to a laminar pattern (Rexed’s laminae) (see Figs. 7.4, 7.5, and Table 7.6). The gray The spinal cord is divided into gray matter matter is also divided into a posterior horn (cell bodies, dendrites, axons, and glial cells) (laminae I–VI), an intermediate zone (lamina and white matter (myelinated and unmyeli- VII and X), and an anterior horn (laminae VIII nated axons and glial cells). The nerve fibers and IX). The white matter is divided into three within the gray matter are oriented in the trans- columns (funiculi): posterior, lateral, and ante- verse plane, whereas those of the white matter rior (see Fig. 7.5).

Figure 7.4: The sensory fibers of the dorsal root and the laminae of the spinal cord in which each type terminates. The heavily myelinated A alpha fibers from neuromuscular spindles and Golgi tendon organs terminate in laminae VI, VII, and IX (Chap. 8). The myelinated A beta fibers from cutaneous mechanoreceptors terminate in laminae III–VI (Chap. 10). The thinly myelinated and unmyelinated A delta and C fibers from nociceptors terminate in laminae I–V (Chap. 9). (Adapted from Brodal.) Chapter 7 The Spinal Cord 137

Figure 7.5: Section through a cervical level of the spinal cord to illustrate some subdivisions of the gray matter and white matter. The white matter is composed of three funiculi (columns). The gray matter is divided into two horns and an intermediate zone. Division of the gray matter into Rexed’s laminae is shown on the right.

PATHWAYS AND TRACTS Table 7.6 Lamina Corresponding nucleus Sensory signals originating in sensory I Posteromarginal nucleus receptors in the body and limbs are transmitted II Substantia gelatinosa through the spinal cord to the brain along sen- III and IV Proper sensory nucleus (nucleus sory pathways. Motor commands from the proprius) higher centers in the brain descend through the V Zone anterior to lamina IV spinal cord along motor pathways. Within the VI Zone at base of posterior horn white matter of the spinal cord, the sensory VII Zona intermedia (includes intermediomedial and fibers of the pathways form groups called intermediolateral nuclei, dorsal ascending tracts or fasciculi, and fibers of the nucleus of Clarke, and sacral motor pathways form groups referred to as autonomic nuclei) descending tracts (see Fig. 7.6). The functional VIII Zone in anterior horn (restricted to significance and location of these pathways medial aspect in cervical and form a basis of neurologic diagnosis. Lesions lumbosacral enlargements) within or impinging upon the nervous system IX Medial nuclear column and lateral often are revealed by alterations in sensory nuclear column 138 The Human Nervous System

Figure 7.6: The spinal cord tracts. The ascending tracts are represented as plain outlines on the right, the descending tracts as stippled outlines on the left, and the intrinsic spinal tracts (composed of descending and/or ascending fibers) as solid outlines. The representation of the tracts is arbi- trarily drawn. The lamination of the posterior columns and lateral spinothalamic tracts is indicated: C, cervical; T, thoracic; L, lumbar; S, sacral.

perceptions, balance, movement, or reflex (3) functional connect the various spinal lev- activity, and the site often can be pinpointed by els. The columns are called the spinospinal the examiner who has a thorough knowledge of fasciculi or fasciculi proprii of the spinal cord. these tracts and the associated roots of the The axons of these fasciculi are linked with spinal nerves. the spinoreticular tract, which goes to the Interposed between the afferent neurons of brainstem as the spinoreticulothalamic path- the dorsal roots and the efferent neurons of the way (Chap. 22). ventral roots within the gray matter of the Regional differences are present at various spinal cord are spinal interneurons that send levels of the spinal cord (see Fig. 7.7). The their axons (crossed and uncrossed) to higher amount of gray matter at any spinal level is and lower segmental levels for the execution primarily related to the richness of the periph- of various spinal intersegmental reflexes. eral innervation. Hence, the gray matter is These axons (1) ascend and descend to form largest in the spinal segments of the cervical columns in the white matter adjacent to the and lumbosacral enlargements innervating the gray matter (black band in Fig. 7.6), (2) orig- upper and lower extremities; such large struc- inate and terminate within the spinal cord, and tures require a massive innervation. The tho- Chapter 7 The Spinal Cord 139

Figure 7.7: Representative sections from several levels of the adult human spinal cord. (A) High cervical level; (B) cervical enlargement level; (C) midthoracic level; (D) low thoracic level; (E) lumbar level. All photographs of these Weigert-stained sections are at the same magnification. (Courtesy of Dr. Joyce Shriver, Mount Sinai School of Medicine.) racic and upper lumbar levels have relatively has fewer fibers. The difference occurs because small amounts of gray matter: They innervate (1) additional fibers of the ascending sensory the thoracic and abdominal regions. pathways join the white matter at each succes- The absolute number of nerve fibers in the sive higher level and (2) fibers of the descend- white matter increases at each successive ing motor pathways from the brain leave the higher spinal level. Stated otherwise, the white white matter before terminating in the gray matter of a spinal level caudal to another level matter at each successive level. 140 The Human Nervous System

Coggeshall RE. Law of separation of function of the SUGGESTED READINGS spinal roots. Physiol. Rev. 1980;60:716-755. Crock HV. Atlas of Vascular Anatomy of the Skeleton Abdel-Maguid TE, Bowsher D. 1984. Interneurons and Spinal Cord. London: Martin Dunitz; 1996. and proprioneurons in the adult human spinal Crock HV, Yoshizawa H. The Blood Supply of the grey matter and in the general somatic and vis- Vertebral Column and Spinal Cord in Man. New ceral afferent cranial nerve nuclei. J. Anat. York: Springer-Verlag; 1977. 139(Pt. 1):9-19. Crock HV, Yamagishi M, Crock MC. The Conus Bowsher D, Abdel-Maguid TE. Superficial dorsal Medullaris and Cauda Equina in Man: An Atlas horn of the adult human spinal cord. Neuro- of the Arteries and Veins. New York: Springer- surgery. 1984;15:893-899. Verlag; 1986. Boyd IA, Davey MR. Composition of Peripheral Hopkins WG, Brown MC. Development of Nerve Nerves. Edinburgh: Livingstone; 1968. Cells and Their Connections. New York: Cam- Brodal A. Neurological Anatomy in Relation to bridge University Press; 1984. Clinical Medicine, 3rd ed. New York: Oxford Landon DN. The Peripheral Nerve. New York: University Press; 1981. Wiley; 1976. Brown MC, Hopkins WG, Keynes RJ, Hopkins WG. Schiebel A. The organization of the spinal cord. In: Essentials of Neural Development. New York: Davidoff RA ed. Handbook of the Spinal Cord. Cambridge University Press; 1991. New York: Dekker; 1984: vol. 2. 8 Reflexes and Muscle Tone

Organization of the Somatic Motor (Efferent) System Spinal Reflex Arcs Muscle Spindles Stretch (Myotatic, Deep Tendon) Reflex Gamma Reflex Loop Golgi Tendon Organ and Reflex Loop Flexor Reflexes Muscle Tone (Tonus) Coactivation Integration of Spinal Reflexes: Role of Interneurons

The spinal cord contains the local neuronal body, selections are made by sensory receptors circuits that coordinate somatic reflexes. These within the skin, voluntary muscles, tendons, circuits are participants in the complex volun- and joints. From them, a continuous flow of tary movements of the body that are governed sensory messages is transmitted via spinal and by the higher centers of the brain. One expres- cranial sensory nerves to the spinal cord and sion of somatic motor function is the effortless brainstem for processing in order to achieve ease with which humans carry out the most response goals. These are realized by informa- dexterous of motor activities without a con- tion conveyed via alpha motoneurons to the scious awareness of joint movements and the extrafusal muscle fibers and via gamma accompanying muscle contractions synchro- motoneurons to the intrafusal muscle fibers nized with the required “relaxing” of antago- (see later). The alpha and gamma motoneurons, nistic muscles. The quality of sequential called lower motoneurons, comprise the final combinations of movements is dependent on common pathway that controls skeletal muscle the continuous flow of visual, somatosensory, activities expressed as reflex, postural, rhyth- and postural (vestibular and joint senses) infor- mic, and voluntary movements. mation that results in seemingly immediate The motor apparatus consists of a mechani- integrated responsive actions. Although we cal arrangement of muscles, bones, and joints might be consciously aware of making deci- organized as levers. Each movement at a joint sions regarding execution of the movements to involves the interplay between agonist muscles accomplish the goal, we are unaware of the and antagonist muscles (including accessory details that are instrumental in creating the muscles for adjustments). The agonist muscles motions, as they seem to take place automati- execute the prime movement and the antagonist cally. muscles counterbalance agonists. The antago- Somatic reflexes are the automatic stereo- nist muscles are involved in decelerating and typic motor responses by voluntary muscles to stabilizing the movement. The spinal reflex adequate sensory stimuli. From a vast array of responses, such as the withdrawal of the upper external and internal stimuli bombarding the limb when the finger contacts a hot stove, are

141 142 The Human Nervous System automatic reactions to stimuli involving a sim- reflex, Chap. 10). The conscious senses of ple, neural sequence of a receptor, sensory neu- position sense and kinesthesia are conveyed via rons, interneurons, lower motor neurons, and labeled lines of the dorsal column–medial lem- voluntary muscles. Posture is essential as a niscus system. The unconscious sense of pro- foundation for the performance of other move- prioception is conveyed via the spinocerebellar ments. This positioning and orientation of the tracts to the cerebellum (Chap. 10). body in space is sustained by the constant compensatory adjustments by the musculature in response to shifts in gravity. Rhythmic pat- ORGANIZATION OF THE SOMATIC terned motor movements such as walking, run- MOTOR (EFFERENT) SYSTEM ning, and chewing, once voluntarily initiated, continue to be executed automatically. They The somatic nervous system can be concep- combine voluntary and reflex activity. The vol- tualized as a complex integrated assemblage of untary movements initiated in the highest cen- neural circuits functioning to regulate the activ- ters in the brain utilize the above-stated ity of the voluntary muscles—those that prima- movements to express the goals of the skilled rily act through levers of bones and joints. It is volitional actions. These are learned, mastered, only by influencing muscles to contract (or to honed, and sustained by various amounts of relax) that the somatic nervous system can practice. Included are playing a musical instru- express itself. These influences are made mani- ment, using a word processor, driving a car, rid- fest through postures and movements. Postures ing a bicycle, and participating in such sports are the body poses from which each movement as golf, fly casting, and baseball. The proprio- begins and ends. Each posture is maintained ceptive receptors are the essential sensors and controlled through a series of reflexes and generating a continuous flow of critical infor- reactions that utilize continuously acting feed- mation that enables the central nervous system back circuits operating through several segmen- to activate the exquisite coordination of the tal levels of control. The flow of voluntary body musculature required for these reflexes muscle activity from one posture to another and movements. posture is a movement. In this context, posture Proprioception includes the information is the framework for a movement, whether sensed by low-threshold mechanoreceptors of crude, stereotyped, skilled, or volitional. the musculoskeletal system comprising mus- The motor systems within the central nerv- cles, tendons, joint capsules, and ligaments. ous system (CNS) are hierarchically organized Their activity results in sensing of the position into the (1) spinal cord, (2) brainstem, and (3) and movements of the limbs, head, jaws, and cerebral cortical levels. The spinal cord level is back. Its two submodalities are sense of sta- involved in automatic and stereotypic tionary position (position sense) and sense of responses to peripheral stimuli—known as movement (kinesthesia or kinesthetic sense). reflex responses. Reflex activity can be modu- The peripheral receptors signaling these senses lated from higher levels—that is, either include (1) neuromuscular spindles (stretch enhanced by excitatory influences or sup- receptors in muscle) and Golgi tendon organs pressed by inhibitory influences. The brain- (tension receptors in tendons), (2) mechanore- stem level includes the nuclei of origin and ceptors in joint capsules, and (3) some cuta- their descending motor pathways that project to neous mechanoreceptors (Chap. 10). The modulate the motor activity of the spinal cord information sensed by these somatic receptors reflex circuits (Chap. 11). Brainstem centers is integrated into spinal reflexes and muscle process neural signals from the cerebral cortex, tone involving the voluntary muscles. This also spinal cord, and cranial nerves (particularly the applies to these activities associated with vestibular nerve). They are integrated into the somatic cranial nerves and the brainstem (jaw motor systems projecting to the spinal cord, Chapter 8 Reflexes and Muscle Tone 143 which include the corticoreticulospinal path- mental reflexes. A segmental reflex comprises ways, corticorubrospinal pathway, vestibu- neurons associated with one or even a few lospinal pathways, corticotectospinal pathway, spinal segments. An intersegmental reflex con- and raphe–spinal and ceruleus–spinal projec- sists of neurons associated with several to tions. The cerebral cortical level comprises the many spinal segments. A suprasegmental reflex motor areas, from which, in addition to those involves neurons in the brain that influence the mentioned, originate the corticobulbar and the reflex activity in the spinal cord. corticospinal tracts (Chaps. 11 and 25). From Reflexes in which the sensory receptor is in this level, motor commands stimulate nuclei in the muscle spindle of any muscle group are the brainstem and spinal cord that activate known as myotatic, stretch,ordeep tendon skilled movements such as speech and writing. reflexes (DTR). These are intrasegmental The basal ganglia and cerebellum are major reflexes. Examples are (1) the biceps reflex— neural structures that participate in modulating tapping the biceps brachii tendon results in the activity of the motor systems. The basal flexion of the forearm at the elbow, (2) the tri- ganglia are specifically involved with move- ceps reflex—tapping the triceps tendon results ments formulated at the cortical level, includ- in extension of the forearm at the elbow, (3) the ing planning of synergies among the muscles quadriceps reflex (knee jerk—tapping of the during movements (Chap. 24). The basal gan- quadriceps tendon results in extension of the glia receive influences from all neocortical leg at the knee, and (4) the triceps sural reflex areas and, following processing, send their out- (ankle jerk)—tapping of the Achilles tendon put back to the motor and premotor cortical results in plantar flexion of the foot. areas. The cerebellum has a critical role in act- Reflexes in which the sensory receptor is the ing as a modulator during ongoing motor activ- Golgi tendon organ (GTO), located in a tendon ity in coordinating the sequence and strength of at its junction with a muscle, are known as muscular contractions (Chap. 18). Golgi tendon reflexes (see Fig. 8.1). A third kind of reflex, with sensory receptors variously located, is a flexor reflex (see SPINAL REFLEX ARCS Fig. 8.2). In this reflex, for example, the upper extremity withdraws from a noxious stimulus Reflex responses are mediated by neuronal such as a hot stove. The reflex comprises (1) linkages called reflex arcs or loops. The struc- sensory receptors, (2) afferent neurons, (3) ture of a spinal somatic reflex arc can be sum- spinal interneurons, (4) alpha motoneurons, marized in the following manner. (1) A sensory and (5) voluntary muscles. The flexor reflex is receptor responds to an environmental stimu- a protective reflex initiated by a diverse group lus. (2) An afferent fiber conveys signals of receptors in the skin, muscles, joints, and through the peripheral nerves to the gray mat- viscera and conveyed by A-delta and C pain ter of the spinal cord. (3a) In the simplest reflex fibers, as well as group III and IV fibers (called arc, the afferent root enters the spinal cord and flexor reflex afferents [FRA]s). Intense stimula- synapses directly with lower motoneurons tion can elevate the level of excitability within (monosynaptic reflex; see Fig. 8.1). (3b) In the spinal cord to a point at which a crossed more complex, and more common, reflex arcs, reflex is evoked, with such responses as leaning the afferent root synapses with interneurons, or jumping away from a stimulus (see Fig. 8.3). which, in turn, synapse with lower motoneurons (polysynaptic reflex; see Figs. 8.1 and 8.2). (4) A lower motoneuron transmits impulses MUSCLE SPINDLES to effectors—striated voluntary (skeletal) muscles. Spinal reflexes are also classified as (1) A muscle spindle (neuromuscular spindle) is segmental, (2) intersegmental, or (3) supraseg- a 3- to 4-mm-long spindle-shaped (fusiform) 144 The Human Nervous System receptor consisting of a capsule encasing 2–12 the intrafusal fibers is by gamma motoneurons modified striated muscle fibers known as intra- (fusimotor neurons) and the extrafusal fibers by fusal fibers (see Fig. 8.4). The spindles are ori- the alpha motoneurons. The sensory innerva- ented in parallel with the skeletal extrafusal tion of the intrafusal fibers is by group Ia fibers fibers, so designated because of their location and group II fibers. Alpha motoneurons and outside the spindles. Extrafusal fibers are the gamma motoneurons are also called lower voluntary muscles that perform the work of motoneurons. contraction. The capsule of the spindle is con- Three types of intrafusal fiber are located tinuous with the connective tissue between the within a muscle spindle: (1) dynamic nuclear extrafusal fibers and with the tendon of the bag fibers, (2) static nuclear bag fibers, and (3) muscle. nuclear chain fibers (see Fig. 8.4). Each fiber is Muscle spindles are sensory receptors that a specialized muscle fiber with a central region monitor the length and rate of change in length that is not contractile. Bag fibers are relatively of the extrafusal fibers and, thus, are called long and large, with each containing numerous stretch receptors. They have both a motor and a nuclei in a central enlargement or bag (hence, sensory innervation. The motor innervation of bag fibers). Chain fibers are thinner and

Figure 8.1: Three types of reflex loops are illustrated. (1) The myotatic reflex loop consists of a muscle spindle, Ia afferent neuron, alpha motoneuron, and voluntary muscle fiber. (2) The gamma reflex loop consists of the sequence gamma motoneuron, muscle spindle, Ia afferent neuron, alpha motoneuron, and voluntary muscle fiber. (3) The Golgi tendon organ loop consists of the sequence Golgi tendon organ, Ib afferent neuron, spinal interneuron, alpha motoneuron, and voluntary muscle fiber. Chapter 8 Reflexes and Muscle Tone 145

Figure 8.2: The flexor (withdrawal) reflex. This loop consists of the sequence skin receptor, afferent neuron, spinal interneuron, alpha motoneuron and voluntary muscle fiber. shorter, with each containing a row of nuclei in region of the bag fibers and the equatorial the central region resembling a chain (hence, region of the chain fibers. The secondary end- chain fibers). The nuclear bag fibers apparently ings terminate as a spray (flower-spray end- account for the dynamic sensitivity of the pri- ings) on either side of the primary endings on mary sensory endings, whereas the nuclear both types of fiber (see Fig. 8.2). Gamma chain fibers account for the static sensitivity motoneurons terminate on the bag and chain of both the primary and secondary sensory fibers as plate endings (motor end plates) and endings. trail endings. Plate endings terminate primarily The sensory endings are associated with the on the bag fibers and infrequently on the chain central regions of the intrafusal fibers and are fibers. Trail endings also terminate on both responsive to stretching of these muscle fibers. fiber types but primarily in the chain fibers. The gamma motor neurons innervate the con- Group Ia afferent nerve fibers innervate all tractile polar regions of the intrafusal fibers. three types of intrafusal muscle fiber where Contractions of intrafusal fibers tug at the cen- they form primary endings. They are the tral noncontractile central region from both largest-diameter fibers and, hence, the fastest ends and thus increase the sensitivity of the conducting in the peripheral nervous system. sensory endings to stretch. Group II afferent (small myelinated) nerve The spindles are innervated by two types of fibers innervate both chain and bag fibers to sensory ending: (1) primary or annulospiral form secondary endings. The gamma motoneu- endings derived from group Ia fibers and (2) rons and their axons enable the CNS to control secondary or flower-spray endings derived the sensitivity of the muscle spindles to length from group II fibers (see Fig. 8.4). The primary and changes in length. Two types of gamma endings terminate as spiral endings on the bag motor neuron innervate the three types of intra- 146 The Human Nervous System fusal fiber. (1) Dynamic gamma motoneurons fibers to the muscle spindle during constant and only innervate dynamic bag fibers. This type maintained muscle length. increases the dynamic sensitivity of the muscle Muscle spindles are specialized to sense spindle (gamma dynamic). This is important in muscle length and the velocity of change in reacting to external forces that upset body bal- muscle length. Thus, spindles are stretch-gated ance and ongoing movements. (2) Static receptors that respond to muscle stretch. In gamma motoneurons innervate combinations contrast, Golgi tendon organs (GTO) of a mus- of static bag fibers and chain fibers. The static cle tendon are tension-gated receptors that motoneurons act to increase the static sensitiv- respond to muscle tension (see Fig. 8.5). ity of the muscle spindle (gamma static). This Upon entering the spinal cord, the Ia affer- acts to increase the firing rate of the afferent ents in the dorsal root bifurcate. The main axon

Figure 8.3: Reciprocal innervation of the agonist and antagonist muscles in an ipsilateral reflex (left side) and in a contralateral crossed reflex (right side). Chapter 8 Reflexes and Muscle Tone 147

Figure 8.4: Nerve endings in a voluntary muscle and tendon associated with reflexes. The Golgi tendon organ (GTO) consists of afferent terminals intertwined among braided collagenous fibers. The intrafusal muscle fibers in the muscle spindle (enlarged section) are innervated by Ia and group II afferent fibers and by static and dynamic gamma motoneurons. The Ia fiber forms a spiral ending in the bag region of a nuclear bag fiber and in the midregion of a nuclear chain fiber. The group II fiber commences on either side of the primary endings of chain and static bag fibers. Gamma motoneurons terminate in the contractile polar regions of the intrafusal fibers. The static gamma motoneuron terminates as trail endings mainly on the chain fiber and occasionally on a bag fiber. The dynamic gamma motoneuron terminates as plate endings on a bag fiber. The alpha motoneuron terminates as a motor end plate on an extrafusal muscle fiber. The muscle spindle is a stretch- gated receptor (responds to muscle stretch) and the GTO is a tension-gated receptor (responds to muscle tension). 148 The Human Nervous System

Figure 8.5: Golgi tendon organ (GTO, neurotendinous spindle). The GTO is an encapsulated spindle-shaped sensory receptor at the junction of a bundle of muscle fibers and collagenous fibers of a tendon. It is innervated by 1b afferent nerve fibers. Three-dimensional representation of the relationship of a spiraling nerve ending of a 1b afferent fiber among the collagenous fiber bundles of the tendon. The GTO monitors the degree of tensile forces exerted by the collagenous fiber bundles on the nerve ending when “compressed” by the forces exerted by the contracting muscle fibers. The GTO is similar to one’s finger within a braided “Chinese finger wrap”; the more the pull exerted on the wrap (tension from muscle contraction), the straighter the strands of collagenous fibers of the wrap and the greater the squeeze on the finger (GTO). Chapter 8 Reflexes and Muscle Tone 149 ascends toward the brainstem; a collateral of alpha motoneurons, which, in turn, stimulate each Ia sensory neuron has direct monosynap- the quadriceps muscle to contract, and (2) tic connections with alpha motoneurons within through interneurons inhibit the alpha the spinal cord (see Fig. 8.1). Group Ia fibers motoneurons innervating the antagonistic ham- from the primary endings of spindles can string muscles. Thus, the leg extends at the synapse monosynaptically with alpha moto- knee joint as the quadriceps suddenly contracts neurons that innervate the same muscle (called and the hamstrings relax. The brisk knee jerk is a homonymous muscle) or with alpha motoneu- initiated by the sudden synchronous stretch of rons that innervate a synergist. The Ia afferents many quadriceps muscle spindles. In contrast, also can terminate on interneurons, which form the slow continuous contractions maintaining inhibitory synapses with alpha motoneurons to postural muscle tonus are sustained by asyn- an antagonist (called, a heteronymous muscle). chronous stretch and discharge of many spin- Group II afferent fibers have direct monosy- dles over a period of time. naptic connections with alpha motoneurons innervating homonymous muscles. Some gamma motoneurons, called dynamic gamma GAMMA REFLEX LOOP motoneurons, are thought to terminate only on bag fibers as plate endings. They are named for The myotatic reflex acts in the coarse adjust- their involvement in phasic (motion) reflexes. ments of muscle tension; the fine adjustments in The other gamma motoneurons, called static muscle activity are dependent on the integrity of gamma motoneurons, terminate on bag and the gamma reflex loop. Influences from the chain fibers as trail endings. These neurons are brain (supraspinal influences) and some periph- important in tonic (i.e., static or postural) eral receptors regulate the “set” of the muscle reflexes. spindles through gamma motoneurons. Much of the information from muscle spin- The gamma loop (see Fig. 8.1) comprises dles is conveyed via ascending tracts for pro- (1) the efferent gamma motoneuron, (2) the cessing in the brain, especially in the muscle spindle within the voluntary muscle, cerebellum and cerebral cortex (“Sensory (3) the group Ia afferent neuron for feedback, Areas of the Neocortex”; Chap. 25). (4) the alpha motoneuron, and (5) voluntary muscle fibers. The signals conveyed by the gamma motoneuron alter the sensitivity of the STRETCH (MYOTATIC, DEEP muscle spindle by altering the length of the TENDON) REFLEX intrafusal fibers and the tension they exert. As gamma motoneuron activity increases, the set Stretch reflexes have an essential role in the of the muscle spindles is raised to a higher maintenance of muscle tone and posture. The level. This increases the firing rate of the Ia simple knee jerk is a stretch (extensor) reflex fibers, stimulating the alpha motoneurons. initiated by tapping the tendon of the relaxed Many of the descending supraspinal influences quadriceps femoris muscle. Stretch reflexes are from the brain do not act directly on alpha two-neuron (involving the sequences of an motoneurons, but, rather, through the gamma afferent neuron and an efferent alpha motoneu- reflex loop. ron), monosynaptic, ipsilateral (reflex restricted The static gamma neurons are involved pref- to the same side of the body), and intrasegmen- erentially with tonic reflexes (muscle tone). tal. A tap on its tendon stretches the quadriceps The rigidity associated with increased tonic muscle and many of the neuromuscular spin- stretch reflexes (as in Parkinson’s disease) dles. When stretched, the spindles stimulate the might be the result of heightened activity of the group Ia afferent fibers to convey volleys of static gamma neurons. The dynamic gamma impulses that (1) monosynaptically excite the neurons are involved with the phasic stretch 150 The Human Nervous System reflexes (i.e., contraction of muscles for move- and the inhibitory GTO reflex loop is basic to ment). The spastic signs expressed in upper the precise integration of reflex activity. The motoneuron paralysis (Chap. 12) might be the GTO reflex loop acts to prevent the overcon- result primarily of increased activity of the traction of an agonist muscle and to facilitate dynamic gamma neurons. In effect, the gamma the contraction of antagonist muscles through system is critical for continuous fine muscle reciprocal inhibition. control. It enables the spindle to maintain a delicate sensibility over a wide range of muscle lengths that are constantly occurring during FLEXOR REFLEXES reflex and voluntary contractions. Flexor reflexes are associated with (1) such behavioral responses as protection against a GOLGI TENDON ORGAN potentially harmful noxious stimuli and (2) AND REFLEX LOOP such locomotor activities as walking and running. These reflexes are initiated by pain recep- Golgi tendon organs (neurotendinous tors (nociceptors) in the skin (cutaneous), spindles) are encapsulated mechanoreceptors fasciae, and joints, as well as by touch, pres- located at the junctions of muscles with ten- sure, and other receptors (see Fig. 8.2). dons (see Figs. 8.1 and 8.4). Within the capsule of the GTO are endings of Ib afferent Withdrawal, Protective, and nerve fibers intertwined among collagenous Escape Responses fibers of the tendon (see Fig. 8.5). The short- The flexor reflex is fundamentally a with- ening of the muscle during contraction tight- drawal response from a noxious stimulus. ens the braided collagenous fibers, which, by Depending on the seriousness of a potential squeezing the nerve endings, generate action threat of this type, an individual reacts with potentials. In general, the GTOs in a tendon protective and even escape responses. Cuta- respond to varying degrees of muscle tension. neous receptors in skin and deep receptors in Specifically, the GTOs within each tendon muscles and joints react to intense touch pres- respond differentially because each GTO is sure, heat, cold, and tissue trauma, along with linked through collagenous fibers to a different the associated pain. These stimuli are conveyed number of muscle fibers and to different types via group II, III and IV (FRA) fibers to of motor unit. Thus, different degrees of interneurons in the CNS. The effect of these “squeezing” exerted within a GTO on the Ib inputs is a flexion response through (1) excita- ending contribute to the subtlety of the neural tion of the alpha motoneurons to the flexor influences conveyed from a variety of GTOs to muscles, and (2) inhibition of the alpha moto- the spinal cord. neurons to the antagonistic extensor muscles. This polysynaptic loop comprises (1) the The high intensity of the stimuli results in the Golgi tendon organ (GTO) in muscle tendons, spread of the activity via commissural neurons (2) group Ib afferent fibers, (3) interneurons and intersegmental circuits to the contralateral within the spinal cord, (4) alpha motoneurons, side to evoke crossed extensor reflexes (see and (5) striated muscle fibers. As the tension Fig. 8.3) with the synchronous excitation of the within the tendon of a contracting muscle extensor lower motoneurons and the inhibition increases, there is an increase in the number of of the flexor lower motoneurons of the con- action potentials transmitted via the Ib afferent tralateral limb. This occurs as, for example, in neurons to an interneuron pool in the spinal the act of withdrawing an upper limb following cord. These influences tend to inhibit the activ- touching a hot object accompanied by shifting ity of the alpha motoneurons. The exquisite the weight to the contralateral lower limb to balance between the excitatory gamma loop support the body. Chapter 8 Reflexes and Muscle Tone 151

Locomotion opening the blade of a jack knife). Rigidity is In this activity, the brain contributes by expressed as increased tone (hypertonia) in all influencing the integrated rhythms of the muscles, although strength and reflexes are not reflexes of flexion and extension of the upper affected. The rigidity can be uniform through- and lower limbs. The FRAs contribute through out the range of movement imposed by the multineuronal reflex circuits to inhibit the examiner (called plastic or lead pipe rigidity) or extensor motoneurons and to simultaneously it can be interrupted by a series of jerks (called excite the flexor motoneurons of the lower cog-wheel rigidity as in Parkinson’s disease). limb, and to excite the extensor motoneurons and to inhibit the flexor motoneurons of the contralateral limb (see Fig. 8.3). Through COACTIVATION spinal intersegmental circuits, the rhythmic activity of the lower limbs is integrated with the Neural influences from the brain via the rhythmic activities of the upper limbs, as is descending motor pathways to the brainstem characteristic in walking and running. and spinal cord circuits elicit the simultaneous discharge of both alpha and gamma motoneurons of a particular muscle (Chap. 3). This is MUSCLE TONE (TONUS) known as coactivation of these lower motoneurons. Coactivation is essential in the perform- Muscle tone is the minimal degree of con- ance of smooth coordinated muscular activity traction exhibited by a muscle without con- and in sustaining a voluntary contraction. Vol- scious effort; it exists even when a muscle is “at untary activities, ranging from the exquisite rest.” When an examiner manipulates an movements of a figure skater on ice to the lift- extremity (e.g., flexion and extension) of a ing and holding of a heavy object, are largely relaxed normal individual, the muscle tone is dependent on the coordinated contractions of the amount of resistance that is not related to muscle fibers. any conscious effort by the patient. Abnormal- The following is the sequence of events in ities of muscle tone are expressed as hypotonia coactivation. Stimulation of alpha motoneurons (decreased resistance to passive movement) results in the contraction of a muscle with an and hypertonia (increased resistance to passive accompanying shortening of its muscle spin- movement; Chap. 11). dles. This brings about a reduction in the firing Hypotonus is not an expression of the iso- rate of the Ia afferents and of the excitatory lated muscle so much as an expression of reflex influences to the alpha motoneurons. This activity upon the muscle. Hypotonia can be reduction is offset by the stimulation (coactiva- produced (1) by severing the ventral roots con- tion) of gamma motoneurons innervating the taining the motor fibers to a muscle or (2) by intrafusal fibers of the muscle spindles. By severing the dorsal roots containing the sensory stimulating the intrafusal fibers, these neurons fibers from a muscle. Lesions of the cerebellum maintain the appropriate firing rate of the Ia can also result in hypotonia. afferent fibers, which excite the alpha moto- Hypertonia is expressed in two forms: spas- neurons innervating the extrafusal muscle fibers. ticity and rigidity. Spasticity combines an The alpha and gamma motoneurons inner- increase in resistance to passive manipulation vating a specific muscle or muscle group are with the “clasp knife” phenomenon along with simultaneously stimulated by neurons receiving an increase in deep tendon reflexes (hyper- their influences from segmental and interseg- reflexia). The “clasp knife” phenomenon is so mental circuits and from upper motoneurons named because there is a marked increase in originating in the brain. resistance during the initial phases of action, As compared to alpha motoneurons, gamma but suddenly the resistance disappears (as when motoneurons (1) only innervate intrafusal 152 The Human Nervous System muscle fibers, (2) have smaller cell bodies and such integrated rhythmic movements of the thinner myelinated fibers, (3) are not excited upper and lower extremities as walking and monosynaptically by afferent fibers from running. However, interneuronal circuits are peripheral receptors, (4) are not integrated into crucial in all movements. For example, in a the inhibitory Renshaw cell feedback circuit, smooth flexion movement, the flexor (agonist) and (5) tend to discharge spontaneously. The muscle group contracts while the extensor gamma motoneurons are influenced through (antagonist) muscle group relaxes for this type the descending tracts by the activity of the cere- of action; reciprocal inhibition and feedback bellum (Chap. 18), reticular system (Chap. 22), inhibition are required. In reciprocal inhibition, and basal ganglia (Chap. 24). by means of interneurons the lower motoneurons innervating the agonist muscles are excited while those innervating the antagonist INTEGRATION OF THE SPINAL muscles are inhibited. In feedback inhibition, REFLEXES: ROLE OF INTERNEURONS the interneurons selectively inhibit the lower motoneurons so that each agonist group con- Somatic movements are the motor expres- tributes by contracting to the proper degree to sions of the integrated activity of the supraspinal perform the movement. pathways from the brain (Chap. 11) and many Commissural interneurons relay influences reflex loops; all are realized through the lower from one side across the midline to the gray motoneurons. The placement of interneurons matter of the contralateral side. These are within most of these reflex loops adds to the important in crossed extensor reflexes (see Fig. complexity and versatility of the motor control. 8.3). The extremity opposite to that in which The descending motor supraspinal pathways the FRA fibers are stimulated responds in the from the brain influence either (1) indirectly by reverse fashion; that is, the extensor muscles synapsing with interneurons integrated into contract and the flexor muscles relax. This spinal neural circuits or (2) directly by synaps- crossed (extensor) reflex utilizes the commis- ing with the lower motoneurons. The alpha sural neurons to relay neural information to the motoneurons are stimulated primarily through opposite side. A painful stimulus to the foot indirect supraspinal connections. Some fibers (stepping on a tack) evokes a reflex flexor with- of the corticospinal tract, lateral vestibulospinal drawal of the ipsilateral extremity and espe- tract, reticulospinal tracts, and raphe–spinal cially an enhancement of extensor musculature tract make monosynaptic connections with the contractions of the contralateral extremity to alpha motor neurons. These alpha motoneurons enable the contralateral extended limb to sup- contribute to the intrinsic spinal circuitry port the body while the flexed ipsilateral through collateral branches that excite inter- extremity is off the ground. The interplay of neurons called Renshaw cells (see Fig. 3.11). these crossed reflexes is utilized in the alternate In turn, the excited glycinergic Renshaw cells rhythms of both upper and lower extremities are intercalated in a negative feedback circuit during running and walking. that directly inhibits the same alpha motoneu- The afferent neurons innervating the sensory ron. This tends to turn off the firing activity of receptors are integrated into the spinal reflexes the alpha motoneuron so that it will be ready to for feedback purposes. In addition to their role respond to firing again in response to excitatory as monitors of new and naive information, the stimulation. Intersegmental interneurons con- receptors sense the effects of motor activity and vey influences from one spinal segment via feed this information back to the CNS. Through axons to one or more other spinal segments on this input, the circuitry within the CNS is con- the same side of the spinal cord. These neurons tinuously informed of its effects on muscular are connected with commissural interneurons activity. In this role, these neurons are known (see next paragraph) and together they act in as feedback (reafferent or re-entry) neurons. Chapter 8 Reflexes and Muscle Tone 153

The receptors at work in this feedback schema Jewett DL, Rayner MD. Basic Concepts of Neuronal are known as direct receptors and indirect Function: A Multilevel Self-Teaching Textbook. receptors. Direct receptors (the muscle spin- Boston: Little, Brown; 1984. dles) are directly innervated by gamma moto- Matthews PB. What are the afferents of origin of the neurons from the CNS and, thus, are integrated human stretch reflex, and is it a purely spinal reaction? Prog. Brain Res. 1986;64:55–66. into direct feedback circuits. Indirect receptors, Matthews PB. Proprioceptors and their contribution such as the GTO, joint, and cutaneous recep- to somatosensory mapping: complex messages tors, do not have a direct efferent innervation require complex processing. Can. J. Physiol. from the CNS and, thus, are integrated into so- Pharmacol. 1988;66:430–438. called indirect feedback circuits. Matthews PB. The human stretch reflex and the motor cortex. Trends. Neurosci. 1991;14:87–91. Matthews PB. Spindle and motoneuronal contribu- SUGGESTED READINGS tions to the phase advance of the human stretch reflex and the reduction of tremor. J. Physiol. Brooks VB. The Neural Basis of Motor Control. 1997;498(Pt. 1):249–275. New York: Oxford University Press; 1986. Phillips CG. Motor apparatus of the baboon’s Desmedt J. Motor Control Mechanisms in Health hand. Proc. R. Soc. Lond. B. Biol. Sci. 1969;173: and Disease. New York: Raven Press; 1983. 141–174. Freund HJ. Motor unit and muscle activity in Phillips CG. Central control of movement. How can voluntary motor control. Physiol. Rev. 1983;63: one discover the relative functional roles of 387–436. pyramidal inputs to alpha as compared to gamma Freund HJ. Functional organization of the human motoneurons? Neurosci. Res. Program Bull. supplementary motor area and dorsolateral pre- 1971;9:135–139. motor cortex. Adv. Neurol. 1996;70:263–269. Phillips CG. Proceedings: Hughlings Jackson Lec- Freund HJ. Mechanisms of voluntary movements. ture. Cortical localization and “sensori motor Parkinsonism Relat. Disord. 2002;9:55–59. processes” at the “middle level” in primates. Gandevia SC, Refshauge KM, Collins DF. Proprio- Proc. R. Soc. Med. 1973;66:987–1002. ception: peripheral inputs and perceptual interac- Sherrington CS. The Integrative Action of the Ner- tions. Adv. Exp. Med. Biol. 2002;508:61–68. vous System. Originally published: New York: Hasan Z. Role of proprioceptors in neural control. Scribner’s, 1906. London: Routledge/Thoemmes; Curr. Opin. Neurobiol. 1992;2:824–829. 2002. 9 Pain and Temperature

Features of Sensory Systems Receptors Afferent (First-Order) Neurons Pathways From the Body, Limbs, and Back of Head Major Classes of Functionally Defined Neurons and the Spinothalamic Tracts Wall’s Concept of Pain in Target Motor Responses Pathways From the Anterior Head Temperature (Thermal) Sense Perception of Pain The Gate Control Theory of Pain Modulation Descending Control Mechanisms of Pain Modulation Endogenous Pain Control Referred (Transferred) Pain Stimulus-Induced and Stressed-Induced Analgesia Central Pain Syndrome (Thalamic Syndrome) Phantom Limb Sensation Somatotopic Organization of the Lateral Spinothalamic Tract

We perceive the external world and become coordinated movements by providing appropri- alert, create body image, and regulate our ate feedback to the somatic motor system about movements through sensory systems. The term joint position, muscle tension, velocity of mus- somatosensory system refers to the sensory cular contractions, and contact of the body with receptors that respond to a particular physical external surfaces (Chaps. 8 and 11). Sensations property (e.g., temperature), together with tracts occur when stimuli interact with receptors (sen- and nuclei that transmit information about four sors). Sensory information then is transmitted major general somatic modalities—the sensa- cephalically as patterns of action potentials by tions of pain (signaling tissue damage or chem- individual neurons and by assemblies of neu- ical irritation), temperature (warmth or cold), rons acting in consort. All sensory systems, touch, (for recognition of size, shape, and tex- regardless of modality, transmit information ture), and proprioception (sense of static posi- pertaining to the intensity, duration, and location and movements of the limbs, body, and tion of the stimuli that activate them. head) (see also Chap. 10). Somatosensory There are four classes of somatic sensory receptors are located in the skin, muscles, receptor, each of which is sensitive to one form joints, and viscera, a distribution that makes this of physical energy. These are sensors for a vari- system the largest and most varied of the sen- ety of mechanical, thermal, chemical and elec- sory systems. Although primarily sensory, this tromagnetic events. (Photoreceptors in the system also is of importance in the control of retina are the only electromagnetic energy

155 156 The Human Nervous System detectors in humans.) The specificity of each modality is maintained within the nervous sys- FEATURES OF SENSORY SYSTEMS tem by being segregated into discrete anatomi- The term sensory is used to include all affer- cal pathways and processing centers. As a ent input from the peripheral nerves, whether schema, every general sensory system consists consciously perceived or not. Sensations are of a core sequence of primary afferent fibers, conscious perceptions and experiences associ- relay nuclei located in the spinal cord, brainstem, and thalamus, together with interconnec- ated with stimuli arising directly from the stim- tions and culminating at the cerebral cortex. ulation of receptors of the sense organs. The Each processing nucleus not only consolidates sensory systems are involved in (1) the aware- inputs from adjacent receptors but also inte- ness of sensations, (2) the unconscious inputs grates signals from inhibitory neurons and that underlie the control of movements and descending projections to transform and many bodily functions, and (3) neural activities enhance the sensory information (see Fig. 3.13). associated with arousal. The sensory systems The nervous system responds to stimuli have evolved to provide information from both from a variety of environmental energies that the internal and external environments of the are sensed by receptors associated with each organism. Receptors are the monitors sensing modality. The recipient information is transmit- the environment. They are involved with trans- ted by neurons with their cell bodies located in duction, which is the conversion of stimulus the dorsal root ganglia or its equivalent ganglia energy into neural activity. The quality of each in the cranial nerves to neurons within the cen- stimulus results in a form of sensation called a tral nervous system (CNS). The receptor for modality, such as pain, thermal sense, touch, or each modality has a singular morphological vision. Each modality has submodalities (e.g., and functional specialization that monitors a vision—perceptions of color, form, depth, and specific type of environmental stimulus. motion). The three receptor types and some Pain sensations are mediated by nociceptors associated modalities are (1) mechanoreceptors (free nerve endings) that are stimulated by such as temperature (thermal), noxious (pain or tissue-damaging impacts such as pinching or nociceptors), auditory (sound) and touch recep- injury and chemical substances released from tors. (2) chemoreceptors (taste and smell) and tissue cells physically damaged or injured from (3) photoreceptors (light). Transduction in a extreme heat or cold resulting from burns and mechanoreceptor is brought about by the direct frostbite (Chap. 9). Temperature is sensed by mechanical interaction of a stimulus with the naked nerve endings of unmyelinated or lightly channels on a receptor membrane. In an myelinated nerve fibers. These endings sense unstimulated membrane, only a few channels what is then processed into the everyday per- are open. When the receptor membrane is ceptions of cool, cold, warmth, and hot sensa- deformed by a stimulus, more channels open tions. Discriminative touch is a mental and Na+ and K+ shift to produce depolarization, response to signals from encapsulated recep- called the receptor potential. Transduction in a tors sensitive to physical distortions, indenta- chemoreceptor results from the interaction of a tions, and movements across the skin (Chap. chemical with a receptor linked to a second- 10). Proprioception refers to stretch or contrac- messenger system to mediate channel open- tions of muscles and joint movements involv- ings. This is the means utilized by olfactory ing the head, trunk, and limbs (Chap. 10). receptors and certain gustatory receptors. The Spatial resolution, mediated by mechanorecep- transduction in a photoreceptor is associated tors, is most accurate on the fingertips and lips, with absorption of light by the membranous where these sensors are most abundant. Propri- disks of the rods and cones of the retina. The oceptors utilize pressure and motion to sense resulting change in receptor membrane perme- the shape and surface texture of objects handled. ability involves a second-messenger system. Chapter 9 Pain and Temperature 157

Four distinct elementary general somatic brainstem with axons that ascend to terminate modalities are recognized: (1) pain elicited by in the thalamus. An assembly of axons of noxious stimuli in damaged tissue (Chap. 9), second-order neurons is called a tract (fascicu- (2) thermal sensations elicited by warm and lus or pathway) in the white matter of the spinal cool stimuli, (3) touch elicited by mechanical cord and could be called a lemniscus (ribbon) stimuli applied to the body (Chap. 10), and (4) in the brainstem. Third-order neurons are those proprioceptive sensations elicited by the with cell bodies in the thalamus and axons that mechanical displacement of muscles and joints terminate in the somatosensory cortex (areas 3, (Chap. 10). 1, and 2) of the parietal lobe. Two major general sensory systems are The centers and nerve fibers involved with associated with sensory input from the spinal the processing and transmission of signals nerves from the body. Equivalent systems are resulting in the conscious appreciation of pain associated with similar input from the head and temperature are in such close proximity (e.g., from the trigeminal nerve). They are (1) that their pathways are collectively called the the anterolateral system of pathways for pain pain and temperature pathways. and temperature and somewhat for touch and (2) the dorsal column–medial lemniscal system of pathways for touch and proprioception RECEPTORS (Chap. 10). Each of the systems is organized (1) with most of the sensory submodalities Receptors have been variously classified. conveyed by functionally separate pathways, Exteroceptors, located near the body surface, (2) hierarchically with successive serial pro- are generally stimulated by external environ- cessing centers (called relay nuclei) terminat- mental energies. They are sensed as touch, ing at the cerebral cortex, and (3) for parallel light touch, pressure touch, pain (noxious processing at each level (Chap. 3). These two stimuli), temperature, odor, sound, taste, or systems and their pathways converge on dis- light. Proprioceptors are located within deep tinct and separate populations of neurons structures of the head, body wall, and extrem- within the ventral posterior nucleus of the ities. Proprioception includes such modalities thalamus. From the thalamus, neural informa- as position sense, vibratory sense, balance, and tion is projected to the sensory areas of the sense of movement. Interoceptors monitor the cerebral cortex, where the various submodali- viscera and project information sensed as ties are integrated into the experience of per- cramps, pain, and fullness and are utilized in ception. It is at these higher centers that the visceral reflexes (e.g., carotid sinus reflex). several aspects of sensations are finely honed, Mechanoreceptors respond to mechanical including (1) quality (e.g., pain), (2) intensity, stimuli (touch, hearing). Chemoreceptors (3) location on body, (4) duration, and (5) respond to chemical stimuli (taste, smell). affect (e.g., range from pleasant to unpleas- Chemesthesis is now recognized as a common ant). It is these attributes that make a percep- chemical sense comprising irritant-detecting tion more than a sensation. receptors, resembling pain receptors (nocicep- The pathways of the general sensory sys- tors), that are sensitive to chemicals applied to tems usually consist of a sequence of first- the skin, mucosal membranes of the oral cav- order, second-order, and third-order neurons. ity, nasal cavities, respiratory tract, and genital The first-order neurons are those peripheral orifices. The free nerve endings that respond to sensory neurons with cell bodies in spinal dor- chemicals including irritants do not constitute sal root ganglia, or cranial nerve ganglia, and a separate, independent sense, but, rather, are axons that terminate in the spinal cord or brain- part of the general somatic nervous system. stem. Second-order neurons are those with cell The chemosensitive fibers appear to be a sub- bodies in the nuclei of the spinal cord and/or set of pain and temperature fibers. Thermore- 158 The Human Nervous System ceptors (temperature receptors) respond to with C fibers (see Fig. 9.1). Following trauma, various degrees of warmth and cold. chemical mediators are released locally from the damaged tissues that can sensitize and, at Peripheral Pain Mechanisms times, activate the nociceptors of the A-delta Receptors of “painful” stimuli are collec- and C fibers. Two such agents are the eicosa- tively referred to as nociceptors. They are free noid prostaglandins that are sensitizers derived (naked) nerve endings that respond to direct from injured cells and the peptide bradykinin stimulation and to chemical products associ- that is an activator derived from plasma kinino- ated with local injury (noxious stimuli) (see gens. The activation of nociceptors results in Figs. 10.1 and 10.2). Three types of free nerve the release from C fiber terminals of the pep- ending receptor are associated with two types tide substance P that, in turn, causes mast cells of afferent fiber. On the basis of functional cri- to release histamine, which excites nociceptors. teria, they are (1) mechanosensitive nocicep- The edema associated with an injury results tors with A-delta fibers, (2) mechanothermal from the actions of substance P, which pro- nociceptors with A-delta fibers, and (3) poly- duces plasma extravasations, and of calcitonin modal nociceptors (respond to thermal, gene-released peptide that results in the dilation mechanical, thermal, and chemical stimuli) of blood vessels. In addition, the edema causes

Figure 9.1: Spinal cord terminations of dorsal root fibers that mediate pain. The A-delta fibers (pain, temperature, and touch) terminate in laminae I and V, where they synapse with projection neurons (P) whose axons ascend in the pain pathways illustrated in Fig. 9.2. The C fibers (pain and temperature) terminate in lamina II. Interneurons (I) in lamina II have axons that synapse with projection neurons in laminae I and V. (Refer to Table 7.4.) Chapter 9 Pain and Temperature 159 release of more bradykinin. Other chemical ficient to alter the firing rate of the endings. In mediators include (1) serotonin (5HT) derived essence, thermoreceptors are not objective sen- from platelets, (2) potassium ions derived from sors of actual skin temperature; rather, their damaged tissue cells acting as activators of role is to signal information resulting in adjust- nociceptors, and (3) substance P released from ments to the environment. A perception is espe- the afferent nerve terminals acting as a sensi- cially vigorous when the change is rapid. For tizer of nociceptors. The effectiveness of aspirin example, the perception of hot occurs when a and other anti-inflammatory analgesics in the “cold” hand is placed in lukewarm water. Also, control of pain occurs because they inhibit an a momentary distorted feeling of coolness is enzyme involved in the synthesis of prosta- perceived when a foot is placed in a bathtub glandins. The subjective perception elicited by with hot water. a brief, intense stimulus is of a sharp, short- duration pain (first pain) followed by a dull, prolonged pain (second pain). First, pain is AFFERENT (FIRST-ORDER) NEURONS transmitted by the A-delta fibers that convey information from the thermal and mechanical Pain and temperature inputs are conveyed receptors. Second, pain is transmitted by C via two types of first-order afferent neuron fibers activated by polymodal receptors. The whose cell bodies are in dorsal root ganglia, or viscera contain silent receptors. Usually, these the trigeminal ganglion: (1) faster-conducting, receptors are activated by noxious stimuli. lightly myelinated A-delta fibers and (2) slow- However, their stimulation (firing threshold) is conducting, unmyelinated C fibers (see Fig. markedly reduced by inflammation and a vari- 9.1); maximum velocities are 30 and 2 m/s, ety of chemicals that produce a syndrome called respectively (see Table 7.4). The A-delta affer- hyperalgesia (excessive response to a minimal ents have low-threshold receptors and conduct stimulus that is often perceived spontaneously). signals perceived as sharp localized pain. The To distinguish between nociception and pain C fiber afferents have high threshold receptors is basic to an understanding of sensory sys- and are involved in diffuse persistent pain that tems. Nociception implies the reception by might possess aching, burning, or itching qual- nociceptors of stimuli that form signals to pro- ities. Diffuse pain, presumably the result of vide information to the CNS of tissue damage released chemicals, often is preceded by sharp eliciting a noxious stimulus. Pain is the percep- stabbing pain. tion of an unpleasant sensation. Perceptions, Neurons excited exclusively by nociceptors such as pain, are abstractions of the sensory are called nociceptive-specific neurons. Other input by the CNS. Pain is said to be a subjec- first-order neurons involved with the pain path- tive perception with a psychological dimen- way conveying input from low-threshold sion. A noxious stimulus that triggers a mechanoreceptors are called wide dynamic nociceptor to respond is not necessarily per- range neurons. Both the A-delta and C fibers ceived as pain. release the excitatory transmitter glutamate and Neurologists usually test for cutaneous pain various neuropeptides, especially substance P. simply by pricking the skin with a sterile, dis- The A-delta afferents, with low-threshold posable, hypodermic needle. Thermal sensibil- receptors, conduct impulses perceived as sharp, ity is evaluated by applying a tube containing pricking sensations that are accurately local- ice (40°F) and another containing warm water ized and categorized as fast or initial pain. (110°F) to a body part. Temperature differences The C afferents, with high-threshold recep- of 5–10°F are normally detected subjectively. tors, sense pain as a burning sensation with a The thermal receptors sensing heat and cold slower onset and as a more persistent and less are located in free nerve endings. Small shifts distinctly localized modality known as slow or in the skin temperature, of about 0.2°F, are suf- delayed pain. Both fast pain and slow pain are 160 The Human Nervous System essentially somatic sensations from superficial the coronal plane through the ears (see Fig. 9.2), receptors in the body. are components of the anterolateral pathway In addition, deep or visceral pain, subjec- (located in the white matter of the anterolateral tively characterized as aches with at times a quadrant of the spinal cord). The tracts are the burning quality, results from stimulation of deep (1) (lateral) spinothalamic tract, terminating in somatic and visceral receptors. This form of pain the thalamus, (2) spinomesencephalic tract, ter- is associated with inputs conveyed by A-delta minating in the periaqueductal gray (PAG) of and C fibers in both somatic and visceral nerves. the midbrain, and (3) spinoreticular tract, ter- Stimulation of mechanoreceptor nocicep- minating in the brainstem reticular formation. tors (e.g., from a knife cut or pin prick) and The anterior spinothalamic tract conveying thermal nociceptors in free nerve endings light touch is included in the anterolateral path- evokes a neural code that is conveyed via way (see Fig. 10.3). Additional fibers conveying A-delta fibers and perceived as sharp and nociception are incorporated in the spinocervi- pricking pain (or temperature). Stimulation of cothalamic pathway located in the dorsal thermal and polymodal nociceptors (mechani- columns of the lemniscal system (Chap. 10). cal, heat, and chemical noxious stimuli) in free The A-delta and C fibers enter the spinal nerve endings evokes codes that are conveyed cord as the lateral bundle of the dorsal root. by C fibers and perceived as slow, burning pain They bifurcate into branches that ascend and (or temperature). Thermal nociceptors respond descend one or two spinal levels in the postero- selectively to heat and cold. In humans, heat lateral fasciculus (tract of Lissauer; see Fig. receptors respond selectively when the temper- 7.6), from where they enter and terminate in the ature exceeds the heat pain threshold of 113°F. dorsal horn (see Fig. 9.2). The A-delta fibers Cold receptors respond to noxious cold stimuli. have excitatory synapses with projection neu- Pain in Dermatomes rons. The C fibers synapse with interneurons interacting with (1) projection neurons whose A dermatome is a sensory segment of skin axons ascend to higher centers in the brain and innervated by fibers from one dorsal root (see (2) inhibitory interneurons that modulate the Fig. 7.3). Dermatomes from successive spinal flow of nociceptive information to higher cen- segments overlap. Hence, the interruption of ters. The A-delta fibers synapse with neurons in one complete dorsal root could result in only laminae I, II, and V; C fibers synapse with neu- the diminution (not loss) in sensation in part of rons in laminae I and II. Branches of each fiber the dermatome. However, the irritation of a terminate in several spinal levels. According to dorsal root can produce pain in one or more the gate control theory (see Fig. 9.3), process- dermatomes. In herpes zoster (shingles), there ing of these inputs occurs within the dorsal is an intense and persistent pain in one or more horn by interactions involving nociceptive-spe- dermatomes. This pain is a consequence of the cific neurons, wide dynamic range neurons, activation of pain fibers by vericella zoster virus, which primarily affects one or more interneurons, and projection neurons. Descend- dorsal root ganglia or the trigeminal ganglion. ing control mechanisms also are important in Mechanical compression (e.g., following a pain modulation (see Fig. 9.4). slipped disk) of a dorsal root can irritate the Cells in several laminae contribute differen- dorsal root and produce pain over a dermatome. tially to separate components of the spinothalamic tract. About half of the fibers arise from lamina I, and the rest arise equally from lami- PATHWAYS FROM THE BODY, nae IV–V, and VII–VIII. Roughly 90% of the LIMBS, AND BACK OF HEAD second-order fibers decussate; the remainder ascends ipsilaterally. Pain and temperature pathways from the The pain and temperature pathways termi- body, limbs and back of the head, posterior to nate in several thalamic nuclei including but Chapter 9 Pain and Temperature 161

Figure 9.2: The pain and temperature pathways originating in the spinal cord: the lateral spinothalamic tract, spinomesencephalic (spinotectal), and spinoreticulothalamic fibers. Note that the ventral posterolateral (VPL) thalamic nucleus projects to the body regions of both SI and SII of somatosensory cortex and that the intralaminar thalamic nuclei project diffusely and widely to the cerebral cortex. The lamination of the lateral spinothalamic tract is shown on the right side of the cross-sections of the spinal cord (C, cervical; T, thoracic; L, lumbar; S, sacral levels). 162 The Human Nervous System not limited to the ventral posterolateral nucleus the spinothalamic pathway, which conveys (VPL), posterior nucleus (PTh), and intralami- information primarily from nociceptive-spe- nar nuclei (Chap. 23). VPL and the ventral pos- cific and wide dynamic range neurons. teromedial nucleus (VPM), which receives The (lateral) spinothalamic tract originates somatosensory information from the head, are from projection neurons of laminae I, V, VI, called the ventrobasal complex (VB). In terms and VII. After the axons of its second-order of the nature of the nociceptive inputs, there are neurons decussate in the anterior white com- two significant differences between these thal- missure (anterior to central canal), they ascend amic nuclei: (1) The intralaminar nuclei, acti- in the anterolateral pathway and terminate pri- vated via the spinoreticulothalamic pathway, marily in VPL and PTh thalamic nuclei (see receive input from neurons of spinal laminae Fig. 9.2). Some collateral branches terminate in VI, VII, and VIII conveying information from the brainstem reticular formation. This tract large complex nociceptive fields; (2) VB and conveys information perceived with an overlay PTh, part of the ventral group of thalamic of the discriminative aspects associated with nuclei, receive input from laminae I and V via various subtleties associated with the sensation

Figure 9.3: Gate control model for pain modulation. The model postulates the interaction of (1) the C pain fibers that have inhibitory synapses with an interneuron and excitatory synapses with a projection pain neuron, (2) the myelinated A-alpha and A-beta non-nociceptive fibers that have excitatory synapses with both the interneuron and the projection pain neuron, and (3) the interneurons that have inhibitory synapses with the projection pain neuron. See text for further explanation. Chapter 9 Pain and Temperature 163

Figure 9.4: Pain control and modulation. Pain can be modulated by the release of opioid peptides. Neurons of the periaqueductal gray in the midbrain have excitatory synaptic connections with serotonergic neurons in nucleus raphe magnus and with noradrenergic neurons in the lower brainstem reticular formation. The serotonergic neurons (1) have inhibitory synapses with nociceptive projection neurons and (2) excitatory synapses with endorphin-containing interneurons (E), which have inhibitory synapses with the nociceptive projection neurons (P). The noradrenergic (norepinephrine) neurons also have excitatory synapses with the endorphin-containing interneurons. These activities modulate the excitatory synaptic influences of the glutamate and substance P transmitters of the A-delta fibers with the nociceptive projection neurons. of sharp pain and, in addition, with thermal aspect; this produces a laminated somatotopi- sense (temperature). cally organized tract; that is, each body seg- At successively higher levels of the spinal ment (or dermatome) is represented in a cord, new fibers join the tract on its medial portion of the tract (see Fig. 7.6). As a conse- 164 The Human Nervous System quence, in the upper spinal cord, pain and tem- nuclei of the thalamus, in the hypothalamus, perature fibers from the sacral region are and in limbic structures. From the spinal cord, located posterolaterally and those from the there are direct projections to the hypothala- sacral region are located anteromedially. The mus. This slowly conducting multisynaptic VPL thalamic nucleus is also somatotopically pathway conveys diffuse poorly localized pain organized with the sacral and lumbar (lower from both somatic and visceral sources. The body) levels located laterally and the thoracic intralaminar nuclei project to widespread areas and cervical levels medially. This tract is also of the cerebral cortex, including the frontal called the lateral pain system or neospinothal- lobes. The influences exerted by this pathway amic tract (meaning new phylogenetically). are integrated into autonomic and reflex Axons of the third-order pain and tempera- responses to pain and to affective–motivational ture neurons located in the thalamus ascend responses. As a consequence, this pathway is through the posterior limb of the internal cap- also called the paramedian pain pathway or the sule and corona radiata and terminate in the paleospinothalamic pathway (old phylogenetic parietal lobe of the cerebral cortex (Chap. 25). pathway) or medial pain system. Fibers from VPL terminate in lamina IV of the The neospinothalamic pathway, via the VPL primary somatosensory cortex (SI; areas 3, 1, nucleus, projects to the primary and secondary and 2 of the postcentral gyrus), whereas fibers somatic sensory areas of the cerebral cortex. from PTh terminate in lamina IV of the sec- These are essential for spatial and temporal dis- ondary somatosensory cortex (SII; areas 3, 1, crimination of painful sensations. In contrast, and 2 near the lateral fissure; Chap. 25). The the paleospinothalamic pathway mediates the thalamus might be associated with the percep- autonomic and reflexive responses associated tion of pain, whereas the parietal lobe and other with pain and, in addition, the emotional and cortical areas are involved in the appreciation affective responses. and the localization of pain and of the integra- The roles of the cerebral cortex and the thal- tion of stimuli from the pain pathways with the amus in the perception of pain are complex. other sensory modalities. Several clinical observations following certain The spinomesencephalic tract is composed surgical procedures are relevant to an under- of the fibers of projection neurons in laminae I standing of the perception of pain. Surgical and V that decussate in the anterior white com- intervention in various locations, both of the missure and ascend in the anterolateral path- peripheral and central nervous systems, has not way. It terminates in the periaqueductal gray proven to be effective in permanently relieving (PAG) of the midbrain (see Fig. 9.4) and is pain. Surgery can abolish the perception of involved in the modulation of pain and in the pain temporarily, but it subsequently can return functioning of the reticular system (Chap. 22). with new manifestations that are unpleasant The spinoreticular tract is integrated into and frequently different than any pain the the spinoreticulothalamic pathway terminating patient has experienced previously. These in the intralaminar thalamic nuclei (Chap. 21). include shooting pain, numbness, cold, burn- The spinoreticular fibers originate from neu- ing, and aching sensations. Some procedures in rons in laminae VII and VIII, which receive the brain can elicit more distress to the patient inputs from large, complex, receptive fields in than the original pain. Spontaneous lesions can the periphery. The spinoreticular tract consists result in marked distortions of pain and pain- of crossed and a few uncrossed fibers that, related symptoms (see Thalamic Syndrome, along with collateral fibers from the spinothal- Chap. 23). The bizarre sensations perceived by amic tract, terminate in the multineuronal, mul- an amputee in a phantom limb are expressions tisynaptic complex known as the brainstem of processing within neural centers deprived of reticular formation (Chaps. 13 and 22). Reticu- normal stimulation (see later). Destructive sur- lothalamic fibers terminate in the intralaminar gical lesions of the intralaminar and posterior Chapter 9 Pain and Temperature 165 thalamic nuclei can alleviate intractable pain; joints, and viscera, Polymodal nociceptive neu- in time, the pain might return. rons (PC), dominated by C fiber input, respond Several surgical interventions suggest some to noxious heat, cold, or pinch and also might functional roles for various regions of the brain: respond to stimulation of muscles, joints, or (1) Nociceptive information from one half of viscera. Thermoreceptive-specific neurons the body is conveyed to the same side of the (COLD) respond to innocuous cooling. spinal cord and then crosses over to the con- Laminae IV and V contain two major types tralateral side to ascend as the neospinothala- of anterior spinothalamic tract cell. Low- mic pathway to where aspects of perception threshold cells (LT) respond only to innocuous occur in the thalamus and the somatosensory mechanical stimulation such as brushing (hair) areas of the cortex. Painful stimuli can be per- or to both brushing and graded pressure. Wide ceived on the contralateral side of the body fol- dynamic range nociceptive neurons (WDR) lowing ablation of the somatosensory cortex of respond to innocuous and noxious stimuli over a hemisphere. This is accomplished when the fairly large cutaneous fields in a graded manner. entire thalamus and other subcortical structures are intact. (2) The cortex of the frontal lobe and Functional Considerations cingulate gyrus are involved in some way with Studies of the anatomy of the pain system the psychological responses to pain (Chap. 25), indicate that painful stimuli activate multiple as are the dorsomedial and anterior thalamic pathways and, therefore, multiple nuclei, gan- nuclei with connections to the cortex of the glia, and cortical areas of the forebrain, The frontal lobe (Chap. 22). Lesions of these nuclei, processing nuclei assimilate past experiences or of the nerve fibers linking them to the frontal and present context that collectively produce lobe (called prefrontal leukotomy), lowers the and result in the total multidimensional pain agony associated with the persistent pain by experience. These pathways and centers can altering the psychological response to the contribute different aspects of pain sensation. painful stimuli. The downside to this approach The conscious pain–emotion content is con- is the negative changes in the personality and structed by the integration of contributions of intellectual status of the patient (Chap. 25). the constellation of neural activity within the Bilateral severing of the fibers linking the cin- processing centers of the pain pathways. gulate gyrus to the frontal lobe (cingulotomy) Recent functional positron-emitting tomog- can relieve the response to pain without the raphy (PET) and magnetic resonance imaging concomitant personality changes. (MRI) investigations of the cerebrum have shown cortical areas that are activated by noxious heat and noxious cold stimuli, including MAJOR CLASSES OF FUNCTIONALLY the primary and secondary somatosensory cor- DEFINED NEURONS AND THE tices, lateral operculum (Chap. 25), insula and SPINOTHALAMIC TRACTS anterior cingulate gyrus ((see Fig. 1.5). Accompanying the perception of pain, PET Major Classes of Neurons in the activation has been observed in the periaque- Spinal Cord Associated with “Pain”, ductal gray, hypothalamus, amygdala, cerebel- and Ascending Projections lum, and some nuclei of the basal ganglia, Lamina I contains three major classes of lat- structures that all receive some ascending noci- eral spinothalamic tract neurons (Figs. 9.1 and ceptive input. 9.4). Nociceptive-specific neurons (NS) with small cutaneous receptive fields respond to Salient Features of the Spinothalamic and noxious mechanical and/or thermal stimuli, but Trigeminothalamic Pain Pathways not to innocuous stimulation. In addition, they The lateral spinothalamic tract pain and tem- respond to noxious stimulation of muscles, perature system (LSTT; see Fig. 9.2) arises 166 The Human Nervous System from neurons called cold cells, polymodal roles of the pain pathways are subtlety influ- nociceptive cells, and nociceptive-specific cells enced by the tracts and nuclei of the reticular located in lamina I of the spinal cord that system (ascending reticular activating system decussate and form the ascending LSTT. Dur- [ARAS], Chap 22). These include (1) the spin- ing its ascent into the thalamus, the tract emits oreticular and spinomesencephalic tracts from collateral branches that terminate in parts of the the spinal cord (see Fig. 9.2) reticuloreticular brainstem reticular formation (Chap. 22) and and reticulothalamic tracts from the reticular the periaqueductal gray. Within the thalamus, formation of the brainstem, and the thalamo- fibers are distributed to several nuclei and their cortical projections to the cerebral cortex and subdivisions, including the ventral caudal por- (2) nuclei such as the reticular nuclei of the tion of the dorsomedial nucleus (DM), the ven- brainstem and the CL and other intralaminar tral posterolateral nucleus (VPL), ventral thalamic nuclei. posterior inferior nucleus (VPI), the central lat- An insight into the intricacies of pain is eral and parafascicular intralaminar nuclei, and provided by Craig and Dostrovsky (1999), who the posterior portion of the ventral medial wrote “The most parsimonious and prospective nucleus (VMpo), part of the posterior thalamic view is that the activity of all of these ascend- group (see Fig. 9.5). In turn, DM projects to the ing pathways must be integrated in the fore- base of the anterior cingulate gyrus; when acti- brain in the context of current conditions and vated, the sensation of burning pain can be felt. past experience in order for all aspects of the The densest LSTT terminations are in VMpo, sensation of pain to be generated.” Elimination which projects to the dorsal margin of the of a portion of the system or a given pathway, insula within the lateral fissure and is involved such as by a partial lesion in the periphery, in in “sensory representation of the physiological the spinal cord or in the forebrain, could cause condition of the body” (lesions of this area an imbalance that could have variable effects have a minimal effect on the pain sensation) on integrated sensation or in the central pain and in VPI, which also projects to the insula syndrome (see later). For example, it may (activated by noxious heat or cold stimuli). result in pain without a noxious stimulus as in Trigeminothalamic pain pathways are basically the phantom limb and central pain syndromes. similar to the spinothalamic pain pathways These conditions emphasize the complexity of except that fibers to the ventrobasal complex ter- the spinal and supraspinal connections still to minate in VPM rather than VPL (see Fig. 9.6). be identified that are involved in the experience The anterior spinothalamic tract crude of pain. touch and movement sensation system (ASTT) projects from neurons called wide dynamic range and low-threshold neurons in lamina 5) WALL’S CONCEPT OF PAIN IN whose axons decussate and form the ascending TARGET MOTOR RESPONSES ASTT (see Figs. 10.3 and 10.4). As the tract ascends, its collateral branches terminate in “Pain for me arrives as a complete package,” some brainstem reticular formation nuclei at the same time painful and miserable” (Wall before terminating in the central lateral (CL) and Melzack, 1999). Pain is also thought of as nucleus of the intralaminar nuclear group, a subjective phenomenon perceived both as a VPL, and VPI. VPL projects somatotopically sensation (cognitive) and as an affective (e.g., mainly to the primary somatosensory cortex fear, miserableness) feeling tone. Thus patients (areas 3 and 1) and VPI projects mainly to sec- suffering from intense pain and given morphine ondary somatosensory cortex in the insula describe affect perceptions in the absence of (Chap.25). The trigeminothalamic tracts have cognitive pain. Other definitions are that pain is equivalent connections, which within the ven- an abstraction of nociception or that pain is not trobasal complex involve VPM. The functional a sensation, but a perception. Pain has been Chapter 9 Pain and Temperature 167

Figure 9.5: The ascending projections of the lateral spinothalamic tract (LSTT) activated by nociceptors and thermoreceptors of spinal cord lamina I neurons associated with the sensory modalities of pain and temperature. From cell bodies in lamina I, axons decussate in the anterior white commissure and ascend in the LSTT. Collateral branches synapse with nuclei of the brainstem reticular formation (RNu) and the periaqueductal gray (PAG; see Fig. 13.15). The main axons terminate at thalamic levels in the posterior zone of the ventral posteromedial nucleus (VMpo), the ventral posteroinferior (VPI), and the dorsomedial (DM) thalamic nuclei (see Table 23.1). In turn, these thalamic nuclei project to the secondary somatic sensory area (S2), insula (In), and anterior cingulate gyrus (area 24) of the cerebral cortex (see Figs. 25.3 and 25.6). Of significance is the sparse projection (thin line) to the primary somatic sensory cortex, area 3 (see Figs. 25.3 and 25.5). (Adapted from Craig and Dostrosky, 1999.) 168 The Human Nervous System

Figure 9.6: The pain and temperature pathways originating in the brainstem: the anterior trigeminothalamic tract and the trigeminoreticulothalamic pathway. Note that the ventral posteromedial thalamic nucleus projects to the head regions of both SI and SII of somatosensory cortex and that the intralaminar thalamic nuclei project diffusely and widely to the cerebral cortex. For details of structures in the brainstem sections, refer to the figures in Chap. 13. Chapter 9 Pain and Temperature 169 conceived as a learned component with a motor planning that is appropriate to the event selection-attentive role that commands and itself and (2) triggering the motor movements directs attention to only one target. When sev- that result in the target motor responses. Con- eral pain sites burst out almost simultaneously, vincing support for this alternate concept is attention is directed to the “nothing else mat- derived from observations of PET scan images ters” one target and is followed by a directed obtained from both normal subjects and motor response (e.g., withdrawal from the patients with a variety of noxious pains. These selected noxious target site). high-resolution PET topographic images detect There are two current concepts regarding and map metabolic activities and reveal the the organization and purpose of the pain sys- localization of changes in the cerebral blood tems within the nervous system. (1) Some flow in certain brain areas and sructures. Stud- believe that pain can be adequately explained ies of these PET scans led Wall (Wall and by the neural activity of dedicated pathway Melzack, 1999) to some of his reasoned inter- systems, which originate in peripheral pain pretations. receptors that result in the sensation of pain and elicit protective reflex response patterns. This traditional scheme commences with a PATHWAYS FROM THE stimulus followed by the conducting path- ANTERIOR HEAD ways to a combined memory–emotional response. (2) Others propose a more complex Pain and temperature pathways from recep- approach that takes into account the plasticity tors in the head and scalp, anterior to a coronal of all of the conducting pain pathways, plane through the ears, are the (1) trigemino- involvement of successions of parallel pro- thalamic and (2) trigeminoreticulothalamic cessing centers (nuclei), basal ganglia, cere- tracts, both of which terminate in nuclei of the bral cortical areas, and even the cerebellum thalamus. These fibers convey impulses via and, in addition, the active participation of the three divisions of the trigeminal nerve the brain in perception. (ophthalmic, maxillary, and mandibular) and In his discussion on the sensation of pain, cranial nerves VII, IX, and X (see Figs. 9.6 Wall (Wall and Melzack, 1999), a premier and 14.5). authority, documents a new concept in answer The cell bodies of the first-order fibers to the question “How does the brain interpret (A-delta and C fibers) are located in the trigem- input” with regard to “pain” stimuli?” The inal ganglion (V), the geniculate ganglion classical theory is that the brain analyzes the (VII), and the superior ganglia (IX and X). The sensory input to determine what has happened fibers enter the brainstem and descend as the and then presents the answer as a pure sensa- spinal tract of n.V (spinal trigeminal tract) on tion. One among several objections to this the lateral aspect of the lower pons, medulla, theory is that the primary somatic sensory and upper two cervical spinal cord segments. cortex (postcentral gyrus of the cerebral cor- The spinal trigeminal tract is somatotopically tex Chap, 25), which has been assigned a key organized with fibers from the ophthalmic divi- role in pain sensation analyses, often is silent sion most anterior, maxillary in an intermediate in PET imaging studies although the subject position, and mandibular division fibers reports pain. together with those from nerves VII, IX, and X The alternate concept proposed by Wall most posterior in the sequence; fibers from (Wall and Melzack, 1999) is that “the brain each of these nerves descend to the C2 level. analyzes its sensory input in terms of the possi- They terminate in the spinal nucleus of n.V, ble action which would be appropriate to the which is located medial to the tract. The spinal event or which triggers the whole process.” tract and nucleus of n.V are the brainstem’s Two critical items in this concept are (1) the counterpart of the posterolateral tract of Lis- 170 The Human Nervous System sauer and lamina I and II and deeper laminae of sory inputs associated with these modalities are the spinal cord. conveyed via lightly myelinated A-delta and The spinal nucleus of n.V is a continuous unmyelinated C fibers. Cold is associated with structure that is subdivided into (1) the rostrally both types of fiber and warmth is associated located pars oralis (nucleus oralis), which with C fibers. An intense heat stimulus can receives touch input from the mouth, lip, and evoke the perception of cold, as can occur nose, (2) the intermediately located pars inter- when one places a hand in hot water; this is polaris (nucleus interpolaris), which receives called the paradoxical cold sensation. It results pain input from the tooth pulp (dental pain), because heat does, at times, stimulate cold and (3) the caudally located pars caudalis receptors. Although thermal pathways are vir- (nucleus caudalis), which receives pain, tem- tually indistinguishable from those for pain, perature, and light touch input from the face, some researchers contend that the thermal mouth, and tooth pulp. The pars caudalis senses are conveyed only by fibers of the antero- extends caudally to the C2 level (see Fig. 9.5). lateral pathway and trigeminothalamic tract. From cell bodies in the spinal nucleus of n.V, axons of second-order neurons decussate through the lower brainstem reticular forma- PERCEPTION OF PAIN tion and ascend near the medial lemniscus as the anterior trigeminothalamic tract (anterior Pain is primarily a warning signal to the trigeminal tract) to terminate in the ventral pos- organism; it is often accompanied by with- teromedial nucleus of the thalamus and in the drawal from a noxious stimulus via a flexor posterior thalamic region. Axons of third-order reflex. In a phylogenetic sense, pain must be neurons pass from the thalamus through the one of the oldest protective responses of living posterior limb of the internal capsule and organisms. The awareness of pain might be corona radiata before terminating in the head centered in the thalamus, as are certain associ- region of the primary and secondary somato- ated aspects. For instance, a lesion of the dor- sensory cortices (SI and SII). The trigemino- somedial nucleus can reduce the intensity or thalamic tract is included in the lateral pain anguish of the pain experience. A lesion of the system. ventral posterior and intralaminar nuclei might Diffuse, poorly localized pain from the head relieve intractable pain, but in many patients, is probably conveyed by means of the trigemi- this is temporary, suggesting the existence of noreticulothalamic pathway, in which fibers alternative pathways. Portions of the cortex synapse within the reticular formation whose seem to be important as well. The various neurons project to the thalamic intralaminar nuances of pain (sharpness, dullness) seem to nuclei (except the centromedian). The trigemi- require activity of the secondary somatosen- noreticulothalamic pathway is part of the sory area (SII). Portions of the parietal lobe medial pain system. appear necessary for a subject to locate the In summary, two pain and temperature path- source of pain. On the other hand, large corti- ways are recognized. They are called (1) the cal ablation, including all of SI and SII, leaves anterolateral and trigeminothalamic pathways chronic pain undiminished. The interplay of and (2) the spinoreticulothalamic and trigemi- cortex and thalamus is uncertain, and some noreticulothalamic pathways. authorities conclude that the responses to a pain stimulus are indivisible. Dissociation between the perception and tolerance of pain TEMPERATURE (THERMAL) SENSE has been noted following psychosurgical treatment of patients suffering from chronic pain. Free nerve endings are the peripheral recep- The surgery consists of a lobotomy of the pre- tors for the sensations of warmth and cold. Sen- frontal cortex (Chap. 24) or lesions of the dor- Chapter 9 Pain and Temperature 171 somedial and anterior thalamic nuclei (nuclei the inhibitory interneuron. In addition, the having connections with the prefrontal cortex). reflected feedback descending influences from These patients report the perception of the pain, the brain can modulate the excitability of these but are no longer bothered by it. neurons (see Figs. 9.4 and 3.13, and Chap. 10). Itching is related, in some unknown way, to pain. It originates from the stimulation of free nerve endings within or just deep to the epi- DESCENDING CONTROL dermis of the skin. It is transmitted by C fibers MECHANISMS OF PAIN and relayed to the brain via the anterolateral MODULATION (Fig. 9.4) pathway. Pain and other sensory systems can be modulated and biased by influences conveyed from THE GATE CONTROL THEORY OF higher centers via descending tracts, known as PAIN MODULATION reflected feedback pathways or pain-modulating pathways to lower levels of the ascending A clinical method used to relieve pain (pro- pathways. Through these connections, the sen- duce analgesia) is to stimulate the appropriate sitivity of receptors and processing centers can peripheral nerve with surface electrodes. The be enhanced or suppressed much like the procedure is called transcutaneous nerve stim- gamma motor neurons modify the responsive- ulation (TNS). An explanation for the success ness of muscle spindles (Chap. 8). of this therapy is based on the gate control the- The descending influences from higher cen- ory. In this concept, pain can be modulated by ters modulating pain are organized in the fol- the balance of the interactions among the (1) lowing way. Output from the frontal cortex and nociceptive C fibers and (2) non-nociceptive hypothalamus activates centers in the PAG and A-alpha (proprioception) and A-beta afferent adjacent areas of the midbrain, which have (touch) fibers of the peripheral nerves, and the connections with tegmental nuclei of the ros- (3) interneurons and (4) projection neurons of tromedial medulla (see Fig. 9.4). Another area the dorsal horn. The latter are the neurons of involved with pain modulation is located in the the pain pathways (see Figs. 9.3 and 9.4). tegmentum of the dorsal and dorsolateral pons. The following describes the presumed Fibers from these pontine and medullary actions of the neurons comprising the circuitry tegmental nuclei project (1) to the spinal tri- of the gate control model (see Fig. 9.3). The geminal nucleus, and (2) via the pain-modulat- unmyelinated nociceptive C (pain) fiber inhibits ing dorsolateral tract (located in the lateral the inhibitory interneuron and the projection funiculus adjacent to the dorsal horn) to lami- neuron. The interneuron, which normally nae I and II of the spinal cord. Many of the neu- inhibits the projection neuron, is spontaneously rons in the pons are adrenergic (contain active and, thus, reduces (inhibits) the intensity norepinephrine), and those of the medulla are of the noxious input from the C fibers. The serotonergic (contain serotonin) (Chap. 15). influences exerted by the spontaneous activity Both of these biogenic amines have been of the interneuron on the projection neuron are implicated in pain modulation. The effect of the modulated by excitation from the non-nocicep- release of these biogenic amines and opioid tive A fibers and inhibition from the nocicep- peptides is that they bind to receptor sites and tive C fibers. In essence, nociceptive C fibers thereby suppress the activity of the “pain” tend to keep the gate open (enhancing percep- neurons. tion of pain) by inhibiting the inhibitory Opioid peptides and opiate drugs (e.g., mor- interneuron and exciting the projection neuron. phine) are powerful analgesic agents. They pro- The non-nociceptive A fibers tend to keep the duce analgesia by direct action upon specific gate closed (suppression of pain) by exciting receptor sites (opiate-binding receptors) on the 172 The Human Nervous System cell membrane of neurons. It is likely that the a battle) activates some of its neurons that opioid-mediated analgesic system is activated descend and have excitatory synapses with by stress, pain itself, and suggestion. Certain serotonergic neurons in the nucleus raphe mag- neurons in the brain release neurotransmitters, nus and with groups of noradrenergic neurons called endogenous opioid peptides, that result in the reticular formation of the lower brain- in analgesia. Three families of these peptides stem. The descending fibers from these neu- are recognized: (1) enkephalins, derived from rons (1) directly inhibit the nociceptive proenkephalin A, (2) beta-endorphin, from pro- projection neurons in the dorsal horn and (2) opiomelanocortin (POMC), and (3) dynor- excite the enkephalin-containing interneurons phins, from prodynorphin. These opiates are in laminae I and II of the dorsal horn. These presumed to be natural pain relievers because interneurons, through both presynaptic and they ameliorate pain when microinjected into postsynaptic connections, also inhibit the noci- the PAG or into the superficial layers of the ceptive projection neurons (see Fig. 9.4). Evi- spinal cord. Endogenous opioid peptides are dence indicates that endorphin-containing located in various structures in the CNS associ- interneurons in both the PGA and dorsal horn ated with transmission or modulation of pain. are active in pain modulation. Enkephalins are located in the amygdala, hypothalamus, PAG, rostroventral tegmentum of the medulla, and dorsal horn of the spinal cord. REFERRED (TRANSFERRED) PAIN Less widely distributed are beta-endorphins, located in the hypothalamus (arcuate nucleus), Pain of visceral origin usually is vaguely PAG, and in small amounts in the medulla and localized. The site of visceral irritation and the spinal cord. Dynorphin peptides are roughly locale where the pain is felt are not necessarily similar to the enkephalins in their distribution. the same. The pain can be referred (transferred) from the visceral source to a corresponding dermatomal segment on the body, extremity, or ENDOGENOUS PAIN CONTROL head. Referred pain can also apply to pain from a somatic source. The natural variability of pain thresholds The brain and the parenchyma of visceral can be affected by the emotional state of an organs do not have pain receptors. Such recep- individual and by pharmacological agents such tors are primarily in the walls of arteries, as aspirin and morphine. The control and mod- meninges, and all the pleural and peritoneal ulation of nociception involves descending membranes. They are often the sources of influences involving several descending neuro- severe pain when they are inflamed, irritated, transmitter systems. Aspirin apparently acts or subjected to mechanical friction. Excessive peripherally, presumably by inhibiting trans- contraction (cramps) or dilation (distention) of duction, and thereby minimizes the nociceptive the body’s hollow viscera (e.g., intestines) can signal. Aspirin is a true analgesic because it also produce pain. affects the entire sensation of pain. In contrast, The following are examples of referred pain morphine acts at synaptic sites in the CNS that from visceral sources. The pain of coronary reduce and modulate nociceptive signals. Mor- heart disease can be referred to the chest wall, phine and other narcotics seem to mimic the left axilla, and the inside of the left arm. The effects of the endogenous opioids (Chap. 15). spinal cord segments T1 and T2 innervate the The following pathway contributes to the heart and the skin (dermatomes) areas of the control of nociceptive neurons in the spinal chest, axilla, and left arm. An inflammation of cord (see Fig. 9.4). Stimulation of the PAG of the peritoneum on the diaphragm (often related the midbrain (e.g., from the limbic system fol- to the gallbladder) can be referred to the shoul- lowing a stressful episode such as a fire-fight in der region. Spinal segments C3–C5 supply sen- Chapter 9 Pain and Temperature 173 sory as well as motor innervation to the likely that pain stimuli evoke some of this diaphragm (via the phrenic nerve) and, in addi- response via pathways from the frontal cortex, tion, to the shoulder region. The source of limbic system, and hypothalamus that activate headaches is not the brain per se. Headaches the nonopiate biogenic amine analgesic system are thought to be referred from irritated nerve and the opiate-mediated analgesic system to endings in the intracranial (meningeal) and suppress the sensation of pain. other blood vessels. Conceptually, the withdrawal reflex is a A somatic source of referred pain is from the response of drawing back from a noxious stim- back. The sources of the pain can be receptors ulus and the pain sensation correlated with the associated with the ligaments and muscles reflex. In this respect, pain reflex withdrawal is attached to the bony vertebral column. The pain a normal reaction to protect the organism, and is often referred to a different spinal level. the analgesic systems are the organism’s means One concept to explain the phenomenon of of controlling the pain system. referred pain is based on the demonstration that nociceptive fibers conveying information from a cutaneous source and those from a visceral CENTRAL PAIN SYNDROME source can converge within the same projection (THALAMIC SYNDROME) neuron pool in the dorsal horn. The projection neurons of the pain pathways receiving these Injury involving the lateral spinothalamic dual inputs project to higher centers, which tract system or trigeminothalamic tract system cannot discriminate the precise source. The can result in the central pain syndrome charac- pain often is incorrectly attributed to the skin, terized by spontaneous, often excruciating which is normally the source of greater noci- burning pain (causalgia) in the region of the ceptive input. head, limbs, or body represented by the damaged tract. Other effects of the lesion are discussed in Chapters 12 and 17. Such lesions can STIMULUS-INDUCED AND occur in such locations as the cerebral cortex, STRESS-INDUCED ANALGESIA thalamus, brainstem, and spinal cord. Stimula- tion of anesthetic areas in the periphery can Severely wounded soldiers, athletes injured elicit the central pain syndrome. in sports, and professional boxers state that A lesion (e.g., produced by a stroke) in VPL they do not feel pain during and even just after and VPM and the adjacent corticospinal tract in the stressful events of combat. During a race, the internal capsule produces a central pain marathon runners undergo the feeling of “run- syndrome called the thalamic syndrome, char- ning through pain”. Electric stimulation of the acterized by hemianesthesia and an upper periaquaductal gray in humans produces a dras- motor neuron paralysis on the opposite side tic reduction in clinical pain, called stimulus- (Chaps. 12 and 17). Numerous explanations induced analgesia. Patients describe a pain that have been advanced to explain the causes of the fades away over a few minutes, and even a feel- symptoms of the thalamic syndrome (Chap. 23). ing of warmth and relaxation. The stimulation presumably activates the pain-modulating networks, including the biogenic amine analgesic PHANTOM LIMB SENSATION system and the opioid-mediated modulating system. The phantom limb is an expression of The ability to respond during emergency sit- activity in nuclei deprived of normal stimula- uations and to stress by suppressing or reduction. An amputee might feel diffuse pain in an ing the sensitivity to pain is known as amputated extremity. The phantom limb behavioral stress-produced analgesia. It is “moves” easily, even through objects and the 174 The Human Nervous System remaining limb. The wristwatch, formerly Beggs J, Jordan S, Ericson AC, Blomqvist A, Craig worn, might still be felt on a nonexistent AD. Synaptology of trigemino- and spinothala- wrist. An explanation is that the nuclear com- mic lamina I terminations in the posterior ventral plexes that previously received input from the medial nucleus of the macaque. J. Comp. Neurol. phantom limb are still present in the nervous 2003;459:334–354. Blomqvist A, Zhang ET, Craig AD. Cytoarchitec- system; when these complexes are stimulated tonic and immunohistochemical characterization in some way, they set in motion neural activi- of a specific pain and temperature relay, the ties that produce sensations felt as though posterior portion of the ventral medial nucleus, coming from the absent limb. in the human thalamus. Brain 2000;123(Pt. 3): 601–619. Craig AD. Pain mechanisms: labeled lines versus SOMATOTOPIC convergence in central processing. Annu. Rev. ORGANIZATION OF THE Neurosci. 2003;26:1–30. LATERAL SPINOTHALAMIC TRACT Craig AD, Dostrovsky JO. Medulla to thalamus. In Wall PD, Melzack R, editors. Textbook of pain. The laminated, somatotopic organization of New York: Churchill Livingston; 1999:183–214. the lateral spinothalamic tract, with fibers from Craig AD, Bushnell MC, Zhang ET, Blomqvist A. A thalamic nucleus specific for pain and tempera- successively higher levels being located antero- ture sensation. Nature. 1994;372:770–773. medial to those from lower levels, has signifi- Dubner R, Gold M. The neurobiology of pain. Proc. cance in analyzing distributions of pain Natl. Acad. Sci. USA 1999;96:7627–7630. sensation (see Fig. 7.6). Pressure on the lateral Fields HL. Pain modulation: expectation, opioid aspect of the cervical spinal cord (e.g., from an analgesia and virtual pain. Prog. Brain Res. extramedullary tumor) would interrupt pain 2000;122:245–253. and temperature fibers from the contralateral Iggo A. Sensory receptors in the skin of mammals sacral region first and then, as the tumor and their sensory functions. Rev. Neurol. (Paris) enlarges, those from lumbar, thoracic, and cer- 1985;141:599–613. vical regions. A lesion in the middle of the Ito S, Craig AD. Vagal input to lateral area 3a in cat spinal cord surrounding the central canal in the cortex. J Neurophysiol. 2003;90:143–154. Julius D, Basbaum AI. Molecular mechanisms of region of the cervical enlargement (e.g., as in nociception. Nature. 2001;413:203–210. syringomelia) would interrupt pain and temper- Light AR, Perl ER. Unmyelinated afferent fibers are ature fibers that results in the loss of pain and not only for pain anymore. J. Comp. Neurol. temperature bilaterally in both upper extremi- 2003;461:137–139. ties (Syringomelia, Chap.12). Loeser JD, Bonica, JJ, eds. Bonica’s Management of Pain. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001. SUGGESTED READINGS Melzack R. Phantom limbs. Sci. Am. 1992;266: 120–126. Andrew D, Craig AD. Spinothalamic lamina I Melzack R. Pain and the neuromatrix in the brain. J. neurons selectively sensitive to histamine: a cen- Dent. Educ. 2001;65:1378–1382. tral neural pathway for itch. Nature Neurosci. Mitchell JM, Basbaum AI, Fields HL. A locus and 2001;4:72–77. mechanism of action for associative morphine Basbaum AI. Distinct neurochemical features of tolerance. Nature Neurosci. 2000;3:47–53. acute and persistent pain. Proc. Natl. Acad. Sci. Potrebic S, Ahn AH, Skinner K, Fields HL, Bas- USA 1999;96:7739–7743. baum AI. Peptidergic nociceptors of both trigem- Basbaum AI, Woolf CJ. Pain. Curr. Biol. 1999;9: inal and dorsal root ganglia express serotonin 1D R429–R431. receptors: implications for the selective antimi- Beecher H. Pain in man wounded in battle. Ann , graine action of triptans. J. Neurosci. 2003;23: Surg. 1944;123:96–105. 10,988–10,997. Chapter 9 Pain and Temperature 175

Price DD, Greenspan JD, Dubner R. Neurons Willis WD, Westlund KN. Neuroanatomy of the involved in the exteroceptive function of pain. pain system and of the pathways that modulate Pain 2003;106:215–219. pain. J. Clin. Neurophysiol. 1997;14:2–31. Saab CY, Willis WD. Nociceptive visceral stim- Willis WD, Al Chaer ED, Quast MJ, Westlund KN. ulation modulates the activity of cerebellar A visceral pain pathway in the dorsal column of Purkinje cells. Exp. Brain Res. 2001;140:122– the spinal cord. Proc. Natl. Acad. Sci. USA 1999; 126. 96:7675–7679. Saab CY, Willis WD. The cerebellum: organization, Willis WD, Jr., Zhang X, Honda CN, Giesler GJ, Jr. functions and its role in nociception. Brain Res. Projections from the marginal zone and deep dor- Brain Res. Rev. 2003;42:85–95. sal horn to the ventrobasal nuclei of the primate Wall PD, Melzack R. Textbook of Pain. 4th ed. New thalamus. Pain 2001;92:267–276. York: Churchill Livingstone; 1999. Willis WD, Jr., Zhang X, Honda CN, Giesler GJ, Jr. Wall PD, Melzack R. Handbook of Pain Manage- A critical review of the role of the proposed ment. New York: Churchill Livingstone; 2003. VMpo nucleus in pain. J. Pain. 2002;3:79–94. 10 Discriminative General Senses, Crude Touch, and Proprioception

Somatosensory Receptors (Mechanoreceptors) Pathways Serving the Discriminative General Senses and Proprioception Pathways Serving Crude (Light) Touch and Movement Sensation Proprioceptive Pathways of the Head Proprioceptive Pathways to the Cerebellum Functional Correlations

Touch and the discriminative general senses Mechanoreceptors are encapsulated nerve end- encompass a number of sensory modalities. ings named Meissner, Ruffini, and Pacinian Touch by itself refers to crude (also called light) corpuscles and Merkel disks (see Figs. 10.1 and movement sensation, which yields little and 10.2 and Table 7.3). The mechanical information apart from the fact of contact with an transduction (mechanotransduction), from the object. The discriminative general senses (DGS) application of stimuli to these receptors to the also include the following: “pressure touch,” generation of action potentials in the sensory which enables an awareness of shape, size, and neurons, is conventionally viewed as a three- texture; stereognosis, appreciation of an object’s stage process: (1) The stimulus (touch or move- three dimensionality; perception of an object’s ment) is mechanically applied to the cells weight; vibratory sense (as tested with a tuning encapsulating the receptor nerve ending; (2) fork); position sense (awareness of body parts, the deformation is transduced into an electrical especially joints); and awareness of body and signal), the receptor (generator) potential; (3) limb movement, including direction. The last two the receptor potential is encoded into action are often grouped as kinesthetic sense. potentials (at first node of Ranvier) for trans- These modalities are monitored by extero- mission by the sensory neuron to the central ceptors located in the surface layers of the skin nervous system (CNS). Each receptor can be and oral mucosa and by proprioceptors located characterized by the quality of the modality in the deeper skin layers, joint capsules, liga- perceived, size of receptive field, stimulus ments, tendons, muscles, and periosteum. With threshold, speed of adaptation, and the first- the proviso that the correlation of a specific order fiber type projecting to the CNS. modality of sensation with a morphologically The receptive field is the region of skin identifiable nerve ending is not completely capable of activating a receptor. The stimulus conclusive, it is possible to assign the following threshold is the intensity level required to acti- receptors to modalities. vate the receptor. Adaptation is the response and adjustment a receptor makes to a stimulus. Some receptors generate action potentials SOMATOSENSORY RECEPTORS when the stimulus starts and then soon ceases (MECHANORECEPTORS) to respond. This type of receptor, called a rapidly adapting receptor, provides information Four types of somatosensory receptor are primarily when a stimulus changes. When an located in the skin and subcutaneous tissues. object (e.g., clothes) touches our skin, we soon

177 178 The Human Nervous System become unaware of the object because the the tactile sense called fluttering (felt as a gen- reacting sensors are rapidly adapting receptors. tle trembling of the skin). Each has a large Other receptors that continue to respond as receptive field and is a rapidly adapting recep- long as the stimulus is applied are called slowly tor. Merkel disks and Meissner corpuscles adapting receptors. Such receptors include have large fields and are rapidly adapting nociceptors that are responsible for the warning receptors. The Pacinian corpuscle is involved that is the perception of pain. with vibratory sense (felt as a diffuse hum- Merkel disks respond to steady skin inden- ming sensation). Vibratory sense is poorly tation from a tactile stimulus. Each has a large localized because Pacinian corpuscles have receptive field and is a slowly adapting recep- large receptive fields. In addition, they are tor. Meissner corpuscles are associated with rapid adapting receptors. Pacinian corpuscles

Figure 10.1: Sensory nerve endings in the skin. Receptors located in the epidermis include free nerve endings associated with pain and thermal sense and Merkel’s corpuscles, activated by steady skin indentation—a form of touch. Receptors located in dermal papillae, at the junction of the dermis and epidermis, are Meissner’s corpuscles, which monitor touch, especially sensing fine spatial differences. The hair receptors (plexus around each hair follicle) subserve tactile sense and flutter. Receptors located in the dermis are the pacinian corpuscles and corpuscles of Ruffini. Pacinian corpuscles are involved with sensing deep pressure and vibration. The corpuscles of Ruffini and a variant called the end bulbs of Krause subserve touch pressure and vibratory sense. Chapter 10 Discriminative Senses, Touch, and Proprioception 179

Figure 10.2: Sensory receptors of the skin. (A) Corpuscle of Ruffini, an encapsulated receptor, is supplied by a single myelinated axon that branches repeatedly to form diffuse unmyelinated terminals among bundles of collagen fibers in the core of the capsule. These terminals are presumably stimulated by the displacement of the collagen fibers among which they are intertwined. Modified Schwann cells are absent. (B) Free nerve endings in the epidermis where they lie between contiguous epithelial cells. (C) Pacinian corpuscle, an encapsulated receptor, is innervated by a single myelinated axon that extends as an unmyelinated ending through the center of the bulb. The flattened cells surrounding the axon in the core of the capsule are presumably modified Schwann cells. (D) Meissner’s corpuscle, an encapsulated receptor, is innervated by a myelinated axon that forms an unmyelinated spiral ending amid flattened transversely oriented Schwann cells. (E) Merkel’s corpuscle is a modified epidermal cell located in the basal layer of the epidermis. It is innervated by a myelinated nerve fiber “synapsing” as a free nerve ending with a Merkel’s cell. (Adapted from Cormack, 1987). 180 The Human Nervous System are also located in the connective tissues of object by palpation, otherwise known as stere- mesenteries, muscles, and interosseous mem- ognosis. Proprioception takes on various forms, branes. Ruffini corpuscles are associated with including vibratory sense, static propriocep- the sense of touch pressure and vibratory tion, and dynamic proprioception. Perceiving sense. These corpuscles are of significance to vibrations when the stem of a vibrating tuning the blind in “reading Braille” because they fork is placed on a joint or other body part can have small receptive fields and adapt rapidly, test vibratory sense. Static proprioception is enabling them to resolve fine spatial differ- expressed as the ability to sense the position of ences quickly. Each of these four receptor a body part from information received from types has a low stimulus threshold and con- that part (called position sense). Dynamic pro- veys information to the CNS via A-beta nerve prioception or kinesthetic sense is the ability to fibers of first-order neurons. Of the rapidly sense movement and balance. adapting receptors, the polymodal nociceptors of free nerve endings can act as somatosensory receptors (Chap. 9). PATHWAYS SERVING THE Receptors, especially muscle spindles and DISCRIMINATIVE GENERAL Golgi tendon organs (GTOs), are continuously SENSES AND PROPRIOCEPTION monitoring the degree of muscle contraction and tension within the tendons (Chaps. 8 and DGS Pathway From the Body, 11). The resulting “unconscious propriocep- Limbs, and Back of Head tion” is utilized in reflex arcs and by many pro- The primary role of the DGS pathway is to cessing centers, especially the cerebellum. It is convey, in response to stimuli, neural informa- now recognized that signals from spindles and tion associated with kinesthetic sense and stere- GTOs are also integrated into the lemniscal ognosis. The latter is a complex sense that is system and contribute to the conscious appreci- based on such qualities as location, spatial form, ation of position and movement sense. and the sequence of inputs over time: The inte- The major somatic modalities elicited by gration of these qualities results in the percep- mechanoreceptors are (1) tactile sensations tion of form and shape of objects that are evoked by the application of mechanical stim- touched, felt, and held in hand. In addition, (1) uli to the body surface and (2) proprioceptive the trigeminothalamic pathway responds to sim- sensations evoked by the mechanical displace- ilar stimuli from the rest of the head, (2) the lat- ments of muscles, ligaments, and joints. Pro- eral cervical system (also called the spin cervical prioception is the sense of balance, position, tract) responds to certain touch and DGS stim- and movement. uli, and (3) the anterior spinothalamic pathway The two types of tactile sensation are crude is involved in mediating crude touch and move- (light) touch and tactile discrimination. Crude ment sensations (see Figs. 10.3, 10.6, and 10.7). touch is that felt by lightly stroking the skin The DGS pathway is serially organized as a with a wisp of hair or cotton. It can be tested by basic sequence of three orders of neurons con- having an individual, with eyes closed, identify veying information to the cerebral cortex. the location of a touch. Tactile discrimination Information from the body, limbs, and back of or pressure touch is often called two-point dis- the head (scalp posterior to the coronal plane crimination, which is the ability to distinguish through the ears) is conveyed from the periph- two separate loci where two points (e.g., a pin) eral receptors over first-order neurons of the are applied to the skin; spatial resolution is spinal nerves with cell bodies in the dorsal root directly related to receptor density and is very ganglia (Features of Sensory Systems, Chap. fine at the fingertips. Tactile discrimination is 9). Their heavily myelinated fibers enter the also expressed as the ability to localize and to spinal cord as the medial bundle of the dorsal perceive the shape, size, and texture of an roots (see Figs. 10.3 and 10.4) and branch into Chapter 10 Discriminative Senses, Touch, and Proprioception 181

Figure 10.3: The discriminatory general sensory pathways originating in the spinal cord comprise the posterior column–medial lemniscus pathway and the anterior spinothalamic tract. Note that the ventral posterolateral (VPL) thalamic nucleus projects to body regions of both SI and SII. 182 The Human Nervous System

(1) collaterals, which terminate mainly in laminae III and IV of the posterior horn and (2) fibers that ascend in the ipsilateral fasciculi gracilis and cuneatus of the dorsal (posterior) column before terminating in the nuclei gracilis and cuneatus of the lower medulla. Some of the collaterals ending in the posterior horn synapse with interneurons involved with spinal reflex arcs (Chap, 8). The ascending axons of the dorsal column– medial lemniscus pathway exhibit a somatotopically organized lamination according to body area innervated (see Fig. 7.6). Fibers are added to the lateral aspect of the dorsal column (fasciculi gracilis and cuneatus) at each successively higher spinal cord level. The medial– lateral lamination at upper cervical levels consists, in sequence, of fibers from sacral, lumbar, thoracic, and cervical segments of the body. Fibers from the sacral, lumbar, and lower six thoracic levels compose the fasciculus gracilis of the posterior column and those of the upper six thoracic and all cervical levels (includes innervation of the back of head) form the fasciculus cuneatus. The fibers terminating in the nucleus gracilis originate from below T6 (including the lower extremity); those termi- Figure 10.4: The ascending projections of nating in the nucleus cuneatus originate from the anterior spinothalamic tract. Receptors above T6, including the upper extremities. The mediating crude touch and movement sensa- proprioceptive fibers from the lower extremity tions are innervated by fibers that terminate in ascend in the dorsolateral fasciculus (located the dorsal horn of the spinal cord. Axons arising from cell bodies located in the dorsal horn dorsally in the lateral column between the pos- decussate in the anterior white commissure and terior gray horn and the posterior spinocere- ascend in the anterior quadrant of the spinal bellar tract; see Fig. 7.6) with the fibers of the cord as the anterior spinohalamic tract crude lateral cervical system to the lateral cervical touch and movement sensation system (ASST); nucleus (see later). Following neural process- collateral branches terminate in brainstem ing within the nucleus gracilis and nucleus reticular nuclei B.R.nu). The main axons termi- cuneatus information is projected to the ven- nate in the ventral posterior inferior nucleus tral posterolateral (VPL) nucleus of the thala- (VPI), ventral posterolateral nucleus (VPL), mus. The processing within the posterior and central lateral (CL) nucleus of the column nuclei consists of both feedback inhi- intralaminar group of thalamic nuclei (Chap. bition and feed-forward inhibition and, in 22). VPI and VPL thalamic nuclei project to primary (S1) and secondary (S2) somatic sen- addition, modulation by distal (reflected) inhi- sory cortex (Fig. 25.3). IV and V, spinal cord bition from the cerebral cortex (Chap. 3; see laminae IV and V, respectively; S1 (area 3), pri- Fig. 3.13). The axons of second-order neurons mary somatic sensory cortex; S2, secondary that emerge from the nuclei gracilis and cunea- somatic sensory area. (Adapted from Craig and tus arc anteriorly as the internal arcuate fibers, Dostrosky.) decussate in the lower medulla, ascend as the Chapter 10 Discriminative Senses, Touch, and Proprioception 183 somatotopically organized medial lemniscus, There are somatotopic projections (1) from and terminate in the VPL nucleus of the thala- the medial lemniscus and spinothalamic tracts to mus. As it ascends, the medial lemniscus grad- the VPL nucleus and (2) from the core and shell ually shifts from a medial location in the of VPL to somatosensory cortex (areas 1, 2, 3a, medulla to a posterolateral location in the and 3b) (see Fig. 10. 5). (1) The core neurons upper midbrain. receive cutaneous input from slow and rapidly adapting receptors involved with the discrimina- Thalamus and Somatic Sensory (Somato- tion of texture. The third-order thalamic neurons sensory) Cortex. The VPL thalamic nucleus of the core receiving inputs from these receptors receives sensory input from the body via have substantial projections that terminate in fibers of the medial lemniscus and spinothala- area 3b. Those thalamic neurons of the core mic tract, which terminate in a somatotopic receiving inputs from rapidly adapting receptors pattern. VPL is parceled functionally as fol- involved with sensing texture have sparse pro- lows: The central core of the nucleus is jections that terminate in areas 1, 3b, and SII. (2) responsive to stimuli from cutaneous recep- The shell neurons receive inputs from the deep tors; the surrounding shell is responsive to tissue receptors monitoring muscle stretch, deep stimuli from deep receptors (e.g., muscle pressure, and joint sense. Those thalamic neu- spindles) (see Fig. 10.5). In addition, VPL rons of the shell receiving inputs from muscle receives reflected (distal) inhibitory influ- spindle stretch receptors have substantial projec- ences from somatosensory cortex. Axons of tions that terminate in area 3a. Those thalamic third-order neurons emerge from VPL, pass neurons of the shell receiving stimuli from deep through the posterior limb of the internal cap- pressure and joint receptors involved with sens- sule and corona radiata, and terminate in laming size and shape of objects held in the hand ina IV of the somatosensory cortex of the have sparse projections that terminate in areas parietal lobe, located in the postcentral gyrus 3a, 2, and SII. In turn, neurons from areas 3a and and in the adjacent paracentral lobule on the 3b project to areas 1 and 2 and all four areas medial surface of the hemisphere (Organiza- project to SII, which is involved in the discrimi- tion of Neocortex, Chap. 25). The somatic nation of shape, size, and texture. All five areas sensory cortex consists of the primary of SI and SII have connections with parietal lobe somatosensory cortex (SI; areas 1, 2, 3a, and association areas 5 and 7 (Chap. 25). 3b), secondary somatosensory cortex (SII) A similar structural and functional organiza- (both located in the postcentral gyrus), and the tion is expressed in the ventral posterior medial posterior parietal cortex (areas 5 and 7). (VPM) thalamic nucleus, which is the nucleus The somatotopic representations of the body receiving somatosensory input from the head surface are present in the cortex in an orderly primarily from the trigeminal nerve (see manner, but with the cortical receptive field Figs. 10.6, 14.5, and 23.3). The VPM nucleus size of the two homunculi of the primary and receives input from the trigeminothalamic secondary somatosensory cortices roughly pro- pathways and projects to the head region of the portional to the resolution of stimuli from somatosensory cortex. regions of different densities of receptors (e.g., skin); one each for areas 1, 2, 3a, and 3b of SI The Paths From Receptors to Columns of and one for SII (see Fig. 25.4) The receptive the Cortex. The sensory pathways involved field sizes are directly related to the density of with sensation are composed of sequences of receptors on the body. The back with a low neurons forming paths transmitting labeled line density of receptors has a small cortical repre- codes and pattern codes. The lemniscal and sentation compared to the much larger cortical trigeminal pathways consist primarily of pro- representation of the fingertips, which have a jections extending from the somatic receptors high density of receptors. in the body to functional columns (slabs) in the 184 The Human Nervous System

Figure 10.5: Schema illustrating the projections from the ventral posterior lateral (VPL) and ventral posterior medial thalamic (VPM) nuclei to somatosensory cortex. VPL receives input from the medial lemniscus and spinothalamic tracts, and VPM receives input from the trigeminothalamic tracts. These nuclei are organized into a central core consisting of two zones, each responsive to cutaneous stimuli, and an outer shell responsive to deep stimuli. Neurons of the central core project to cortical areas 3b and 1 (cutaneous). Neurons of the outer shell project to areas 3a (muscle spindles) and 2 (deep receptors). These projections are somatotopic. The somatosensory cortex of the parietal lobe consists of three major subdivisions: primary somatosensory cortex (SI of areas 3, 1, and 2), secondary somatosensory cortex (SII of areas 3, 1, and 2), and posterior parietal cortex (areas 5 and 7). Neurons in areas 3a and 3b project to areas 1 and 2. Neurons of SI (areas 3a, 3b, 1, and 2) project to the secondary sensory cortex (SII). Neurons from SI and SII and some thalamic neurons project to area 5, and the latter to area 7. (Adapted from Carpenter and Sutin, 1983.) Chapter 10 Discriminative Senses, Touch, and Proprioception 185 postcentral gyrus of the parietal lobe (Chap. nal nucleus and rostral portion of the spinal 25). Each receptor exhibits specificity, in that it trigeminal nucleus, axons decussate in the pon- responds to specific stimulus energy. Each line tine tegmentum and ascend as the trigemino- conveys a specific stimulus quality (e.g., posi- thalamic tract (anterior trigeminal tract) before tion sense) and processes the message in each terminating in the ventral posteromedial thala- nucleus of the pathway before arriving for mic nucleus (see Fig. 10.6). Some axons of more processing in a cortical column. The second-order neurons of the principal sensory stimulus feature encoded by a receptor in the trigeminal nucleus ascend uncrossed as the body is faithfully reproduced by the signal posterior trigeminothalamic tract (posterior received by that line in the cortex. For example, trigeminal tract) to the same thalamic nucleus. slowly adapting receptors are coupled to slowly Axons of third-order neurons arising in the adapting neurons of the thalamus that are ventral posterior medial thalamic nucleus pass sequentially coupled with slowly adapting neu- through the posterior limb of the internal cap- rons in a column of areas 3a and 3b of the sule and corona radiata before terminating in somatosensory cortex. It is of significance that the head area of the postcentral gyrus. Follow- all six layers in each cortical column represent ing processing within this gyrus, connections the same modality. Thus, many lines transmit- via association fibers are made with areas 5 ting different features of each sensation are and 7 of the parietal lobe (see Fig. 10. 5 and paths where parallel processing of the stimulus Chap. 25). features occurs. It is in the highest centers in This trigeminal pathway is structurally and the cortex that the features are integrated into a functionally the same as the dorsal column– sensation. The paths are not redundant because medial lemniscal pathway. (1) The axonal pro- they accent different features. Parallel process- jections from sensory receptors to columns in ing of stimulus features in several lines has a the postcentral gyrus are similar. (2) These con- significant role in the generation of the variety nections are maintained and sharpened by the and subtleties associated with perceptions. same processing circuits. (3) The projections from the ventral posterior medial nucleus are Trigeminothalamic Pathway From the similar to those of the ventral posterior lateral Facial Region nucleus. The projection fibers terminate in The discriminative general senses from the areas 1, 2, 3a, and 3b of the postcentral gyrus. facial region (head anterior to a coronal plane Subsequent connections with SII and areas 5 through the ears) are served via neurons of the and 7 of the parietal lobe are equivalent. trigeminal nerve, which enter the brainstem through the lateral midpons. Most fibers terminate in the principal sensory trigeminal PATHWAYS SERVING CRUDE nucleus. Other fibers bifurcate into collaterals, (LIGHT) TOUCH AND which branch and terminate in the principal MOVEMENT SENSATION sensory trigeminal nucleus and/or descend for a short distance in the spinal tract of n.V (spinal Pathway From the Body, Limbs, and trigeminal tract) and terminate in the pars oralis Back of Head of the spinal nucleus of n.V (spinal trigeminal Crude touch and movement sensation from nucleus). The principal trigeminal nucleus is the body and the back of the head (C2 der- the cranial equivalent of the nuclei gracilis and matome) is conveyed from peripheral receptors cuneatus. In all of these nuclei are located the via first-order neurons with cell bodies in the cell bodies of the second-order neurons of the dorsal root ganglia of the peripheral nerves to discriminative general senses (see Fig. 10.6). the posterolateral tract of Lissauer where the From cell bodies of neurons of the second fibers bifurcate (see Fig. 7.6). In addition to order, located in the principal sensory trigemi- those that terminate at the level of entry, some 186 The Human Nervous System

Figure 10.6: The discriminatory general sensory pathways originating in the brainstem are the anterior and posterior trigeminothalamic tracts. Note that the VPM thalamic nucleus projects to head regions of both SI and SII. The jaw reflex, illustrated on the left side of the figure, comprises (1) afferent fibers with cell bodies in the mesencephalic nucleus of n.V and (2) efferent (lower motoneurons) fibers with cell bodies in the motor nucleus of n.V. For details of structures in the brainstem, refer to Figs. 13.7, 13.10, 13.11, and 13.14. Chapter 10 Discriminative Senses, Touch, and Proprioception 187 ascend and descend several spinal levels before Lateral Cervical System terminating on interneurons of the posterior (Spinocervicothalamic Pathway) horn. Processing occurs within the interneu- The lateral cervical system mediates touch, ronal circuits of the posterior horn. proprioception, vibratory sense, and to a small The axons of neurons of the second order, degree, noxious stimuli. This system is a fast- with cell bodies presumably in laminae VI and conducting four-neuron pathway (see Fig. VII, decussate through the anterior white com- 10.7). missure, ascend as the anterior spinothalamic The first-order neurons, with cell bodies in tract which is somatotopically organized, and the dorsal root ganglia, have axons that termi- terminate in the ventral posterolateral nucleus nate in laminae III, IV, and V of the dorsal horn. of the thalamus. The anterior and lateral Second-order neurons from these laminae emit spinothalamic tracts together are referred to as axons that ascend without decussating in the the anterolateral tract or system (Chap. 9). dorsolateral fasciculus of the lateral column to Third-order neurons in VPL emit axons that the lateral cervical nucleus (see Fig. 7.6). Third- pass through the posterior limb of the internal order fibers from this nucleus, located in the capsule and the corona radiata before terminat- upper two cervical spinal segments and the ing in the postcentral gyrus. After neural pro- lower medulla, decussate in the lower medulla, cessing in the gyrus, pyramidal neurons of the ascend in the contralateral medial lemniscus, cortex project to the parietal association cortex. and terminate in the ventral posterior lateral Crude touch is also conveyed via the posterior nucleus of the thalamus. The fourth-order neu- column–medial lemniscus pathway and the rons project from VPL to the somatosensory spinocervicothalamic pathway (see Fig. 10.7). cortex (SI and SII). Pathways From the Facial Region From receptors in the facial region (anterior to coronal plane through the ears), light touch PROPRIOCEPTIVE PATHWAYS fibers convey impulses via the three divisions OF THE HEAD of the trigeminal nerves (ophthalmic, maxillary, and mandibular) and to a small extent via cranial nerves VII, IX, and X. The cell bodies Mesencephalic Nucleus of the of first-order fibers are located in the trigeminal Trigeminal Nerve; Jaw Jerk Reflex ganglion, geniculate ganglion, and superior Information from proprioceptive endings ganglia of nerves IX and X. Upon entering the (e.g., muscle spindles) in the extraocular mus- brainstem, some of these fibers terminate in the cles and muscles of mastication and facial principal trigeminal nucleus and others expression are conveyed to the CNS by Ia nerve descend in the spinal tract of n.V and terminate fibers of cranial nerves III to VII. These Ia fibers in the caudal part of the spinal trigeminal have their cell bodies in the mesencephalic nucleus known as nucleus caudalis. Second- nucleus of the trigeminal nerve. This nucleus is order neurons from these nuclei have axons unique, in that, it is the only nucleus of primary that decussate and join the ascending sensory neurons located in the CNS and is actu- trigeminothalamic tract and terminate in the ally composed of unipolar dorsal root (trigemi- ventral posteromedial nucleus of the thalamus. nal) ganglion cell bodies (see Fig. 14.2). From this thalamic nucleus, axons pass through The jaw jerk is a two-neuron reflex, similar the internal capsule before terminating somato- to the knee jerk reflex (see Fig. 10.6), which topically as a homunculus in both the primary involves the temporalis, masseter, and internal and secondary somatosensory cortex. In turn, pterygoid muscles. Tapping the chin of the SI and SII project to the parietal association slightly opened mouth with a reflex hammer cortex, where more processing occurs. evokes this reflex. The afferent limb of the 188 The Human Nervous System

Figure 10.7: Ascending tracts from the spinal cord, including the anterior and posterior spinocerebellar tracts, cuneocerebellar tract, and spinocervicothalamic pathway.

reflex arc is composed of neurons with cell motoneurons in the motor nucleus of the bodies of the mesencephalic nucleus. These trigeminal nerve. These lower motoneurons neurons convey influences from the muscle form the efferent limb innervating the muscles spindles directly via collateral fibers to lower of mastication. Chapter 10 Discriminative Senses, Touch, and Proprioception 189

T1 through L2, and ascend uncrossed as the PROPRIOCEPTIVE PATHWAYS TO posterior spinocerebellar tract. The fibers enter THE CEREBELLUM the cerebellum by way of the inferior cerebellar peduncle, one of three fiber bundles on each The cerebellum plays an essential role in side giving access to the cerebellum. The pos- body movement and maintenance of equilib- terior spinocerebellar tract is primarily con- rium. Thanks to the cerebellum, voluntary mus- cerned with conveying information from cles are coordinated in their contraction and muscles and joints in the lower limbs. relaxation so as to permit smooth movement. For this, the cerebellum requires a continuous Cuneocerebellar Tract supply of unconscious information from mus- First-order neurons ascend in the ipsilateral cles, tendons, and joints to which receptors fasciculus cuneatus of the spinal cord and ter- throughout the body and limbs contribute. The minate in the accessory cuneate nucleus (equiv- pathways for this input are outlined here (see alent to the dorsal nucleus of Clarke), which is Fig. 10.7); the main discussion of the cerebel- located lateral to the cuneate nucleus (see Fig. lum is in Chapter 17. 13.9). Second-order fibers, identified now as Information that arrives from muscle spin- the cuneocerebellar tract, enter the cerebellum dles (Ia fibers) and Golgi tendon organs (Ib through the inferior cerebellar peduncle and fibers) is primarily unconscious and proprio- terminate in portions of the anterior and poste- ceptive in nature, but, in addition, there are rior lobes dedicated to the upper extremities. inputs from exteroceptors for crude touch, This pathway is the rostral equivalent of the pressure, and pain. There are direct and indirect posterior spinocerebellar tract. pathways from these receptors. The direct pathways convey input without an intervening Anterior Spinocerebellar Tract (see Fig. 10.7) synapse from the spinal neurons to the cerebel- This tract originates from cells, called spinal lum. They are (1) the posterior spinocerebellar border cells, in the lumbosacral cord on the tracts for information from the lower limbs and periphery of the anterior horn and other cells in lower half of the body and (2) the cuneocere- the posterior horn and intermediate gray. bellar tracts for information from the upper Second-order fibers decussate in the spinal limbs and upper half of the body (see Fig. cord and ascend through the brainstem as the 10.7). The indirect pathways are (1) the spin- anterior spinocerebellar tract, which enters the ocervicocerebellar pathway, with a synaptic cerebellum along the dorsal margin of the supe- relay in the lateral reticular nucleus of the rior cerebellar peduncle. Most fibers terminate medulla (see Fig. 13.9), and (2) the spinoolivo- somatotopically in the vermis of the anterior cerebellar pathway, with a synaptic relay in the lobe on the contralateral side in that part of the inferior olivary nucleus of the medulla (see Fig. homuncular area representing the lower 13.10). extremity and trunk. Some recross within the Two complete somatotopic representations cerebellum to terminate on the same side as can be traced on the cerebellar cortex, one origin, whereas others terminate bilaterally homunculus on the anterior lobe and the other (see Fig. 18.2). (in halves) on the posterior lobe (see Fig. 18.2). Rostrospinocerebellar Tract Posterior Spinocerebellar Tract This tract is presumed to arise from cells in First-order neurons that convey impulses the intermediate gray zone of the cervical from peripheral receptors into the spinal cord enlargement. It ascends as an uncrossed tract terminate in the dorsal nucleus (Clarke’s whose fibers pass through both the inferior and nucleus), found in lamina VII. Second-order superior cerebellar peduncles before terminat- fibers arise from this nucleus, located at levels ing in the area of the homunculus representing 190 The Human Nervous System the upper extremity in the anterior lobe of the glia (with no synapses within them) just out- cerebellum. side the CNS: dorsal root ganglia, trigeminal The pattern of termination of the posterior ganglion, geniculate ganglion, and superior spinocerebellar and cuneocerebellar inputs to ganglia of cranial nerves IX and X. The neu- the cerebellum is somatotopic to form separate rons of the second order have cell bodies in a homunculi rostrally in the anterior lobe and nucleus on the ipsilateral side and give rise to caudally in the posterior lobe (see Fig. 18.2). axons that decussate to the contralateral side The anterior spinocerebellar and rostrospino- and ascend as tracts, which terminate in the cerebellar tracts were previously thought to thalamus (ventral posterior nucleus and poste- convey somatic sensory information from the rior thalamic region). The neurons of the third lower and upper limbs, respectively. It is now order project from the thalamus to the postcen- thought that they relay feedback signals to the tral gyrus (primary somatic area) and adjacent cerebellum, monitoring the amount and quality to the secondary somatic area (see Fig. 25.3). of activity in the descending motor pathways, Note that the spinothalamic fibers (neurons of rather than conveying information from the the second order) decussate at all levels of the periphery (Chap. 17). spinal cord, with each fiber crossing at a spinal level near the location of its cell body, whereas Indirect Pathways all second-order neurons of the posterior The spinoreticular fibers of the anterolateral column–medial lemniscal pathway have axons pathway include a population originating at all that decussate at a common level in the lower spinal levels and terminating in the lateral cer- medulla, where they are known as internal vical nucleus and other small nuclei in the arcuate fibers. medulla. This spinocervicocerebellar pathway Crude touch can be conveyed via two path- is completed by neurons arising from these ways: (1) the anterior spinothalamic tract (and nuclei and terminating in the cerebellum. In its cranial equivalent, the anterior trigeminal this way, the cerebellum receives exteroceptive tract) and (2) the posterior column–medial lem- input. niscal pathway (and its cranial equivalent, the The spinoolivary tract, activated by cuta- anterior and posterior trigeminal tracts). neous and proprioceptive afferent fibers of the Loss of tactile sensibility is known as tactile spinal nerves, originates from cell bodies anesthesia. Diminution is tactile hypesthesia located at all spinal levels (see Fig. 7.6). The and an exaggeration, which is often unpleasant, tract terminates in the inferior olivary nuclei is tactile hyperesthesia. The latter can be accom- of the medulla (see Fig. 13.10). Olivocerebel- panied by paresthesias, the sensations of lar fibers cross the midline and enter the numbness, tingling, prickling, and feeling of cerebellum through the inferior cerebellar discomfiture. peduncle. Impairment of the Posterior Column-Medial Lemniscus Pathway FUNCTIONAL CORRELATIONS Interruption of the posterior column-medial lemniscus pathway causes disturbances in the The general sensory pathways conveying appreciation of certain sensations and in the pain and temperature, tactile sensibility, and regulation and control of movements. discriminative senses have, with a few excep- The alterations in the appreciation of the tions, similar features. The neurons of the first- discriminative general senses include the order innervate receptors in the periphery and following: terminate within nuclei (or laminae) in the ipsilateral half of the spinal cord or brainstem. The 1. Diminution, not loss, of crude touch. This cell bodies of these neurons are located in gan- modality is partially retained because the Chapter 10 Discriminative Senses, Touch, and Proprioception 191

anterior spinothalamic tract is intact and Spinal Cord Lesions and the Crude (Light) functional. Touch Pathways 2. Loss of vibratory sense. The perception of Following a lesion in the spinal cord, the the “buzz” of vibrations is tested by placing appreciation of light touch is less apt to be the base of a vibrating tuning fork on a joint impaired than any of the other sensory modali- or bone (e.g., knee, elbow, finger, spinous ties. This is because light touch is conveyed by process of vertebra). more than one route: the posterior columns, the 3. Astereognosis (literally meaning not know- anterolateral pathway, and the lateral cervical ing solids) refers to loss of the ability to rec- pathway. A unilateral lesion of the posterior ognize a common object by feel and columns results in the loss of two-point dis- palpation. For example, a patient with aster- crimination on the same side of the body as the eognosis is unable to identify a key, coin, or lesion while light touch persists, although it pencil by handling or touch. The ability to might be marginally lowered, because the recognize objects by sight is unimpaired. anterolateral pathway is intact. A unilateral 4. Loss of two-point discrimination refers to lesion of the anterolateral pathway results in the ability to recognize two blunt points as loss of pain perception on the opposite side of two points when applied simultaneously. body, but, again, light touch persists or might 5. Loss of position sense refers to the ability to be marginally lowered because the posterior know where a part of the body is located or columns are intact. to appreciate movement of a joint.

Ataxia (without order) refers to unsteady, SUGGESTED READINGS awkward, and poorly coordinated movements. It can be caused by lesions in the pathways for Brown AG. The spinocervical tract. Prog. Neuro- proprioceptive stimuli (i.e., the posterior col- biol. 1981;17:59–96. umn–medial lemniscus pathway including the Burgess PR, Wei JY, Clark FJ, Simon J. Signaling of dorsal roots, posterior column [posterior col- kinesthetic information by peripheral sensory umn ataxia], nuclei gracilis and cuneatus, and receptors. Annu. Rev. Neurosci. 1982;5:171–187. medial lemniscus. Patients show an unsteady Carpenter MB, Sutin J. Human Neuroanatomy. Bal- gait while walking or turning; to reduce the timore: Williams & Wilkins; 1983. unsteadiness, they walk with a broad base. In Cascio CJ, Sathian K. Temporal cues contribute to severe cases, a patient might stagger and fall tactile perception of roughness. J. Neurosci. 2001;21:5289–5296. while the eyes are closed. The signs of ataxia Connor CE, Johnson KO. Neural coding of tactile are more pronounced in the dark or with eyes texture: comparison of spatial and temporal closed. The severity of the symptoms is mechanisms for roughness perception. J. Neu- reduced when the subject can use visual cues; rosci. 1992;12:3414–3426. this is consistent with the concept that two or Cormack DH. Ham’s Histology. Philadelphia: Lip- three of the following sources of sensory input pincott Williams & Wilkins; 1987. are essential for adequate regulation of pos- Craig AD, Dostrovsky JO. Medulla to thalamus. In ture and movement: proprioceptive general Wall PD, Melzack R, eds. Textbook of pain. New senses, vision, and vestibular sense. York: Churchill Livingston; 999:183–214. Romberg’s sign is often used to detect poste- Darian-Smith I. Touch in primates. Annu. Rev. Psy- rior column ataxia. In the erect position with chol. 1982;33:155–194. Field T. Touch. Cambridge, MA: MIT Press, 2001. feet close together, an ataxic patient will sway Garcia-Anoveros J, Corey DP. The molecules of when the eyes are closed; swaying is reduced mechanosensation. Annu. Rev. Neurosci. 1997; or abolished when the eyes are opened. Cere- 20:567–594. bellar ataxia is another form of this disorder Goodwin AW, Wheat HE. How is tactile information (Chap. 17). affected by parameters of the population such as 192 The Human Nervous System

non-uniform fiber sensitivity, innervation geom- Lindsay RM. Role of neurotrophins and trk etry and response variability? Behav. Brain Res. receptors in the development and maintenance 2002;135:5–10. of sensory neurons: an overview. Philos. Goodwin AW, Wheat HE. Sensory signals in neural Trans. R. Soc. Lond. B. Biol. Sci. 1996;351: populations underlying tactile perception and 365–373. manipulation. Ann. Rev. Neurosci. 2004;27:53–77. Mountcastle VB. The columnar organization of the Goodwin AW, Macefield VG, Bisley JW. Encoding neocortex. Brain 1997;120(Pt. 4):701–722. of object curvature by tactile afferents from human Pare M, Elde R, Mazurkiewicz JE, Smith AM, Rice fingers. J. Neurophysiol. 1997;78:2881–2888. FL. The Meissner corpuscle revised: a multiaffer- Hudspeth AJ, Logothetis NK. Sensory systems. ented mechanoreceptor with nociceptor immuno- Curr. Opin. Neurobiol. 2000;10:631–641. chemical properties. J. Neurosci. 2001;21:7236– Iggo A. Sensory receptors in the skin of mammals 7246. and their sensory functions. Rev. Neurol. (Paris) Schmidt RF, ed. Fundamentals of Sensory Physiol- 1985;141:599–613. ogy. New York: Springer-Verlag; 1986. Iggo A, Andres KH. Morphology of cutaneous Sinclair DC. Mechanisms of Cutaneous Sensation. receptors. Annu. Rev. Neurosci. 1982;5:1–31. New York: Oxford University Press; 1981. Iwamura Y, Iriki A, Tanaka M. Bilateral hand repre- Vallbo AB, Olausson H, Wessberg J, Kakuda N. sentation in the postcentral somatosensory cor- Receptive field characteristics of tactile units tex. Nature. 1994;369:554–556. with myelinated afferents in hairy skin of Jenmalm P, Birznieks I, Goodwin AW, Johansson human subjects. J. Physiol. 1995;483 (Pt. 3): RS. Influence of object shape on responses of 783–795. human tactile afferents under conditions charac- Wessberg J, Olausson H, Fernstrom KW, Vallbo AB. teristic of manipulation. Eur. J. Neurosci. 2003; Receptive field properties of unmyelinated tactile 18:164–176. afferents in the human skin. J. Neurophysiol. John KT, Goodwin AW, Darian-Smith I. Tactile dis- 2003;89:1567–1575. crimination of thickness. Exp. Brain. Res. 1989; Wheat HE, Goodwin AW, Browning AS. Tactile res- 78:62–68. olution: peripheral neural mechanisms underly- Johnson KO. The roles and functions of cutaneous ing the human capacity to determine positions of mechanoreceptors. Curr. Opin. Neurobiol. 2001; objects contacting the fingerpad. J. Neurosci. 11:455–461. 1995;15:5582–5595. 11 Motoneurons and Motor Pathways

Lower Motor Neurons Upper Motor Neurons Motor Areas of the Cerebral Cortex Motor Pathways Voluntary Movements

The sensory systems create our mental are the cerebellum (Chap. 18) and the four prin- images of the external world. These representa- cipal nuclei of the basal ganglia (striatum, tions provide us with information and cues that globus pallidus, substantia nigra, and subthala- guide the motor systems to generate move- mic nucleus; Chap. 24). Both are integral neu- ments produced by the coordinated contrac- ral structures involved in parallel re-entrant tions and relaxations. The motor systems are circuit systems. Both the cerebellum and basal hierarchically organized in the central nervous ganglia receive direct or indirect input from the system (CNS) as the spinal neuronal circuits cerebral cortex and, following processing, proj- that control the automatic stereotypic reflexes ect influences to discrete nuclei of the thalamus (Chap. 8). Higher centers in the brainstem that relay (re-entry) via the thalamocortical cir- mediate postural controlled and rhythmic loco- cuit to the cerebral cortex. Their outputs are motor movements. The highest centers, includ- also conveyed to the brainstem and, subse- ing the motor areas of the cerebral cortex, quently, to the spinal cord (Chaps. 3 and 24). initiate and regulate complex skilled voluntary Each re-entrant circuit includes both direct and movements. indirect pathways that facilitate and inhibit The major components of the somatic motor movement. The cerebellum is involved in mod- system are organized and longitudinally ori- ulating motor systems, coordinating eye move- ented along the neuraxis as two pathway sys- ments, balance, body and limb movements, tems: (1) the phylogenetically new direct motor learning, and even some cognitive func- pathways that fine-tune and control voluntary tions. The basal ganglia have major roles in the movements namely the corticospinal tract and control of voluntary movements and, to some the corticobulbar tract originating in the cere- degree, with cognition and nonmotor behavior. bral cortex and project to terminate in the anterior horn of the spinal cord and nuclei of the brainstem; (2) the phylogenetically old more LOWER MOTOR NEURONS diffuse and indirect pathways that primarily mediate reflex and postural control of the mus- The voluntary (striated, skeletal) muscles are culature, namely descending indirect pathways innervated by alpha motoneurons, which have from the cerebral cortex to brainstem nuclei heavily myelinated, fast-conducting axons that that project to the anterior horn of the spinal terminate in motor end plates of extrafusal stri- cord (e.g., corticoreticular and cortico pretico- ated muscle fibers. Because these neurons are spinal tracts). the only pathway through which the sensory Two prominent neural structures related to systems and the descending upper motoneuron these major components of the motor system pathways of the CNS exert their influences

193 194 The Human Nervous System upon striated muscles, they function as the final active alpha motoneuron so that it can be common pathway, the final link between the excited again (see Fig. 3.11). Gamma moto- CNS and the voluntary muscles. The intrafusal neurons are not linked to Renshaw cells. striated muscles of the muscle spindles are innervated by gamma motoneurons, which have The lower motoneurons are the general lightly myelinated, slow-conducting axons. somatic efferent (GSE) components of spinal The term lower motoneuron, as used in clini- nerves and of cranial nerves III, IV, VI, and cal neurology, refers to motor neurons that inner- XII, which innervate the extraocular and vate the voluntary muscles. Destruction of the tongue musculature. They are also special vis- lower motoneurons results in abolishing volun- ceral efferent (SVE) components of cranial tary and reflex responses, rapid atrophy, and (branchiomeric) nerves V, VII, IX, X, and XI, flaccid paralysis of the muscles innervated; these which innervate the muscles of mastication and signs are referred to as a lower motoneuron facial expression as well as the pharyngeal and paralysis (Chap. 12). The lower motoneurons laryngeal musculature (Chap. 14). have their cell bodies within the anterior horn of Lower motoneurons of the spinal cord are the spinal cord and in the motor nuclei of the often called anterior horn motoneurons brainstem; the latter innervate voluntary muscles because of the position of their cell bodies. It is supplied by the cranial nerves (e.g., muscles of important to recognize that lower motoneuron facial expression) (see Figs. 8.1 and 8.2). axons are in both cranial and spinal nerves. As The term upper motoneuron refers to indicated in Chapter 7, an alpha motoneuron descending motor pathways within the CNS that and all the muscle fibers it innervates is called either directly or indirectly exerts influences on a motor unit. lower motoneurons. The activities of alpha and gamma motoneurons are affected by inputs from Location of Cell Bodies of peripheral receptors via the spinal and cranial Lower Motoneurons nerves and from upper motoneurons. At spinal The cell bodies of the alpha and gamma cord levels, local interneurons, part of intraseg- motoneurons are organized into functionally mental and intersegmental circuits within the defined groups in lamina IX of the ventral horn gray matter, exert both excitatory and inhibitory and into general somatic cranial motor nuclei influences on these lower motoneurons. in the brainstem (Chap. 14). The dendrites of these neurons extend beyond the designated Alpha and Gamma Motorneurons Compared borders of lamina IX. Several differences exist between alpha and gamma motoneurons: 1. Motoneurons are arranged in a medial– lateral topographic pattern in the anterior 1. Alpha motoneurons can be stimulated horn (see Fig. 11.1). The medial group com- monosynaptically (i.e., directly, not through prises motoneurons that innervate axial interneurons) by groups Ia and II afferent muscles (neck and back). An intermediate fibers from muscle spindles and by some group innervates proximal muscles of the terminals of the corticospinal, lateral limbs (shoulder and arm, hip and thigh). The vestibulospinal and medullary reticulospinal most lateral group consists of neurons that tracts. Gamma motoneurons are not stimu- innervate the distal muscles of limbs (fore- lated monosynaptically. arm and hand, leg and foot). 2. Alpha motoneurons emit axon collaterals 2. The motoneurons follow a flexor–extensor that terminate on Renshaw cells, which in pattern (see Fig. 11.1). The flexor muscle turn, have inhibitory synapses with the same group is located dorsally and the extensor alpha motoneurons. This forms a negative muscle group is located ventrally in the feedback circuit that serves to turn off an anterior horn. Chapter 11 Motoneurons and Motor Pathways 195

3. The motoneurons innervating a specific segment. Thus, a lesion limited to one spinal muscle or related muscles are clustered in root or nerve will result in only a partial a narrow, longitudinally oriented, three- paralysis (paresis) of the muscles involved. dimensional column. This column extends 4. The alpha motoneurons are presumed to be through more than one spinal segment. As a organized into groups on the basis of their consequence, each muscle is innervated by functional attributes as (1) phasic motoneu- axons originating from more than one spinal rons and (2) tonic motoneurons. The phasic

Figure 11.1: The alpha and gamma motoneurons are arranged in functionally defined groups in lamina IX of the ventral horn. The motoneurons located medially innervate axial (neck and back) musculature and those located laterally innervate the proximal and distal limb musculature. The motoneurons located dorsally innervate flexor muscles and those located ventrally innervate extensor muscles. The medial motoneurons are interconnected by intersegmental neurons with long axons, and the lateral motoneurons are interconnected by intersegmental neurons with shorter axons. The cylinder extending through more than one spinal segment in lamina IX represents the distribution of lower motoneurons innervating a specific muscle or related muscles. 196 The Human Nervous System

motoneurons are large and fire with brief Clinicians often equate the term upper bursts at high frequencies. They are active motoneuron paralysis with injury to the lateral during rapid movements of short duration corticospinal tract, sometimes including the that exert great force. The tonic motoneu- corticobulbar tract (cortical fibers that termi- rons are relatively small and fire with brief nate in the brainstem). In addition, the corti- bursts at low frequencies. They are active cospinal tract is referred to as the pyramidal during delicate movements requiring little tract because its fibers go through the medul- force and that sustain moderate tension for lary pyramid. The term extrapyramidal system an extended period of time. refers to all other descending motor tracts, 5. The intersegmental interneurons (pro- which do not go through the pyramid, and their priospinal interneurons, Chap. 6) coordinat- processing centers. ing alpha and gamma motoneurons at Upper motoneurons have significant roles in different spinal cord segments have axons voluntary motor activity, maintenance of pos- located in the white matter (see Fig. 11.1). ture and equilibrium, control of muscle tone, The medial motoneurons (axial muscles) are and reflex activity. In general, the influences interconnected by intersegmental neurons conveyed via the descending supraspinal path- with long axons. The latter extend through ways exert their effects (1) on groups of mus- many spinal levels in the anterior funiculus. cles and movements (e.g., flexion, extension, The lateral motoneurons (limb muscles) are adduction) not primarily on one specific mus- interconnected by intersegmental neurons cle, and (2) reciprocally upon agonist and with shorter axons. The latter extend antagonist muscle groups (e.g., they facilitate through a lesser number of spinal segments flexion and inhibit extension, or inhibit flexion in the lateral funiculus. and facilitate extension). The upper motoneurons exert their influences on lower motoneurons through both direct monosynaptic UPPER MOTOR NEURONS connections and via indirect multisynaptic connections with interneurons. Upper motoneuron pathways convey facilitatory (excitatory) and inhibitory signals to control lower motoneuron activity. These MOTOR AREAS OF THE descending pathways are regulated directly or CEREBRAL CORTEX indirectly by the cerebral cortex, cerebellum, and basal ganglia (Chaps. 24 and 25). In turn, Several areas of the cerebral cortex are des- the upper motoneurons synapse directly, and ignated as motor areas. These include the pri- indirectly through interneurons, with the alpha mary motor cortex (area 4, motor strip, MI), and gamma motoneurons that integrate coordi- premotor cortex (areas 6 and 8), supplementary nated skeletal muscle reflexes and voluntary motor cortex (portion of area 6), and secondary movements. motor cortex (MII) (see Figs. 25.3 and 25.4). The descending upper motoneuron path- The primary motor cortex (area 4) is located ways, located exclusively within the CNS; com- in the precentral gyrus and the rostral half of prise the corticospinal (pyramidal) and the paracentral lobule. Direct electrical stimula- corticobulbar tracts originating in the cerebral tion of this area evokes movements associated cortex (see Figs. 11.2 and 11.3), the rubro- with the voluntary muscles on the contralateral spinal and tectospinal tracts, originating in the side. A map of this electrically excitable cortex midbrain (see Fig. 11.3), and the reticulospinal produces a somatotopically organized motor and vestibulospinal tracts, originating in the homunculus (little man; see Fig. 25.4). The lower brainstem (pons and medulla) (see Figs. homunculus hangs upside down with the lar- 11.3 and 16.9). ynx and tongue in the lowest part adjacent to Chapter 11 Motoneurons and Motor Pathways 197

Figure 11.2: Corticospinal pathways. These pathways are composed of descending fibers that originate from widespread areas of the cerebral cortex and pass through the posterior limb of the internal capsule, crus cerebri, pons, pyramid, and spinal cord. Most fibers terminate upon spinal interneurons that, in turn, synapse with lower motoneurons. Some fibers terminate directly upon lower motoneurons. The lateral corticospinal tract crosses over at the lower end of the medulla as the pyramidal decussation, and the anterior corticospinal tract crosses over in upper spinal cord levels. A small number of lateral corticospinal tract fibers do not decussate (not illustrated). 198 The Human Nervous System the lateral fissure, followed upward by the tional to the skill, precision, and control of the head, upper limb, thorax, abdomen, and lower movements in that region (e.g., large area for extremity; the latter is located in the rostral larynx, tongue, thumb, and lips). The role of paracentral gyrus. The amount of motor cortex area 4 is to participate in the execution of devoted to specific regions is roughly propor- skilled and agile voluntary movements.

Figure 11.3: Descending motor pathways to the spinal cord including the reticulospinal tracts (corticoreticulospinal pathways), rubrospinal tracts (corticorubrospinal pathways), and vestibulospinal tracts. The corticoreticular fibers terminate bilaterally but with a slight contralateral pre- ponderance. Chapter 11 Motoneurons and Motor Pathways 199

Although the motor cortex contributes to the (4) corticotectospinal pathway, (5) vestibulo- regulation of axial and proximal limb muscula- spinal tracts, and (6) raphe–spinal and ceruleus– ture, it has a more critical role in the control of spinal pathways (aminergic pathways). These the distal muscles on the contralateral side of pathways are involved with motor circuits asso- the body. ciated with the spinal cord and spinal nerves. The premotor cortex, located rostral to area These systems also have equivalent roles influ- 4, consists of areas 6 and 8. Area 8, known as encing local motor circuits of the brainstem the frontal eye field, is concerned with eye and the cranial nerves. Many of the fibers of the movements. Stimulation of this area results in systems have significant roles in feedback cir- conjugate movements of the eyes directed to cuits that modulate the activities of the ascend- the opposite side. The premotor cortex on the ing sensory pathways (Chaps. 9 and 10). lateral surface of the lobe has (1) a primary role in the control of the proximal limb and axial Corticospinal Tract musculature and (2) an essential role in the ini- The fibers of the corticospinal tract (CST) tial phases of orientation movements of the originate from pyramidal cells (cell bodies with body and upper limbs directed toward a target. pyramid shape) in the cerebral cortex and ter- The supplementary motor cortex, located on minate in the spinal cord. About one-third of the medial aspect of area 6, has a somatotopic the fibers originate from Brodmann’s area 4, organization. It is important for programming one-third from area 6 of the frontal lobe, and of patterns and sequences of movements. For the remainder from areas 3, 1, 2, and 5 of the example, the response to electric stimulation on parietal lobe. Most fibers terminate on inter- one side of this area activates complex patterns neurons of spinal cord circuits that synapse on of movement not only of the contralateral limbs the lower motoneurons. About 3% of CST but also includes bilateral movements of the axons originate from giant pyramidal cells in limbs of both sides. Both the premotor cortex area 4, called Betz cells; these axons have and the supplementary motor cortex project to monosynaptic contacts with some alpha moto- the primary motor cortex. neurons and interneurons in lamina IX. The axons of the somatotopically organized General Statement corticospinal tract descend through the ipsilat- The primary motor cortex (area 4), premotor eral posterior limb of the internal capsule (near cortex, and supplementary motor cortex are the genu), the middle portion of the crus cere- somatotopically organized. Area 4 and the sup- bri of the midbrain, the basilar pons and the plementary motor cortex have direct projec- pyramids of the medulla (see Figs. 1.8, 11.2, tions via the corticospinal tracts to the spinal 13.4, and 13.5). The CST emits collateral cord. The premotor cortex projects primarily to branches to some nuclei of the basal ganglia, the reticular formation of the pons and medulla. thalamic nuclei, the red nucleus, and brainstem The premotor cortex and the supplementary reticular nuclei, thereby exerting widespread motor cortex are higher ordered motor cortical influences on nuclei within the brain as well as regions that have connections with the primary on lower motoneurons. motor cortex. At the junction between the medulla and spinal cord, approximately 90% of the 1 million fibers in each tract cross as the pyramidal MOTOR PATHWAYS decussation and descend in the posterior half of the lateral funiculus as the lateral corticospinal The descending motor pathways are subdi- tract, which terminates at all spinal levels in vided into systems called the (1) corticospinal laminae IV through VII and IX (see Fig. 7.5). and corticobulbar tracts, (2) corticoreticulo- About 10% of the fibers descend without cross- spinal pathways, (3) corticorubrospinal pathway, ing in the ipsilateral anterior funiculus as the 200 The Human Nervous System anterior corticospinal tract (CST), which termi- 17). These interneurons are integrated in cir- nates after crossing in the anterior white com- cuits, which innervate the cranial nerve motor missure in lamina VIII in cervical and upper nuclei, including nerves III, IV,V,VI, VII, and thoracic cord levels. A small proportion of XII and the nucleus ambiguus. The descend- fibers, roughly 2%, descend without decussating ing influences to the nucleus of the accessory as the uncrossed lateral corticospinal tract. nerve are probably conveyed via uncrossed The functional roles of these pathways can indirect corticobulbar projects, which facili- be summarized as follows: (1) The lateral CST tate the contraction of the ipsilateral stern- is preferentially involved with movements of ocleidomastoid and trapezius muscles. the distal upper and lower extremities (hands 2. Direct corticobulbar fibers from each hemi- and feet) and, thus, has a key role in the execu- sphere to the motor nuclei of the cranial tion of skilled movements; (2) the anterior CST nerves originate in the cerebral cortex, is preferentially involved with control of axial descend in the genu of the internal capsule, muscles (neck, shoulder, and trunk); and (3) and pass as crossed and uncrossed fibers to those lateral CST fibers originating from the and through both the ipsilateral and contralat- parietal lobe form a reflected feedback path- eral brainstem before synapsing with the way modulating sensory input in the dorsal lower motoneurons of the motor nuclei of cra- horn of the spinal cord (Chap. 9). nial nerves V (muscles of mastication), VII The CST exert their influences on local (muscles of facial expression), and XII spinal reflex circuits involving interneurons (tongue musculature. The lower motoneurons and both alpha and gamma motoneurons. Glu- innervating the muscles of facial expression tamate is the likely neurotransmitter released below the level of the eye (e.g., buccinator, by these tracts (Chap. 15). Acting through labial muscles) are a clinically significant interneurons (any neuron that is intermediary exception (Chap. 14); they are innervated only in position between two neurons), the CST by corticobulbar fibers, which have decus- generally evokes excitatory postsynaptic poten- sated, not by descending uncrossed fibers. tials [EPSPs] on the local circuits involved with 3. Fibers of reflected feedback pathways proj- the flexor limb musculature (agonists) and ect influences from sensory cortical areas 3, IPSPs on the circuits involved with the extensor 1, 2, and 5 (parietal lobe) to sensory relay musculature (antagonists). nuclei of the ascending pathways, including the nuclei gracilis and cuneatus of the poste- Corticobulbar Tract rior column–medial lemniscal pathway, The cerebral cortical (supranuclear, upper principal sensory trigeminal nucleus, spinal motoneuron) projections to the nuclei of the trigeminal nucleus, and the nucleus of the cranial nerves and brainstem nuclei of the solitary fasciculus. These fibers are involved ascending pathways are known as corticobul- with processing sensory influences in the bar fibers. This pathway has a role similar to nuclei of ascending pathways. that of the CST: Extrapyramidal System 1. Indirect corticobulbar fibers (often included With the exception of the pyramidal system, with corticoreticular fibers) originate in the the descending supraspinal tracts, together premotor, motor, and somesthetic areas (areas with their nuclei and feedback circuits, influ- 6, 4, 3, 1, 2, and 5) of the cerebral cortex, encing somatic motor activity of voluntary descend in the genu of the internal capsule, muscles, are incorporated into the so-called and pass through both the ipsilateral and con- “extrapyramidal system.” The term is loosely tralateral brainstem before synapsing directly used and many authorities have discarded it. with interneurons of the brainstem reticular The descending tracts, which convey influ- formation (see pseudobulbar palsy in Chap. ences to the lower motoneurons, are actually Chapter 11 Motoneurons and Motor Pathways 201 neuronal links in pathway systems of complex nate on interneurons and some on gamma circuitry involving the cerebral cortex, basal motoneurons (see Fig. 11.3). They can facili- ganglia, thalamus, cerebellum, brainstem tate and inhibit local spinal circuits involved in reticular formation, and related structures. both reflex and voluntary movements. These Such systems include the corticorubrospinal, corticoreticulospinal pathways are involved in cerebellorubrospinal, corticoreticulospinal, maintaining posture (upright position) for cerebelloreticulospinal, cerebellovestibulo- movements that orient the body toward the spinal, and vestibular nerve–vestibulospinal external stimuli and for crude stereotypic vol- pathways. The extrapyramidal system is dis- untary movements of the extremities, such as cussed in Chapter 24. extending the limb toward an object. This pathway acts as a link in the autonomic Corticoreticulospinal: Corticoreticular and nervous system, conveying influences to the Reticulospinal Tracts sympathetic and parasympathetic centers in the The sequence of corticoreticular and reticu- spinal cord (see Fig. 11.3). Descending fibers lospinal tracts comprises the corticoreticu- from the autonomic centers in the hypothala- lospinal pathway (see Fig. 11.3). From their mus project their influences directly to spinal origin in the premotor cortex (area 6) of the levels and to visceral centers in the reticular frontal lobe, corticoreticular fibers descend formation of the lower brainstem. This region, along with the corticospinal tract and terminate including the nucleus gigantocellularis, con- in the pontine and medullary reticular nuclei of tains cardiovascular, respiratory, and other vis- the brainstem reticular formation on both sides. ceral centers. Their influences are conveyed to The latter also receives input from ascending the spinal cord via the lateral reticulospinal pathways and the cerebellum (Chap. 13). tract. Expressions of this include the modula- The reticulospinal tracts include the lateral tion of the heartbeat, dilatation of the pupil, (medullary) reticulospinal tract and the medial perspiration, shivering, and the activity of (pontine) reticulospinal tract that extend sphincters of the gastrointestinal and urinary throughout the spinal cord. These tracts are pri- systems. marily uncrossed and are not somatotopically organized. Corticorubrospinal Pathway: The medial (pontine) reticulospinal tract Corticorubral and Rubrospinal Tracts originates from the nuclei reticularis, pontis The corticorubral tract originates in areas 4 oralis, and caudalis (Chap. 13) and descends and 6 and terminates in the ipsilateral nucleus mainly as uncrossed fibers in the anterior ruber (red nucleus) of the midbrain (see Figs. funiculus (included in medial longitudinal fas- 11.3 and 13.16). This nucleus is a processing ciculus [MLF], see Medial Longitudinal Fasci- center of the corticorubrospinal pathway. The culus) and terminates at all spinal levels in the rubrospinal tract originates in the magnocellu- medial parts of the ventral horn and intermedi- lar portion of the red nucleus and crosses over ate zone in laminae VII and VIII (see Figs. 7.5 in the midbrain tegmentum as the ventral and 7.6) tegmental decussation. It descends in the lateral The lateral (medullary) reticulospinal tract funiculus of the spinal cord and terminates in originates from the nucleus reticularis giganto- laminae V, VI, and VII at all spinal levels. This cellularis (see Fig. 13.10) and descends mainly pathway facilitates the local circuitry and the as uncrossed fibers in the anterior funiculus lat- alpha and gamma motoneurons involved with eral to fibers of the MLF. The fibers terminate the flexor musculature and inhibits that at all spinal levels on interneurons in the medial involved with the extensor musculature, espe- part of the ventral horn and intermediate zone cially that of the upper extremity. In this in laminae VII and IX (see Figs. 7.5 and 7.6). respect, it is functionally similar to the lateral The fibers of both reticulospinal tracts termi- corticospinal tract. 202 The Human Nervous System

Vestibulospinal Tracts these muscles. These systems of pathways The lateral vestibular nucleus gives rise to account for turning movements of the head, the lateral vestibulospinal tract, which descends eyes, and trunk in response to visual and as an uncrossed somatotopically organized vestibular inputs (Chaps. 18 and 19). The eye tract throughout the entire length of the spinal movements are essentially reflexive and not cord in the anterior funiculus (see Figs. 11.3 volitional. The influences from visual area 19 and 16.9). It terminates in the medial part of are associated with pursuit movements of the the anterior horn and intermediate zone and eyes (Chap. 19). In essence, these pathways selectively excites motoneurons to the exten- coordinate eye movements involving the axial sors. Fibers from the medial vestibular nucleus (trunk) muscles as well as the vestibular influ- descend mainly, but not entirely, uncrossed as ences on the muscles of the extremities during the medial vestibulospinal tract within the balancing activities. medial longitudinal fasciculus of the anterior funiculus (see Fig. 16.9). The vestibulospinal Medial Longitudinal Fasciculus tracts terminate almost exclusively on interneu- The medial longitudinal fasciculus (MLF) is rons of laminae VII and VIII, which, in turn, a composite bundle of fibers located in the interact with the alpha and gamma motoneu- brainstem (Chap. 13) and spinal cord (see Figs. rons of lamina IX; some fibers terminate mono- 7. and 16.9). It consists of a descending com- synaptically on alpha motoneurons in lamina ponent and an ascending component. The IX. Both tracts exert facilitatory influences on descending component extends from the mid- muscle stretch (myotatic) reflexes. This rein- brain throughout the spinal cord. It comprises forces the tonus of the extensor musculature of the medial vestibulospinal tract, the medial the trunk and extremities to maintain the reticulospinal tract (both described earlier), and upright posture. the tectospinal tract originating from the superior colliculus. The latter descends through the Corticotectal, Tectobulbar, and MLF as far as upper thoracic levels and termi- Tectospinal Tracts nates in laminae VII and VIII. The ascending The corticotectal tract originates in visual component is the vestibuloocular reflex path- association areas 18 and 19 and terminates in way in the pons and midbrain, extending from the superior colliculus and other nuclei in the the level of the abducens nucleus to that of the midbrain tectum. The tectobulbar tract termi- oculomotor nuclei. This pathway originates nates in the paramedian pontine reticular for- from cell bodies located in the vestibular nuclei mation (PPRF). The PPRF is involved with and in the paramedian pontine reticular forma- coordination of the conjugate movements of tion (PPRF, Chap. 16). In addition, the MLF the eyes and their reflexive movements (Chaps. contains reciprocal fiber systems interconnect- 14 and 16). ing the abducens and oculomotor nuclei (for The tectospinal tract from the superior col- conjugate eye movements) (Chaps. 14 and 16). liculus decussates as the dorsal tegmental decussation in the midbrain tegmentum to join Raphe–Spinal and Locus Ceruleus–Spinal and descend in the ventral funiculus of the Pathways (Aminergic Pathways) spinal cord with the MLF. Its fibers terminate The monoamine transmitters they release in laminae VII and VIII of cervical and upper characterize the projections from certain brain- thoracic levels. The corticotectospinal and cor- stem nuclei to the spinal cord, called aminergic ticotectobulbar pathways are involved with pathways. Among these are serotonin (5-HT, 5- conveying influences via interneurons to lower hydroxytryptamine) and norepinephrine (nora- motoneurons innervating the extraocular, neck, drenaline) (Chap. 15). and back musculature. In addition, the vestibu- Serotonin is located in neurons of the lar system is integrated into the activities of nucleus raphe magnus, other raphe nuclei, and Chapter 11 Motoneurons and Motor Pathways 203 some neurons of the brainstem reticular forma- the lateral pathways have a critical role in tion (Chaps. 13 and 15). Axons from these the fine manipulative and independent nuclei descend in the dorsolateral funiculus and movements of the extremities, especially of terminate in laminae I, II, and V and on the pre- the hands and feet. They are involved in the ganglionic sympathetic neurons of lamina VII. fractionation of movement as is expressed in This reflected feedback pathway has a role in the ability to control and execute independ- modulating noxious (pain) signals within the ent finger movements. More specifically, dorsal horn through endorphins (Chap. 9). fractionation is the ability to control, for Norepinephrine is present in the neurons of example, an individual muscle of the hand the locus ceruleus and nucleus subceruleus independently of other muscles involved (Chap. 13). The noradrenergic projections from with normal manual dexterity. The fibers of these nuclei to the spinal cord descends in the the lateral corticospinal tract that terminate ventrolateral funiculus and terminates in lami- directly on the alpha motoneurons have a nae I, II, V, VII, and IX. major role in effecting the expression of frac- These aminergic pathways have roles in (1) tionation of movements. Following a lesion influencing preganglionic sympathetic neurons to this tract, there is a diminution or loss of in the spinal cord, (2) exerting facilitatory fractionation. The rubrospinal tract, although activity on the level of responsiveness of the small in humans, can be clinically signifi- lower motoneurons, (3) modulating the relative cant; it could account for certain residual intensity of various expressions of emotional motor function that persists after a lesion of states, and (4) modulating noxious stimuli the corticospinal tract. associated with pain (Chap. 9). Those fibers of the corticospinal tract originating in the parietal lobe (areas 1, 2, 3, Functional Groups of the Somatic Motor 5, and 7) are components of the reflected (Descending Pathways) feedback pathways, noted previously; these In a general way, each of the descending fibers terminate in the dorsal horn, where tracts of upper motoneurons can be placed into they modulate sensory input. one of three functional groups: (1) lateral 2. The anteromedial group (medial descend- group, (2) anteromedial group, and (3) aminer- ing tract systems), comprises the anterior gic group. corticospinal tract, lateral and medial reticulospinal tracts, lateral and medial vestibu- 1. The lateral group (lateral descending tract lospinal tracts, and tectospinal tract. These systems), comprises the lateral corticospinal tracts terminate in the medial part of the and rubrospinal tracts. It terminates in lat- ventral horn and intermediate zone, which eral portions of the ventral horn and the provides anatomic linkages for coordinated intermediate zone of the spinal gray matter. activity of the axial and limb girdle muscu- Within the spinal gray matter are anatomic lature during postural movements. These linkages involved primarily in the control of tracts exert bilateral control because (1) voluntary movements associated with the most contain both crossed and uncrossed limbs, especially with distal limb muscula- fibers and (2) they terminate on interneurons ture. The corticospinal tract originates pri- that have axons that cross over to the oppo- marily from the primary motor cortex (area site side. This can account for minimal loss 4), supplementary motor cortex (area 6) and of motor control of axial musculature fol- parietal lobe (areas 1, 2, 3, 5, and 7). The lowing unilateral lesions to these tracts, in rubrospinal tract originates from the magno- which limb control is profoundly affected. cellular portion of the nucleus ruber. Because Many of these descending tracts terminate in these tracts decussate, they act on the side the cervical and upper thoracic levels; opposite their sites of origin. Functionally, hence, they preferentially control neck, 204 The Human Nervous System

upper trunk and shoulder girdle muscula- involved with regulating the activity of ture, rather than lower trunk and hip girdle lower motoneurons. musculature. The anterior corticospinal tract is involved with voluntary movements associated with VOLUNTARY MOVEMENTS axial muscles of the neck and trunk. The reticulospinal tracts, which receive a major The spinal cord, brainstem, and forebrain input from the premotor cortex, are thought possess sequentially the three essential features to be involved in the more automatic, invol- of motor circuitry (from reflexes to rhythmic untary movements of the axial and limb motor patterns to complex voluntary move- musculature involved with posture and loco- ments). The command center for these activi- motion. They can be significant in controlling ties is organized as a motor hierarchy with the girdle musculature. The lateral vestibulospinal cord at a lower level comprising a spinal tract that descends as an uncrossed sequence of neuronal circuits mediating a vari- tract throughout the entire length of the ety of reflexes and basic movement rhythms spinal cord is critical in the maintenance of (Chap. 6) A higher level of motor hierarchy is balance (Chap. 16). The medial vestibulo- in the brainstem with its control of rhythmic spinal tract, which is a caudal extension of automatisms. The two motor systems originat- the MLF, descends bilaterally; it is involved ing at this level are (1) the medial descending with orienting head position through coordi- systems and (2) the lateral descending systems nating the activity of the neck and back mus- (noted previously). The medial systems con- culature. The tectospinal tract originates tribute to posture control by modulating the from the deep layers of the superior collicu- axial and limb girdle musculature, whereas the lus, an important structure that receives input lateral systems control the more distal limb from the visual system. This tract is pre- musculature and their important goal-directed sumed to be involved with coordinating head movements, especially of the forearm and and neck movements with eye movements. hand. The cortex of the forebrain mediates vol- The anteromedial pathways exert their untary motor control at the highest level. The influences on musculature bilaterally. Even primary motor cortex and some premotor areas such uncrossed tracts as the lateral vestibu- project (1) via the corticospinal tract directly to lospinal and reticulospinal tracts do so by the anterior horn of the spinal cord and (2) via terminating on interneurons, some of which corticobulbar fibers regulate the motor tracts emit axons that decussate in the anterior originating in the brainstem. commissure to the opposite side. Voluntary purposeful movements, such as the The fibers of these upper motoneuron sequence of motions resulting in catching a ball, control pathways exert their effects by (1) involve several cortical areas, including the (1) direct synaptic connections with lower primary motor cortex (area 4), (2) premotor cor- motoneurons and (2) synaptic connections tex (area 6), (3) supplementary motor cortex with interneurons that are integrated with (area 6), and (4) posterior parietal cortex (areas local circuits influencing lower motoneu- 5 and 7) (see Fig. 25.3). The following is an out- rons. Thus, the activity of lower motoneu- line of a current concept of the interrelation of rons is controlled by direct and indirect these cortical areas involved in the initiation of polysynaptic connections from the upper complex volitional movements. The apprecia- motoneurons and, in addition, from sensory tion of the spatial coordinates of the object of input from spinal nerves to the reflex cir- interest (ball) involves the posterior parietal lobe cuits (Chap. 8). (Chap. 25). This information is conveyed via 3. The aminergic pathways modulate the axons terminating in the primary motor cortex, excitability of the spinal neuronal circuits premotor cortex, and supplementary motor cor- Chapter 11 Motoneurons and Motor Pathways 205 tex, which process these inputs into their cir- to corticoreticular fibers to the brainstem retic- cuitry. These motor cortices have specific roles ular nuclei of both sides. that interact to produce a sequence of coordinated movements that lead to catching the ball. Both the premotor cortex and the supplementary SUGGESTED READINGS motor cortex project somatotopically to the primary motor cortex. In turn, the supplementary Asanuma H. The Motor Cortex.New York: Raven; motor cortex receives a critical input from the 1989. Bock G, Goode J, eds. Sensory Guidance of Move- basal ganglia via a projection from certain neu- ment. New York: Wiley; 1998. rons in the ventral lateral (VL) nucleus of the Brooks VB. The Neural Basis of Motor Control. thalamus. The premotor cortex receives a major New York: Oxford University Press; 1986. input from the cerebellum via a projection from Capaday C. The special nature of human walking another group of neurons in the VL. Details of and its neural control. Trends Neurosci. 2002; the functional aspects of these inputs are pre- 25:370–376. sented in Chapters 18 and 24. Dietz V. Human neuronal control of automatic func- A motor program constitutes sequence of tional movements: interaction between central movements directed to a purposeful goal (e.g., programs and afferent input. Physiol. Rev. 1992; a plan of action to catch a ball). This includes 72:33–69. the selection and coordination of the muscles Dum RP, Strick PL. Motor areas in the frontal lobe of the primate. Physiol. Behav. 2002;77:677–682. involved in the sequence of all the movements Everts E. Role of motor cortex in voluntary move- of the entire action. The posterior parietal lobe ments in primates. In Brooks VE, ed. Handbook contributes processed sensory information that of Physiology. Bethesda, MD: American Physio- is essential for guiding the movement to the logical Society; 1981;1083–1120. goal. The premotor cortex and the supplemen- Fukunaga T, Kubo K, Kawakami Y, Fukashiro S, tary motor cortex are involved in the planning Kanehisa H, Maganaris CN. In vivo behaviour of and programming of the complex sequences human muscle tendon during walking. Proc. R. and guidance of the movements and also con- Soc. Lond. B. Biol. Sci. 2001;268:229–233. tribute information to affect the output of area Georgopoulos AP. New concepts in generation of 4. The premotor cortex exercises a primary role movement. Neuron. 1994;13:257–268. in regulating the axial and proximal limb mus- Georgopoulos AP. Cognitive motor control: spatial and temporal aspects. Curr. Opin. Neurobiol. culature essential in the initial phases of orien- 2002;12:678–683. tating the body and lower limb toward the goal Grillner S. Neural networks for vertebrate locomo- and the upper limb in an appropriate position. tion. Sci. Am. 1996;274:64–69. The supplementary motor cortex exerts a role Grillner S. The motor infrastructure: from ion chan- in the complex movements of the proximal nels to neuronal networks. Nature Rev. Neurosci. limb musculature and, in addition, simultane- 2003;4:573–586. ous movements of the limbs of both sides of the Grillner S, Wallen P. Innate versus learned move- body. The motor cortex (area 4) has an essen- ments—a false dichotomy? Prog. Brain Res. tial role in the control of the distal muscles of 2004;143:3–12. the extremities, especially in the dexterity, Halsband U, Freund HJ. Motor learning. Curr Opin skill, and agility of finger movements. The pre- Neurobiol. 1993;3:940–949. Lam T, Pearson KG. The role of proprioceptive cise control of individual fingers (and even toes feedback in the regulation and adaptation of in some individuals) is the result of the frac- locomotor activity. Adv Exp Med Biol. 2002; tionation of muscle contractions. 508:343–355. The motor areas give rise to corticospinal Lieber R. Skeletal Muscle Structure, Function, & and corticobulbar fibers to the brainstem and Plasticity: The Physiological Basis of Rehabili- spinal cord. These areas also give rise to corti- tation. 2nd ed. Philadelphia: Lippincott Williams corubral fibers to the ipsilateral red nucleus and & Wilkins; 2002. 206 The Human Nervous System

Lieber RL, Friden J. Clinical significance of skeletal Rothwell J. Control of Human Voluntary Movement. muscle architecture. Clin Orthop. 2001;383: 2nd ed. New York: Chapman & Hall; 1994. 140–151. Ungerleider LG, Doyon J, Karni A. Imaging brain MacNeilage PF, Davis BL. Motor mechanisms in plasticity during motor skill learning. Neurobiol. speech ontogeny: phylogenetic, neurobiological Learn. Mem. 2002;78:553–564. and linguistic implications. Curr. Opin. Neuro- Wiesendanger M, Wise SP. Current issues concern- biol. 2001;11:696–700. ing the functional organization of motor cortical McCrea DA. Spinal circuitry of sensorimotor control areas in nonhuman primates. Adv. Neurol. of locomotion. J Physiol. 2001;533:41–50. 1992;57:117–134. Pearson K. Motor systems. Curr Opin Neurobiol. Wing A, Haggard P, and Flanagan J. Hand 2000;10:649–654. and Brain: The Neurophysiology and Psychol- Phillips C. Movements of the hand. Liverpool: Liv- ogy of Hand Movements. San Diego: Acade- erpool University Press; 1986. mic; 1996. Rizzolatti G, Luppino G. The cortical motor system. Wise SP. The primate premotor cortex fifty years Neuron. 2001;31:889–901. after Fulton. Behav. Brain Res. 1985;18:79–88. 12 Lesions of the Spinal Nerves and Spinal Cord

Release Phenomena Lesions of the Ventral Roots Lesions of the Dorsal Roots Lesions of the Upper Motoneurons (Upper Motoneuron Paralysis, Spastic Paralysis) Symptoms of Value in Localizing Lesions to Spinal Levels Spinal Cord Hemisection (Brown’s Quard Syndrome) Spinal Cord Transection Intrinsic Arterial Supply to the Spinal Cord Lesion in the Region of the Central Canal (Syringomyelia) Tabes Dorsalis Amyotrophic Lateral Sclerosis Combined System Degeneration Degeneration, Regeneration, and Sprouting

Injuries to the nervous system, as well as sion of a release phenomenon. It results from neurologic diseases, produce symptoms and the withdrawal (release) of inhibitory influ- clinical signs. This chapter outlines some ences from normal neural circuitry that medi- effects of lesions of the spinal nerves and spinal ates a normal response or capacity. Inhibitory cord. The term lesion refers to pathologic and circuits act as a governor that modulates, traumatic tissue damage. Ensuing impairments shapes, and controls the excitatory circuits include the loss or modification of function from becoming overactive (see Importance of related to the injury. Inhibition, Chap. 3). A lesion incapacitates the regulating inhibitory influences that the injured regulator exerted on a released neural circuit. RELEASE PHENOMENA Release phenomena are expressed (1) in the abnormal movements in Parkinson’s disease The signs associated with a lesion of the and Huntington’s chorea, both of which are nervous system are manifested by two types of associated with lesions in the basal ganglia abnormal function or capacity: (1) with nega- (Chap. 24), or (2) as the distorted pain sensa- tive signs or (2) with positive signs. tions of the thalamic syndrome (Chap. 23) or in Negative signs are expressed as the loss of a the phantom limb (Chap. 9). function or capacity as the result of a lesion. Examples are the loss of strength of a muscle, or its inability to contract (motor), or the loss of LESIONS OF THE VENTRAL ROOTS a sensation such as touch or sight (sensory). Positive signs are expressed as abnormal Depending on the specific spinal level, motor responses (motor) or bizarre sensations lesions of the ventral roots interrupt specific (sensory). A positive sign is usually the expres- alpha and gamma motoneurons and pregan-

207 208 The Human Nervous System glionic autonomic fibers (see Fig. 12.1, nos. 1 from the spontaneous discharge of a motor and 2a). The injury of all the lower motoneu- unit. As a lower motoneuron dies, it dis- rons innervating a muscle or group of muscles charges repetitively to produce fascicula- results in a lower motoneuron paralysis or pare- tions of the muscle fibers it innervates. sis of that muscle or muscles. This occurs in 4. The trophic changes include dry, cyanotic poliomyelitis—the polio virus can selectively skin, which can be ulcerated. affect lower motoneurons of the spinal cord and of the brainstem. When preganglionic auto- Trophic Functions and Changes nomic fibers are injured, trophic effects can The autonomic nervous system includes a accompany the lower motoneuron paralysis. motor system involved with influencing the activities of the involuntary (smooth) muscles, Lower Motoneuron Paralysis cardiac (heart) muscle, and glands (Chap 20). (Flaccid Paralysis) In contrast, the somatic motor system is The signs of a lower motoneuron (flaccid) involved with influencing voluntary (skeletal, paralysis and associated trophic changes striated) muscles. In addition to stimulating include the following: muscles to contract and glands to secrete, both the autonomic and somatic motor systems exert 1. All voluntary movements are abolished, and effects that initiate and regulate the molecular reflex contractions cannot be elicited when organization of other cells. These effects are all of the lower motoneurons innervating a expressions of the trophic (literally nutritional) group of muscles are interrupted. The mus- functions of the nervous system. cles are paralyzed. A paresis (partial paraly- Trophic influences by neurons are directed sis, weakness) results when some, but not to different types of target tissue, including all, of the lower motoneurons normally the epithelium, nerve endings (e.g., taste buds), innervating the muscle remain functional. and muscle cells. Following lesions of fibers 2. The paralyzed muscles have lost their tone; of the autonomic nervous system, trophic therefore, they are flaccid and offer little changes include the following: a warm or resistance to manipulation by the examiner. cool, flushed or cyanotic skin, as a result of Because the myotatic reflex arcs are not changes in capillary circulation; abnormal intact, the deep tendon reflexes (DTRs) are brittleness of fingernails; loss of hair; dryness absent (areflexia). If some of the lower or ulceration of the skin; and lysis of the motoneurons are functional, the tonus is bones and joints. reduced (hypotonus) and the DTRs are weak The atrophy that occurs in skeletal muscles (hyporeflexia). deprived of their lower (somatic) motoneuron 3. Reaching a peak about 2–3 weeks following innervation is more profound than the atrophy denervation, muscles spontaneously con- following disuse. Another effect on the skeletal tract. In time, the muscles atrophy. The muscle fibers in the former case stems from the spontaneous contractions of muscle fibers loss of trophic influences that are essential for are known as fibrillations and fasciculations. the maintenance of the normal condition. Fib- Fibrillation is a single muscle fiber twitch- rillation is another expression of a change in ing, which can be seen only when the trophic influences. affected muscle is thinly covered, as in the tongue and, rarely, in the hand. It can be Myasthenia Gravis: An Autoimmune Disease detected by electromyographic examination. Myasthenia gravis is a muscle weakness Fibrillation is a response associated with the disability that is associated with defects of hypersensitivity of a denervated muscle transmission at the motor end-plate junctions (Chap. 20). Fasciculation is a muscle between nerve endings and the voluntary mus- twitching visibly through the skin, resulting cle acetylcholine receptors (ACh receptors). Chapter 12 Lesions of the Spinal Nerves and Spinal Cord 209

Figure 12.1. Schemata of the spinal cord to indicate the sites of lesions noted in the text. Ara- bic numbers refer to specific lesions. C5 to T1 indicate the cervical enlargement, the region involved with innervation of the upper extremity. 1, ventral roots of spinal nerves; 2a, preganglionic sympathetic fibers from T1 to T2 levels; 2b, postganglionic sympathetic fibers from the superior cervical ganglion; 3, dorsal roots of spinal nerves; 4, hemisection of the spinal cord (Brown–Séquard syndrome) extending through the cervical enlargement (stippled region); 5, transection of the spinal cord at a midthoracic level; 6, lesion in region surrounding central canal throughout the cervical enlargement and extending into the anterior horn at the C8 and T1 level on one side. 210 The Human Nervous System

The defect is caused by an antibody-mediated spinal column. Unmyelinated postganglionic attack, which reduces the number of nicotinic fibers arising from the superior cervical gan- ACh receptors and is accompanied by sparse glion follow arterial blood vessels and have and shallow junctional folds and widened clefts synaptic terminals on sweat glands, smooth of the postsynaptic membrane (sarcolemma) muscle that dilates the pupils of the eyes, (Chap. 15; and Fig. 2.5). As a consequence, smooth muscles of the cutaneous blood ves- there is a reduction in the probability of evok- sels, and smooth muscle (called the tarsal mus- ing an action potential in the sarcolemma. This cle or Muller’s muscle) of the upper eyelid (see neuromuscular disease is characterized by a Fig. 12.1). marked fatigability and weakness of the volun- Lesions of preganglionic sympathetic fibers tary muscles that is improved by inhibitors of from T1 and T2, or of postganglionic sympa- cholinesterase such as physostigmine. Thus, by thetic fibers from the superior cervical gan- inhibiting the degradation of acetylcholine at glion, will result in Horner’s syndrome on the the motor end plate, the time is prolonged for ipsilateral side of the face (see Fig. 12.1, nos. the available transmitter to act on the remaining 2a and 2b). The affected pupil is smaller than receptors. the pupil of the opposite eye; it does not dilate The critical symptom of the affliction is (miosis) when the pupil is shaded (pupillodila- weakness of voluntary muscles. Characteristic tor smooth muscle unit is not stimulated to features include double vision resulting from a contract). The affected eyelid droops a bit (pto- decrease in the coordination of the extraocular sis) because the superior palpebral smooth muscles, drooping eyelids (weak levator palpe- muscle (Muller’s muscle) is denervated. The brae muscles), and weakness of the limb mus- face is dry (anhydrosis from denervated sweat cles. Intense activity of a muscle will rapidly glands), red, and warm (vasodilatation of cuta- lead to severe fatigue. In myasthenia gravis, neous blood vessels). This is the memorable lymphocyte T-cells generated in the thymus triad of symptoms: miosis, ptosis, and anhy- gland become activated to react against the drosis. ACh receptors. The antibodies inactivate the ACh receptors as fast or faster than they can be synthesized for replacement. The normal LESIONS OF THE turnover of ACh receptors is about 5–7 days. DORSAL ROOTS With the increased destruction of ACh receptors in myasthenia gravis, the turnover rate is The irritation of the fibers of one dorsal root increased to 2–4 days. The therapeutic effects (radix) by mechanical compression (tumor or of thymectomy relates to the immunological slipped disk) or a local inflammation can pro- role of the thymus. Following thymectomy, duce pain with a radicular distribution (see Fig. about one-half of patients with myasthenia 12.1, no. 3). Because adjacent dermatomes gravis go into “remission,” showing no symp- overlap, the destruction of one dorsal root (e.g., toms even without drug therapy. by transection) can result in slight diminution of all sensations (hypesthesia) in part of the Horner’s Syndrome dermatome innervated by that dorsal root. Horner’s syndrome occurs as a consequence Destruction of several consecutive dorsal roots of a lesion to certain fibers of the sympathetic does result in the complete absence of all sen- division of the autonomic nervous system. sations (anesthesia) in all but the rostral and With regard to Horner’s syndrome, the critical caudal dermatomes innervated by the sectioned sympathetic components are preganglionic roots. Irritation to the dorsal root fibers can fibers that emerge from T1 and T2 spinal cord result in paresthesia (abnormal spontaneous segments and terminate in the superior cervi- sensations such as numbness and prickling) or cal ganglion, which is located alongside the hyperalgesia (excessive pain in response to an Chapter 12 Lesions of the Spinal Nerves and Spinal Cord 211 otherwise innocuous stimulus). The stimulation of a dorsal root can result in a dermatomal LESIONS OF THE UPPER vasodilatation (because of reflex arcs involving MOTONEURONS (UPPER the autonomic nervous system). MOTONEURON PARALYSIS, If all dorsal roots innervating the upper SPASTIC PARALYSIS) extremity (C5 through T1) are transected Interruption of the upper motoneurons (e.g., surgically by dorsal root rhizotomy), results in motor disturbances known as an several symptoms can be additionally upper motoneuron paralysis. The lesion in the observed. Because the afferent limb of the genu and posterior limb of the internal capsule reflex arcs is interrupted, reflex activity is that results in the most typical constellation absent (areflexia) and muscles are hypotonic. of upper motoneuron (UMN) lesion signs Although the limb muscles are not paralyzed involves the corticobulbar, corticospinal, corti- (lower motoneurons are intact), motor activity corubrospinal, and corticoreticulospinal path- is impaired. The deafferented limb hangs by ways. Often the symptoms of an UMN lesion the side and is generally not used. It can be are attributed to a lesion of the corticospinal volitionally moved when facilitatory influ- tract; but actually other UMN pathways also ences from the descending supraspinal motor contribute to the symptoms, including the cir- pathways stimulate the lower motoneurons. cuitry of the cortical–basal ganglia loops Because the lower motoneurons remain intact (Chap. 24). Apparently, the only neurologic and functional, there is little or no loss in mus- sign associated exclusively with a corticospinal cle strength and no occurrence of fascicula- tract lesion is the Babinski sign (see later in this tions. There is some disuse atrophy, but section). because trophic influences are not lost, there Immediately after the onset of a lesion in the is no trophic atrophy. internal capsule (see Fig. 1.8), the patient Lesions and irritations of the dorsal roots or develops a paralysis of the lower muscles of posterior horn cause segmental (dermatomal) facial expression (below the level of the eye) sensory disturbances. In dorsal root lesions, all and of the upper and lower limb musculature general senses in the region innervated by the (hemiplegia) on the opposite side of the body. root fibers (dermatome) are lost or diminished. The lower facial muscles are paralyzed if the In posterior horn lesions, a dissociated sensory lesion is in the genu and damages the corticob- loss (loss of one sensation and the preservation ulbar fibers passing through (Chap. 11). of others) can occur in the dermatome, with, As a rule, following a unilateral corticobul- for example, pain and temperature sensibilities bar lesion, all voluntary muscles innervated by lost or reduced, but touch and other associated cranial nerves, except those of facial expression general senses intact and normal. Dissociated below the eye, are spared. This is because the sensory loss of pain and temperature also lower motoneurons to all of the other muscles occurs in lesions in the vicinity of the central of facial expression receive bilateral corticobul- canal (see Lesions in the Region of the Central bar innervation, but the lower motoneurons to Canal). muscles of facial expression below the eye Following an injury restricted to one dorsal receive corticobulbar innervation only from the root, no area of anesthesia is revealed in the contralateral side of the cerebral cortex (Chap. dermatome innervated because of the overlap 11). Therefore, a unilateral lesion will lead to from fibers of adjacent dorsal roots. Such an paralysis on the opposite side. injury, however, can produce so-called radicu- In the limbs, deep tendon (stretch) reflexes lar (a root is a radix) pain that is localized in the are temporarily depressed and the muscles dermatome innervated by that root; such exhibit hypotonia. In time, from a few days to patients are aware of a tingling pain or even a a few weeks, the stretch reflexes return and diminished feeling of sensation or numbness. then become hyperactive. Muscle tone increases 212 The Human Nervous System to hypertonia. The expression of hyperreflexia the resisting muscles yield suddenly in a by the muscles is called spasticity and the mus- clasp knife fashion. The sudden yielding of cles are said to be spastic. The basic cause for resistance is ascribed to a surge of afferent the spasticity is not fully understood. One input from group II fibers from the muscle explanation is that the UMN lesions reduce spindles and also possibly from C pain inhibitory influences upon both the gamma and fibers from low-threshold pain receptors alpha motoneurons more than they do excita- and, according to some, from the Ib fibers tory influences. This is accompanied by hyper- from Golgi tendon organs. sensitive dynamic gamma motoneurons, which 2. Clonus is the rhythmic oscillation of a joint stimulate the muscle spindles to increase their (e.g., ankle or knee) that occurs when a sec- rate of discharge and, thus, increase the activity ond party suddenly dorsiflexes the foot of the stretch reflex. Other evidence suggests (light pressure on the sole of foot pushes that the spasticity is primarily the result of toes toward knee) and maintains the dorsi- hyperactive alpha motoneurons because of the flexion attitude under continuous light pres- “filling in” of degenerated UMN synapses by sure. The dorsiflexion puts the gastrocnemius sprouting of local segmental afferent fibers. muscle, its muscle spindles, and the Achilles An upper motoneuron paralysis is called a tendon under moderate stretch. The result- spastic paralysis. Such a paralysis of the upper ing stretch reflex contraction of the gastroc- and lower limbs on one side is called a hemi- nemius produces plantar flexion of the foot. plegia (less than total hemiparesis). The clini- This is accompanied by stretching of the tib- cal signs of an UMN paralysis include ialis anterior and other dorsiflexor muscles increased muscle tone (hypertonia), increased of the foot and their muscle spindles. The deep tendon (stretch) reflexes (hyperreflexia), resulting stretch reflex contraction of the tib- clonus, loss or diminution of cutaneous ialis anterior produces a dorsiflexion of the reflexes, and the Babinski reflex (sign). Spas- foot. The cycle repeats. Clonus persists as ticity is thought to result from damage to UMN long as the gastrocnemius is kept in a mod- pathways other than the corticospinal tract; erate state of contraction by elastic pressure. selective damage to the pyramids in the 3. Superficial reflexes that normally are medulla of laboratory animals produces elicited by stroking certain areas of the skin decreased, not increased, muscle tone. might be absent if the corticospinal tract is injured. When the skin of the abdominal 1. Hypertonus is expressed in the firmness and wall is gently scratched, the abdominal mus- stiffness of muscles—primarily in the flex- cles contract and the resulting reflex diverts ors of the upper limb and in the extensors of the umbilicus momentarily toward the stim- the lower limb. These are antigravity mus- ulated site. Stroking the upper inner aspect cles; the upper limbs are held up by the con- of the thigh normally causes a reflex traction of flexors, and the lower limbs contraction of the cremasteric muscle and support the body by contraction of exten- elevation of the testicle on the stimulated sors. This increased resistance (hypertonus) side. Loss of the abdominal or cremasteric to passive movement is expressed as the reflexes confirms the presence of a corti- examiner tries to flex or extend each limb. cospinal tract lesion. (Absence of these The brisk knee jerk following the tapping of reflexes bilaterally in an otherwise normal the quadriceps muscle tendon is an example individual might have no significance.) of hyperreflexia. The spastic body parts 4. The Babinski reflex (sign) can be elicited. exhibit increased resistance to manipulation, When the lateral aspect of the sole of the especially the flexors of the upper limbs and foot is stroked with a blunt point, the great the extensors of the lower limbs. However, if toe dorsiflexes (hyperextension), the tip of the force exerted by an examiner persists, the toe points to the knee, and the other toes Chapter 12 Lesions of the Spinal Nerves and Spinal Cord 213

spread (fan),—called the extensor plantar where signs are expressed, the site where a response. pathway decussates must be considered with regard to the location of the lesion. (1) Symp- The finding of a Babinski sign in newborns toms occur on the same side (ipsilateral) and and infants up to a year or so of age is not an below the level of the lesion when the damaged indication of an upper motor neuron lesion, but neurons normally convey influences from the rather of incomplete central nervous system same side of the body (ascending sensory tract) (CNS) development—the corticospinal tract is or to the same side of the body (descending not completely myelinated. motor tracts). In the spinal cord, structures involved with ipsilateral functions include the posterior column, dorsal roots, lateral corti- SYMPTOMS OF VALUE cospinal tract, rubrospinal tract, reticulospinal IN LOCALIZING LESIONS tracts, and ventral roots. (2) Symptoms occur TO SPINAL LEVELS on the opposite (contralateral) side below the level of the lesion when the damaged neurons Symptoms with a dermatomal distribution convey information from or to the opposite side are associated with a specific dorsal root or of the body. In the spinal cord, this includes the roots. Furthermore, symptoms that show signs decussated fibers of the anterolateral pathway of lower motoneuron paralysis are associated and the lateral and the anterior spinothalamic with a specific ventral root or roots. For exam- tracts. In the brainstem this includes the ple, (1) a band of anesthesia with a dermatomal spinothalamic tract, medial lemniscus, and cor- distribution results from the destruction of spe- ticospinal tract. cific dorsal root fibers; (2) paresthesias or When the fiber tracts are injured, the result- radicular (root) pain with a dermatomal distri- ant symptoms and signs include the following: bution results from irritation of fibers in specific dorsal roots; the skin eruption and 1. At the spinal levels of transection (C5 hyperalgesia expressed in a dermatomal pattern through T1), the entering fibers of the dorsal known as shingles is caused by a dorsal root roots and the emerging fibers of the lower ganglion infected by herpes zoster virus; (3) motoneurons and preganglionic sympathetic flaccid paralysis and other lower motoneuron fibers (C8 and T1) are interrupted. This signs result from the destruction of motoneuron results in a complete absence of all sensa- cells and fibers in the anterior horn or ventral tions in the upper extremity on the side of roots. lesion. Pain and temperature are lost on the contralateral upper extremity because of interruption of the postdecussational fibers SPINAL CORD HEMISECTION of the lateral spinothalamic tract. Paresthe- (BROWN’S QUARD SYNDROME) sias and radicular pain can be sensed over the ipsilateral C5 and T1 dermatomes from A hemisection (unilateral transverse lesion) the irritation of some intact dorsal root fibers; of the spinal cord results in a number of because of dermatome overlap from C4 and changes in the body at that level or caudal to it T2, the C5 and T1 dermatomes have a (see Fig. 12.1, no. 4). For instructional pur- hypesthesia. The entire ipsilateral limb is poses, assume that the lesion is a hemisection flaccid; it exhibits all of the signs of a lower extending from C5 through T1 spinal levels; motoneuron paralysis. Horner’s syndrome the peripheral nerves associated with these on the ipsilateral side of the face and trophic spinal levels innervate the upper extremity. In changes in the ipsilateral upper extremity the nervous system, in relating the side of a are the result of the interruption of the pre- lesion (right or left) to the side of the body ganglionic sympathetic neurons. 214 The Human Nervous System

2. Posterior column (fasciculi gracilis and All voluntary movements and somatic and cuneatus). The signs are loss of position visceral reflex activities are abolished. Sensa- sense, appreciation of passive movement, tions from the body below the transection level vibratory sense, and two-point discrimination are absent. This period of extremely depressed on the same side at and below the levels of the activity, called spinal shock lasts about 2–3 lesion. The modalities from the neck are weeks in man (it varies in duration from 4 days unaffected because fibers conveying them are to 6 weeks). Spinal shock is apparently the located wholly above the level of the lesion. result of the sudden withdrawal of facilitatory Ataxia (stumbling and staggering gait) asso- influences from the descending pathways, ciated with injury of the posterior column especially the corticospinal tract. cannot be observed because of the paralysis. The isolated spinal cord and its spinal nerves 3. Lateral spinothalamic tract. The sign is loss gradually exhibit autonomous neural activity of pain and temperature on the opposite side that is divided into a sequence of phases of at and below the levels of the lesion. This variable lengths: (1) minimal reflex activity, (2) includes the contralateral upper extremity flexor spasm activity (superficial reflexes), (3) because lateral spinothalamic fibers decus- alternation between flexor and extensor sate within one or two levels of the spinal spasms, and (4) predominant extensor spasms root origin. (deep reflexes). After a year or two, paraplegics 4. Anterior spinothalamic tract. Touch sensi- can fit one of several categories: (1) that in bility is probably little affected on the oppo- which extensor spasms predominate over site side below the spinal level of the lesion flexor spasms, called paraplegia-in-extension because this modality is also conveyed in the (observed in about two-thirds of paraplegics); uncrossed fasciculi gracilis and cuneatus. (2) that in which flexor spasms predominate, 5. Corticospinal tract and other descending called paraplegia-in-flexion; and (3) that in supraspinal tracts. The spastic syndrome which a flaccid paralysis persists (less than following the interruption of these fibers 20%). The absence of autonomic nervous sys- results in an upper motoneuron paralysis, tem impulses from the brain is accompanied by including spasticity, hyperactive deep tendon a variety of disturbances in the control of auto- reflexes (DTRs) (hyperreflexia), diminution matic activities of the urinary, genital, and or loss of superficial reflexes, Babinski sign, anorectal systems. and muscle clonus below (but not at level of) Loss of thermoregulatory control below the the site of lesion on the ipsilateral side. The level of the lesion is expressed with a cool, dry hyperactive DTRs are illustrated by a brisk skin with no evidence of sweating (Chap. 20). knee jerk or ankle jerk. However, reflex sweating can occur when a noxious stimulus is applied (e.g., response to the insertion of the needle during a spinal tap). There is loss of voluntary control of the urinary SPINAL CORD TRANSECTION bladder. The urinary bladder can be evacuated by reflex activity such as by appropriate cuta- Paraplegia neous stimulation. Complete transection of the spinal cord at a midthoracic level (see Fig. 12.1, no. 5) because Quadriplegia of a traumatic event causes immediate paraple- Quadriplegia is the paralysis of all four gia together with a loss of detectable neural limbs and is associated with a transection of the activity caudal to the lesion site. Paraplegia is spinal cord in or above the region of the cervi- a paralysis of both lower limbs resulting from cal enlargement. Because of dermatomal and interruption of the UMNs on both sides of the myotomal overlap, patients with T1 injuries spinal cord. have normal hand function. Transections above Chapter 12 Lesions of the Spinal Nerves and Spinal Cord 215

C3 eliminate descending control of the involved are the result of lesions in the anterior diaphragm, requiring a respirator; the phrenic horns (lower motoneuron paralysis). Spastic nerve arises mainly from C3, but the adjoining paralysis below the level of the lesions results segments usually contribute. Monoplegia from bilateral lesions of the descending motor involves paralysis of one limb. tracts (upper motoneuron paralysis). Pain and temperature sensibilities might be lost bilaterally below the level of a thrombosis because of INTRINSIC ARTERIAL SUPPLY TO involvement of the anterolateral pathways, but THE SPINAL CORD might be spared if adequate blood is supplied by the posterior spinal arteries. In general, two arteries and their branches supply the spinal cord (see Fig. 12.2). Branches of the unpaired anterior spinal artery vascular- LESION IN THE REGION OF THE ize the anterior two-thirds of each spinal CENTRAL CANAL (SYRINGOMYELIA) segment. The branches of the paired posterior spinal arteries supply the remainder of the Syringomyelia is a disease characterized by spinal cord. formation of a syrinx (cavity) in the region of The anterior spinal artery syndrome results the central canal probably caused by incom- in signs resulting from bilateral injury to the plete closure of the central canal; with time, the anterior horns, anterolateral pathways, and lat- cavitation can enlarge and extend to other sites eral corticospinal (pyramidal) tracts. The (see Fig. 12.1, no. 6). Assuming, as commonly symptoms occur suddenly and are often associ- occurs, that the lesion is located in the cervical ated with severe pain. Flaccid paralysis, fascic- enlargement (from C5 to T1 spinal cord levels), ulations, and atrophy bilaterally at the segments the initial clinical signs are a loss of pain and

Figure 12.2: The arterial supply of the spinal cord. 216 The Human Nervous System temperature sensibility in both upper limbs. upright by using visual cues to compensate for The loss is the result of the interruption of the loss of proprioception. decussating pain and temperature fibers as they pass through the anterior white commissure, conveying information from both upper limbs. AMYOTROPHIC LATERAL SCLEROSIS Proprioception and light touch are nowhere affected because the posterior columns are Amyotrophic lateral sclerosis (ALS) is a intact. There is no loss of pain and temperature degenerative motor tract disease with bilateral sensation in the body and lower limbs because involvement of the pyramidal tracts and ante- the anterolateral pathway (except for fibers rior horns. Because there is degeneration of from the upper limb) remains intact. both upper and lower motoneurons, signs of Extension of the lesion into the anterior horn both upper and lower motoneuron paralysis are of C8 and T1 spinal levels on one side produces expressed. Most of the affected muscles show ipsilateral lower motoneuron disturbances and evidence of degeneration of lower motoneu- trophic changes on the ulnar side of the arm, rons, including paralysis, atrophy, fascicula- forearm, hand, and fourth and fifth fingers, as tions, and weakness; these signs are initially well as a possible Horner’s syndrome because expressed by the muscles of the hands and the ulnar nerve originates from C8 to T1 levels, arms. Some muscles exhibit signs of upper as do the preganglionic sympathetic fibers to motoneuron paralysis, hyperreflexia, and, at the superior ganglion. times, Babinski signs. The lower motoneurons of cranial nerves might also exhibit signs of degeneration. Sensory changes do not usually TABES DORSALIS occur.

Tabes dorsalis is a form of neurosyphilis in which the primary pathology of the dorsal root COMBINED SYSTEM DEGENERATION ganglia is accompanied by secondary degenerative changes in the posterior columns, espe- Combined system degeneration is a compli- cially in the fasciculi gracilis bilaterally. Pain cation of pernicious anemia (a disease caused fibers are also involved. In the initial stages, the by a lack of intrinsic factor for absorption of irritation of dorsal root fibers produces pares- vitamin B12) in which there is subacute degen- thesias and intermittent attacks of sharp pain. eration bilaterally of the fibers of the posterior In time, the symptoms include diminished sen- columns and lateral columns, especially those sitivity to pain, loss of kinesthetic sense, dimin- involved with the lumbosacral cord. The clini- ished-to-absent deep tendon reflexes (ankle and cal symptoms include (1) loss of position and knee jerks), loss of muscle tone, and marked vibratory senses, numbness, and dysesthesia in impairment of muscle, joint, and vibratory the lower extremities and (2) such upper senses accompanied by an ataxic gait. Patients motoneuron signs as spasticity, muscle weak- walk with legs wide apart, head bent, and eyes ness, hyperactive deep tendon reflexes, Babin- looking down, raising their knees high and ski reflexes and Romberg’s sign. slapping their feet on the ground. The eyes stare at the ground to pick up visual cues, which substitute for the lost kinesthetic senses. DEGENERATION, REGENERATION, As in ataxia, a patient with tabes dorsalis AND SPROUTING exhibits Romberg’s sign (i.e., the inability to stand with eyes closed and feet together with- An injured neuron reacts to an insult, whether out swaying or actually falling). With the eyes it is a transection, a crush, a toxic substance, or open, an afflicted person might be able to keep a deprivation of blood supply. The entire neuron Chapter 12 Lesions of the Spinal Nerves and Spinal Cord 217 responds and, depending on location and cir- minate in the proper nerve endings. The poten- cumstances, might survive (see Fig. 2.11). tial of each neurolemmal cord to act as a guide for many regenerating axons increases the pos- Degeneration sibility of reinnervating the appropriate recep- The degenerative reactions following tran- tor or effector. When fully myelinated, each section include changes in (1) the cell body regenerating branch tends to have a conduction (chromatolysis), (2) the nerve fiber between the velocity of about 80% of that of the original cell body and the trauma (primary degenera- fiber. Superfluous axonal branches eventually tion), and (3) the nerve fiber distal to the degenerate. trauma (secondary, anterograde, or Wallerian degeneration). The cell body swells, Nissl bod- Collateral Sprouting. A denervated neu- ies undergo “dissolution” or chromatolysis, and rolemmal cord is presumed to exert trophic the nucleus is displaced to the side of the cell influences upon a nearby normal nerve fiber; body. These are manifestations of metabolic the latter responds by sprouting new collateral activities, which can ultimately lead to the branches from its nodes of Ranvier. This is regeneration of the severed fiber. Chromatoly- known as preterminal axonal sprouting or col- sis is indicative of enhanced protein synthesis. lateral nerve sprouting. The collateral branch Degenerative changes in the nerve proximal to joins the axonless neurolemmal cord, grows the cut include breakdown of the myelin sheath down the cord, and reinnervates the nerve end- and axon in the vicinity of the injury. The axon ing. Collateral nerve sprouting occurs in both and myelin sheath of the fiber distal to the the peripheral nervous system and central nerv- trauma become fragmented and are removed by ous system, but the latter does not have neu- macrophages, usually over a period of weeks. rolemmal cords (see Fig. 2.11). Nerve Regeneration in the Peripheral Regeneration in the Central Nervous System Nervous System (see Fig. 2.11) Loss of neurons occurs normally throughout Regeneration is essentially a process of dif- life. This neuronal loss is generally accompa- ferentiation and growth. The cell bodies syn- nied by a compensatory sprouting of axonal thesize proteins and other metabolites that flow branches by other CNS neurons in the vicinity. distally into the regenerating and lengthening Many of these axonal sprouts invade the terri- axons. The neurolemma (Schwann) cells in the tory previously innervated by the dead neuron proximal stump near the trauma, and in the dis- and form new synapses. This activity, known as tal stump, they divide mitotically to form con- reactive synaptogenesis, is an attempt to tinuous cords of neurolemma cells. These cords replace lost synapses. Molecular and trophic extend from the proximal stump, through the factors, which enhance this process, were dis- small gap between the stumps into the distal cussed in Chapter 2. The release of a neu- stump, and to the sites of sensory receptors for rotrophic factor by Schwann cells can be the afferent fibers and motor endings for efferent critical factor that promotes this growth and fibers. In addition, the ends of the proximal regeneration in the peripheral nervous system. axons branch into numerous sprouts that grow Neurons of fetal and neonatal mammals have distally at about 4 mm per day into the gap and a great capacity for regeneration. This is the distal stump along the neurolemmal cords to logic of transplanting young neurons into the the sites of the nerve endings. Each regenerat- brains of adult mammals to attain some degree ing axon of the proximal stump can divide to of functional recovery following dysfunction. form as many as 50 terminal sprouts. In turn, Transplantation of fetal dopaminergic neurons each neurolemmal cord can act as the guiding into the striatum in patients with Parkinson’s scaffold for numerous regenerating axons. The disease is being carried out in an attempt to surviving regenerating axons are those that ter- obtain some clinical recovery (Chap. 24). 218 The Human Nervous System

Hohmann GW. Psychological aspects of treatment SUGGESTED READINGS and rehabilitation of the spinal cord injured person. Clin. Orthop. 1975;Oct(112):81–88. Barbeau H, Fung J. The role of rehabilitation in the Kalb RG, Strittmatter SM, eds. Neurobiology of recovery of walking in the neurological popula- Spinal Cord Injury. Totowa, NJ: Humana; 2000. tion. Curr. Opin. Neurol. 2001;14:735–740. Lance J, McLeod JG. A Physiological Approach to Barbeau H, Ladouceur M, Norman KE, Pepin A, Clinical Neurology. 3rd ed. Boston: Butterworth; Leroux A. Walking after spinal cord injury: eval- 1981. uation, treatment, and functional recovery. Arch McLeod J, Lance J. Introductory Neurology. Phys Med Rehabil. 1999;80:225–235. Boston: Blackwell Scientific; 1989. Brodal A. Self-observations and neuroanatomical Nathan PW. Effects on movement of surgical inci- considerations after a stroke. Brain 1981;96: sions into the human spinal cord. Brain 1994; 675–694. 117(Pt. 2):337–346. Collins R. Neurology. Philadelphia: Saunders; 1997. Rossignol S. Locomotion and its recovery after spinal Dietz V, Colombo G, Jensen L, Baumgartner L. injury. Curr. Opin. Neurobiol. 2000;10:708–716. Locomotor capacity of spinal cord in paraplegic Sunderland S. Nerves and Nerve Injuries. Edin- patients. Ann. Neurol. 1995;37:574–582. burgh: Livingstone; 1978. Hohmann GW. Some effects of spinal cord lesions Sunderland S. Traumatized Nerves, Roots and Gan- on experienced emotional feelings. Psychophysi- glia: Musculoskeletal Factors and Neuropatho- ology 1966;3:143–156. logical Consequences. New York: Plenum; 1978. Hohmann GW. Considerations in management of Tepper MS, Whipple B, Richards E, Komisaruk BR. psychosexual readjustment in the cord injured Women with complete spinal cord injury: a phe- male. Proc. Veterans Admin. Spinal Cord Inj. nomenological study of sexual experiences. J. Conf. 1971;18:199–204. Sex Marital Ther. 2001;27:615–623. 13 Brainstem: Medulla, Pons, and Midbrain

Longitudinal Organization of the Brainstem Surface Landmarks Brainstem Cranial Nerves Functionally Significant Internal Landmarks Transverse Sections Through the Brainstem

The role of the brainstem is divisible into (auditory system; Chap. 16), and the emerging three broad categories. The first is to provide trochlear nerve (n.IV) caudally (see Figs. 13.2 transit and processing nuclei for ascending and and 13.3). descending pathways that convey influences to and from the cerebrum, cerebellum, and spinal Basilar Portion cord. The second is to play a part in a range of The basilar portion is called the crus cerebri activities such as consciousness, the sleep– (pes pedunculi) in the midbrain, basilar pons or wake cycle, and respiratory and cardiovascular pons proper in the pons, and pyramids in the control. The third relates to actions of the cra- medulla (see Fig. 13.4). The basilar portion nial nerves, which are comprised of sensory consists of descending pathways originating in fibers terminating in brainstem nuclei and the cerebral cortex. These include (1) corticob- motoneurons originating in brainstem nuclei. ulbar and corticoreticular fibers, which terminate in the tegmentum, and the corticospinal tract, which terminates in the spinal cord, and LONGITUDINAL ORGANIZATION (2) corticopontine fibers (to pontine nuclei of OF THE BRAINSTEM the basilar pons); pontocerebellar fibers, which form the middle cerebellar peduncle, take ori- The brainstem is longitudinally organized gin from the pontine nuclei (Chap. 18). into three regions: (1) the roof, posteriorly, (2) the base or basilar portion, anteriorly, and (3) Tegmentum the tegmentum in the center. The ventricular The tegmentum extends throughout the cavity is located between the tegmentum and entire length of the brainstem (see Fig. 13.1). the roof (see Fig. 13.1). Major structures within the tegmentum include (1) the reticular formation, which forms the Roof central core of the tegmentum, (2) pathways The posterior boundary of the brainstem is such as the posterior column–medial lemnis- known as the roof. In the midbrain, the roof is cus, anterolateral system (spinothalamic tract), called the tectum (quadrigeminal plate). The trigeminal pathways, medial longitudinal fasci- cerebellum (not a brainstem structure) serves culus, and auditory pathways, (3) cerebellar as the roof of the pons, and the tela choroidea relay nuclei and tracts, and (4) cranial nerve and its choroid plexus form the roof of the nuclei and roots of 10 cranial nerves. The cen- medulla. The tectum includes the pretectum tral tegmental tract, equivalent to the spinospi- (light reflex; Chap. 18), superior colliculus nalis tracts of the spinal cord, is the intrinsic (optic reflexes; Chap. 18), inferior colliculus tract of the tegmentum. This tract, containing

219 220 The Human Nervous System fibers of mixed origins and terminations, con- (Chap. 23), pineal body (Chap. 21) of the dien- veys influences both rostrally and caudally. cephalon, the stria terminalis of the limbic system (Chap. 22), the internal capsule, corona Ventricular Cavity radiata, lentiform nucleus, caudate nucleus, The ventricular cavity includes the cerebral olfactory nerve and trigone, and optic nerve aqueduct (of Sylvius) in the midbrain and the and tract of the cerebrum (Chaps. 22–24). The fourth ventricle in the pons and rostral medulla, location of the emergence of the cranial nerves which continues caudally as the central canal. from the brain is discussed in Chapter 14. Posterior Surface (see Figs. 13.2, 13.3) SURFACE LANDMARKS The roof of the midbrain consists of the cor- pora quadrigemina (tectum) that include the The cerebral structures illustrated in Figs. paired superior colliculi (optic system) and the 13.2–13.5 include the third ventricle, thalamus paired inferior colliculi (auditory system). The

Figure 13.1: Median sagittal section of the cerebrum and brainstem to illustrate the longitudinal stratification of the latter into (1) roof, (2) ventricular portion (3) tegmentum, and (4) basilar (ventral) portions. The roof consists of the tectum (including superior and inferior colliculi), inferior medullary velum, cerebellum, and choroid plexus of the fourth ventricle. The ventricular portion consists of the cerebral aqueduct (CA), fourth (IV) ventricle, and the central canal in the caudal medulla, and it is continuous rostrally with the third ventricle in the diencephalon. The tegmentum occupies the core of the three brainstem subdivisions and includes the reticular formation with its nuclei and pathways, cranial nerves and their nuclei, sensory and cerebellar relay nuclei, the ascending lemniscal pathways, and so forth. The basilar portion comprises the crus cerebri, the basilar portion of the pons, and the medullary pyramids. (Refer to Figs 1.1 and 1.5.) Chapter 13 Brainstem 221

Figure 13.2: Photograph of the posterior (dorsal) surface of the brainstem. Compare with Fig. 13.3. (Courtesy of Dr. Howard A. Matzke.)

superior colliculus and the pretectum are asso- of the tegmentum, contains the facial colliculus ciated with visual guidance and tracking activ- (abducent colliculus) formed by the underlying ities related to eye and head movements, as abducens nucleus and genu of the facial nerve well as the light reflex and accommodation (see Fig. 13.12). The area vestibularis, trigo- (Chap. 19). The inferior colliculus is part of the num vagi, and trigonum hypoglossi (see Fig. auditory pathway, as is the brachium of the 13.3) are eminences formed by the underlying inferior colliculus, which consists of fibers vestibular nuclei, dorsal vagal nucleus and connecting the inferior colliculus with the hypoglossal nucleus, respectively (see Figs. medial geniculate body of the thalamus (Chap. 13.10 and 13.11). The tuberculum cuneatus, 16). The lateral geniculate body is a thalamic tuberculum gracilis, and olive (see Fig. 13.3) nucleus of the visual pathways (Chap. 19). The are protuberances formed by the nucleus trochlear nerve (n.IV) emerges caudal to the cuneatus, nucleus gracilis, and inferior olivary inferior colliculi. nucleus of the medulla, respectively (see Fig. The roof (cerebellum and tela choroidea of 13.9). The obex is a fold of tissue dorsal to the the fourth ventricle) of the pons and medulla site where the fourth ventricle funnels into the has been removed, showing structures on the central canal; it is used as a neurosurgical land- floor of the ventricle, as well as out laterally the mark. cut surface of the three pairs of cerebellar peduncles: inferior, middle, and superior cere- Basal Surface (see Fig. 13.4) bellar peduncles (see Figs. 13.2 and 13.3). The The oculomotor nerve (n.III) emerges from floor of the fourth ventricle, which is the roof the interpeduncular fossa located between the 222 The Human Nervous System

Figure 13.3: Posterior surface of the brainstem. Lines adjacent to the figure indicate the levels of the transverse sections illustrated in Figs. 13.6–13.15. Roman numerals represent cranial nerves visible in this view. crus cerebri of the cerebral peduncles of the Most structures labeled in this view have midbrain (see Figs. 13.15 and 13.16). Note that been noted earlier. The great majority of fibers (1) cranial nerve V emerges laterally from the that form the superior cerebellar peduncle orig- midpons, (2) cranial nerves VI, VII, and VIII inate in the dentate nucleus of the cerebellum. emerge from medial to lateral along the junction The olive is formed by the underlying inferior between the pons and medulla, (3) cranial nerves olivary nucleus. IX, X, and XI emerge in a rostral to caudal continuum from the postolivary sulcus dorsal to the olive, and (4) cranial nerve XII emerges from the BRAINSTEM CRANIAL NERVES preolivary sulcus between the olive and pyramid. The pyramids are paired columns formed Cranial nerves III through XII emerge from by the pyramidal (corticospinal) tracts. the brainstem (see Figs. 13.3 and 13.4). Arising from the basal surface slightly Lateral Surface (see Fig. 13.5) lateral to the midline are n.III (oculomotor) from Note that the rootlets (1) of cranial nerves the interpeduncular fossa, n.VI (abducent) at the 1S, S, and X1 emerge for the goove that is dor- pons–medulla junction, and n.XII (hypoglossal) sal to the olive and (2) of cranial nerve X11 as filaments from the preolivary sulcus located from the groove that is ventral to the olive. between the inferior olive and medullary pyra- Chapter 13 Brainstem 223 mid. Cranial nerve IV (trochlear) emerges from pons–medulla junction, and n.IX (glossopha- the posterior surface of the caudal midbrain (see ryngeal), n.X (vagus) and n.XI (cranial root of Figs. 13.2 and 13.3). spinal accessory nerve) as nerve filaments from The remaining cranial nerves arise from the the postolivary sulcus. The spinal root of n.XI lateral surface of the brainstem. They include arises as filaments emerging laterally between n.V (trigeminal) from the midpons, n.VII the dorsal and ventral roots of spinal cord lev- (facial) and n.VIII (vestibulocochlear) from the els C1 to C6 (see Fig. 13.4).

Figure 13.4: Basal surface of the brainstem and roots of cranial nerves. 224 The Human Nervous System

Figure 13.5: Lateral surface of the brainstem and roots of cranial nerves.

line as the decussation of the pyramidal tract at FUNCTIONALLY SIGNIFICANT the junction between the brainstem and spinal INTERNAL LANDMARKS cord (see Fig. 13.8) and enter the lateral columns of the spinal cord (see Fig. 11.2). The internal anatomy of the brainstem can be visualized by appreciating the topographic Posterior Column–Medial Lemniscus relations of some major tracts and cranial Pathway (See Chap. 10) nerves. The fasciculi gracilis and cuneatus terminate in the nucleus gracilis (forming the tuberculum Corticopontine, Corticobulbar, and gracilis) and nucleus cuneatus (forming the Corticospinal Tracts tuberculum cuneatus) (see Figs. 13.3 and These tracts, originating from the cerebral 13.9). Fibers from these nuclei decussate as the cortex, descend successively through the inter- internal arcuate fibers in the lower medulla to nal capsule, crus cerebri, and basilar pons (see form the medial lemniscus (see Fig. 13.9), Figs. 13.4 and 13.5). The corticopontine fibers which ascends through the tegmentum and ter- terminate in the pontine nuclei. Along their minates in the ventral posterolateral nucleus of course, corticobulbar fibers terminate in neu- the thalamus (see Fig. 10.3). As the medial ronal pools, influencing cranial nerve nuclei lemniscus ascends, it gradually shifts from an located within the tegmentum (see Figs. 13.8 to anteromedial location in the medulla to a pos- 13.16). The corticospinal tracts continue as the terolateral position in the midbrain (see Figs. pyramids of the medulla. They cross the mid- 13.9 to 13.16). Chapter 13 Brainstem 225

Anterolateral Pathway (See Chap. 9) ways ascend as the lateral lemniscus, located in This pathway ascends from the spinal cord the lateral tegmentum just ventromedial to and and continues within the lateral aspect of the interdigitating with the spinothalamic tract (see tegmentum as the spinothalamic tract until it Fig. 13.13). The fibers of the lateral lemniscus terminates in the ventral posterolateral nucleus terminate in the inferior colliculus (see Fig. of the thalamus (see Figs. 9.2, 13.7 to 13.9, 13.14), which gives rise to the brachium of the and 13.12 to 13.16). inferior colliculus. The brachium terminates in the medial geniculate body of the thalamus (see Trigeminal Pathways Figs. 13.15 and 13.16). The trigeminal nerve enters the brainstem laterally in the midpons (see Figs. 13.4 and Spinocerebellar and Pontocerebellar Tracts 14.5). Some of its primary fibers descend as The spinocerebellar pathways are located in the spinal tract of n.V, which forms a ridge, the lateral tegmentum of the brainstem (see the trigeminal eminence (see Fig. 13.2). Some Fig. 10.7). The posterior spinocerebellar tract second-order fibers arising from the principal and the cuneocerebellar tract from the acces- sensory nucleus and spinal nucleus of n.V sory cuneate nucleus enter the cerebellum via decussate to form the anterior trigemino- the inferior cerebellar peduncle (see Figs. thalamic tract, which is located between the 13.10 to 13.12). The anterior spinocerebellar medial lemniscus and the spinothalamic tract tract ascends to the lower midbrain and passes in the pons and midbrain; nondecussating through the superior cerebellar peduncle (see fibers form the posterior trigeminothalamic Fig. 13.13). Fibers from the pontine nuclei tract), located posterolaterally in the tegmen- decussate as pontocerebellar fibers and form tum (see Figs. 10.6, 13.13, and 13.14). Both the middle cerebellar peduncle (see Figs. tracts of trigeminothalamic fibers terminate 13.13, 13.14, and 18.3). The three pair of cere- in the ventral posteromedial nucleus of the bellar peduncles (see Fig. 13.3) gives access to thalamus. the entire cerebellum. Medial Longitudinal Fasciculus Reticular Formation This bundle, which contains fibers from The brainstem tegmentum consists of (1) multiple sources, extends from the midbrain nuclei and fibers of cranial nerves (Chap. 14), through the spinal cord, although most of the (2) long tracts of sensory and motor pathways fibers originating in the brainstem do not (Chaps. 9 o 11), (3) nuclei and tracts related to descend beyond cervical levels. In the brain- the cerebellum (Chap. 18), and the (4) reticular stem, the medial longitudinal fasciculus (MLF) formation. is located anterior to the cerebral aqueduct and The reticular formation (RF) is the central or the fourth ventricle and on either side of the reticular core of the tegmentum. It is an intri- midline (see Figs. 13.10 to 13.16). It shifts cate neural network composed of reticular position slightly in the lower medulla (see Fig. nuclei (see Fig. 13.6), ascending reticular path- 13.8). The MLF contains fibers that are critical ways, descending reticular pathways, and local for the execution of synergistic (conjugate) eye reflex circuits of cranial nerves. Phylogeneti- movements (Chap. 16) and with adjustments cally older than most of the other surrounding for alterations in head position. structures, the RF consists of a diffuse yet organized network of nuclei and tracts (hence, Auditory Pathways (See Chap. 16) the term reticular). The RF network consists of Auditory pathways receive afferent input multipolar neurons with long ascending and from the cochlear nuclei located on the surface descending axons, which have highly collater- of the inferior cerebellar peduncle in the rostral alized branches synaptically linked with medulla (see Fig. 13.11). The auditory path- interneurons into complex loops of circuits 226 The Human Nervous System

(Chap. 22; see Fig. 22.1). The brainstem RF is organized in three longitudinal zones: (1) an anatomical component of the reticular sys- median raphe zone, (2) medial reticular zone, tem (Chap. 22). and (3) lateral reticular zone (see Fig. 13.6). The brainstem component of the reticular Some of the brainstem reticular nuclei are system exerts significant modulatory effects on arranged in distinct groups. On the basis of the activities of the spinal cord, brainstem, and neural connections and the biochemical nature cerebrum, including the cerebral cortex. The of their neurotransmitters, they form three ascending reticular pathways include the reticu- major aminergic (monoaminergic) systems or lar activating system, which is involved with pathways: (1) noradrenergic (transmitter is sleep–wake cycles and in modulating awareness. norepinephrine), (2) dopaminergic (transmit- The descending reticular pathways express their ter is dopamine), and (3) serotonergic (trans- roles in motor activities as manifest in behav- mitter is serotonin) systems (see Figs. 15.2 ioral performances. The nuclei of the RF are and 15.3).

Figure 13.6: Posterior view of the brainstem illustrating some of the nuclei of the reticular formation. Nuclei of the lateral and medial reticular zones are noted on the left, and the raphe nuclei, locus ceruleus, and noradrenergic lateral tegmental nuclei on the right, together with the substantia nigra. Refer to Figs. 13.7–13.16. The reticular nuclei projecting to the cerebellum (e.g., lateral reticular nucleus and pontine reticulotegmental nucleus) are not included. Nu., nuclei; Ret., reticular. (Adapted from DeMyer.) Chapter 13 Brainstem 227

Noradrenergic System. Noradrenergic neu- median forebrain bundle to the oculomotor rons, which characterize the locus ceruleus (LC), nuclei, substantia nigra, striatum, hypothala- a nucleus in the upper pons (see Fig. 13.14), also mus, limbic structures such as the hippocam- form scattered cell groups in the lateral tegmen- pus, and the cerebral cortex. Neurons of the tum of the pons and medulla (see Fig. 13.6). nucleus raphe magnus have fibers projecting The locus ceruleus (cerulean blue color in the locally to the facial nucleus and caudally to the fresh human brainstem) receives major input sensory dorsal horn and the motor ventral horn from nuclei in the vicinity of the nucleus gigan- of the spinal cord. tocellularis. The axon of each LC neuron has a The widespread connections of this system T-like bifurcation, forming ascending and are expressed by its modulatory and augment- descending branches that are more widely dis- ing role, rather than by a specific behavior. It tributed than those of any other known nucleus functions in enhancing learning of avoidance (see Fig. 15.2). The axons profusely collateral- behavior and in increasing the excitability of ize into fibers that sprout thousands of branches, lower motoneurons. Inhibitory roles are which are distributed directly to the thalamus, expressed in the dorsal horn of the spinal cord hypothalamus, hippocampus, cerebral cortex, by modulating and repressing pain, producing cerebellum, and the dorsal and ventral horns of analgesia, and increasing the pain threshold the spinal cord (see Fig. 15.2). Axons arising (Chap. 9). This system can also participate in from the other tegmental adrenergic neurons are initiating sleep. This is consistent with insom- primarily distributed to the brainstem and spinal nia that occurs following experimental destruc- cord and have lesser projections to the thalamus, tion of the raphe nuclei. cerebral cortex and cerebellum. Catecholamine pathways with their diffuse connections modu- Dopaminergic System. Dopaminergic neu- late numerous functions, rather than initiating or rons are present in the substantia nigra (pars mediating specific ones. They play a role in compacta) (see Figs. 13.15 and 13.16) in the phases of the sleep–wake cycle. When activated midbrain, and just medially in the ventral by novel or intense sensory stimuli, the locus tegmental area (VTA). Their axons project ros- ceruleus helps coordinate preparation of appro- trally as the mesostriatal, mesolimbic, and priate responses. The lateral tegmental neurons mesocortical pathways to the cerebrum (meso exert their roles in the autonomic nervous sys- for mesencephalon or midbrain). tem by evoking a decrease in arterial pressure The mesostriatal system from the substantia and heart rate. To be specific about what func- nigra to the striatum (caudate nucleus and tions are evoked is complicated for the following putamen) of the basal ganglia is important in reason. The modulatory activity of the circuits mechanisms of motor function (Chap. 24). can produce differences and nuances in physio- Parkinson’s disease is caused by a reduction or logical and behavioral expressions because of loss of inhibitory projections to the striatum fol- the variety of ways inputs can be biased— lowing damage to the nigra (Chap. 24). The dependent on the degree of stimulation (or inhi- mesolimbic system from the VTA is connected to bition) of excitatory (or inhibitory) neurons in such limbic structures as the nucleus accumbens, the complex circuitry. amygdala, septal region, and ventral striatum (Chaps. 22 and 24). The mesocortical projections Serotonergic System. Serotonergic neurons are from the VTA to frontal and cingulate gyri of in the brainstem outnumber those of the adren- the cortex (Chaps. 22 and 25). The latter two sys- ergic and dopaminergic systems. The cell bod- tems have been linked to schizophrenia ies of the neurons of this extensive system are (dopamine hypothesis of schizophrenia). It is located at the midline in the raphe nuclei (see thought that schizophrenia might be related to a Fig. 13.6). Neurons of the raphe nuclei in the relative excess in dopaminergic neuronal activity. upper pons and midbrain project via the Antipsychotic drugs that have therapeutic effects 228 The Human Nervous System are presumed to block dopamine receptors and, 1. General somatic column associated with thus, reduce dopaminergic transmission. cranial nerves III, IV, VI, and XII. These motor nuclei are located in the posterome- Sensory Nerves, Their Ganglia, and dial tegmentum. Those of nerves III and IV Nuclei of Termination are in the midbrain (see Figs. 13.14 to The sensory cranial nerves and ganglia 13.16), that of n.VI in the lower pons (see (equivalent to dorsal root ganglia) include the Fig. 13.10), and that of n.XII extends the following: trigeminal nerve (n.V), trigeminal length of the medulla (see Figs. 13.9 and (Gasserian, semilunar) ganglion; facial nerve 13.10). (n.VII), geniculate ganglion; vestibulocochlear 2. Special visceral column consisting of three (acoustic/vestibular) nerve (n.VIII), vestibular nuclei associated with cranial nerves V, and spiral ganglia; glossopharyngeal nerve VII, IX, X, and XI. The motor nucleus of (n.IX), superior and inferior ganglia; and vagus n.V is located in the lateral tegmentum of nerve (n.X), also superior and inferior ganglia the midpons (see Fig. 13.13), the motor (see Figs. 14.1 and 14.2). nucleus of n.VII is in the caudal pontine The brainstem nuclei of sensory cranial tegmentum (see Fig. 13.12), and that of nerves are arranged in continuous columns (see IX, X, and XI, known as the nucleus Fig. 14.2) as follows: ambiguus, is within the central tegmentum throughout the medulla (see Figs. 13.9 to 1. General somatic column associated with cra- 13.11). nial nerves V, VII, IX, and X. It comprises 3. General visceral (parasympathetic) col- the mesencephalic nucleus of n.V, located umn emiting preganglionic fibers that are lateral to the ventricular canal in the upper part of cranial nerves III, VII, IX, and X pons and midbrain (see Fig. 13.13), the prin- (see Fig. 14.3). The parasympathetic cipal sensory nucleus of n.V, located in the nucleus associated with n.III is the acces- lateral tegmentum in the midpons (see Fig. sory nucleus of n.III (nucleus of Edinger– 13.13), and the spinal nucleus of n.V, located Westphal) in the midbrain (see Fig. 13.14); laterally in the lower pontine tegmentum, that associated with n.VII is the superior medulla, and first two cervical spinal cord salivatory nucleus in the posterolateral levels (see Figs. 13.7 to 13.12). tegmentum of the lower pons (see Fig. 2. Visceral column associated with cranial 13.12); that associated with n.IX is the nerves VII, IX, and X. This column, known inferior salivatory nucleus located in the as the nucleus solitarius, is located in the posterior tegmentum of the rostral medulla posterior tegmentum of the medulla (see (see Fig. 13.11); and that associated with Figs. 13.9 to 13.11). n.X is the dorsal vagal nucleus located in 3. Special somatic column associated with cra- the posterior tegmentum of the medulla nial nerve VIII. The four vestibular nuclei (see Figs. 13.9 and 13.10). are located in the posterolateral tegmentum of the lower pons and upper medulla (see Figs. 13.10 to 13.12); the paired cochlear TRANSVERSE SECTIONS THROUGH nuclei are located on the outer surface of the THE BRAINSTEM inferior cerebellar peduncle (see Fig. 13.11). In the following account, the anatomic rela- Motor Nerves and Their Nuclei of tions of the intrinsic structures of the brainstem Origin Within the Brainstem are briefly described in a representative series The brainstem nuclei of the motor cranial of transverse sections moving successively nerves are arranged in three discontinuous higher from the upper cervical spinal cord columns (see Fig. 14.3): through the upper midbrain. Chapter 13 Brainstem 229

First Cervical Segment of the Level of the Pyramidal Decussation Spinal Cord (see Fig. 13.7) (see Fig. 13.8) The first cervical segment has several dis- This level is within the medulla. The most tinctive features. The fibers of the lateral corti- distinguishing feature is the crossing of 85– cospinal tract are located more medially than in 90% of the corticospinal tract fibers as the the other spinal levels. Its location, abutting the pyramidal decussation. It is composed of inter- gray matter, indicates that the tract has not digitating descending fibers, which decussate completed its decussation. The myelinated and course in a caudal and posterior direction fibers of the spinal tract of n.V and the large to the dorsal aspect of the lateral funiculus of spinal nucleus of n.V, which extend to the C2 the spinal cord. Dorsal spinal roots are absent. level, are the equivalents of the posterolateral The spinal tract of n.V is composed of first- tract and substantia gelatinosa of the spinal order fibers from cranial nerves V, VII, IX, and cord. The fibers of the spinal root of cranial X, which descend as far as C2; they terminate nerve XI originate in the anterolateral aspect of throughout the length of the spinal nucleus of the anterior horn and pass posteriorly and then n.V (see Fig. 9.6). The fasciculus gracilis is laterally before emerging from the lateral side smaller than the fasciculus cuneatus; both of the spinal cord. Although the dorsal root is tracts are in the same location as in the spinal absent at C1, the ventral root of the first cervi- cord. The nucleus gracilis is present; it is the cal nerve is present. nucleus of termination for the fibers of the

Figure 13.7: Transverse section of the upper portion of the first cervical segment. 230 The Human Nervous System

Figure 13.8: Transverse section of the lower medulla at the level of the pyramidal (corticospinal) decussation. The pars caudalis of the spinal trigeminal nucleus is called the posterior horn of the medulla because it is divisible into a (1) marginal lamina, (2) substantia gelatinosa, and (3) magnocellular layer.

fasciculus gracilis. The posterior and anterior fibers of the first cervical nerves, is called the spinocerebellar, spinothalamic, and spinotectal supraspinal nucleus. tracts have a relatively similar position to those in the spinal cord. The medial longitudinal fas- Level of Decussation of the ciculus passes on the ventrolateral side of the Medial Lemniscus (see Fig. 13.9) decussating pyramidal fibers. The central retic- The distinguishing feature of this level is ular nucleus of the medulla occupies the bulk the curve of the internal arcuate fibers, which, of the reticular formation from the spinal cord– after arising from cells in the enlarged nuclei medulla junction to the midolivary level. In the gracilis and cuneatus, sweep anteriorly in an medial part of the ventral gray matter of the arc and decussate across the midline to form caudal medulla is a rostral extension of the the medial lemniscus of the opposite side. anterior horn (lamina IX) of the spinal cord; Upon entering the medial lemniscus, these this nucleus, which gives rise to ventral root fibers bend and ascend rostrally through the Chapter 13 Brainstem 231 brainstem to the ventral posterolateral nucleus visceral efferent [GVE]) and the nucleus of the thalamus. The fasciculi gracilis and ambiguus (motor, special visceral efferent cuneatus are small because their fibers mainly [SVE]) all have components of the vagus have terminated within the corresponding nerve, which emerges through the dorsolateral nuclei. The spinal tract and nucleus of the sulcus of the medulla. The former two nuclei trigeminal nerve are displaced anteriorly. are located anterior to the nucleus gracilis and Some of the fibers arising from this nucleus medial to the internal arcuate fibers; the cross to the opposite side with the internal nucleus ambiguus is located in the middle of arcuate fibers and ascend to the thalamus as the tegmentum just lateral to the internal arcu- the anterior trigeminothalamic tract to termi- ate fibers. Many of the fibers of the nucleus nate in the ventral posteromedial nucleus (see ambiguus from this level form the cranial root Fig. 9.6). They are second-order neurons, con- of the accessory nerve. The hypoglossal veying pain and temperature information nucleus (general somatic efferent [GSE]), derived from the trigeminal nerve, nervus located anterior to the central canal on either intermedius (VII), and glossopharyngeal and side of the midline,gives rise to axons that pass vagus nerves. In addition to the spinal nucleus downward through the medial tegmentum and of n.V, four other cranial nerve nuclei are pres- emerge from the medulla between the pyramid ent at this level. The nucleus solitarius (sen- and the olive (inferior olivary nuclear com- sory, general visceral afferent [GVA], and plex) at the preolivary sulcus. special visceral afferent [SVA]), the dorsal The ascending tracts located in the lateral motor vagal nucleus (parasympathetic, general medulla (the posterior and anterior spinocere-

Figure 13.9: Transverse section of the lower medulla at the level of the decussation of the medial lemniscus (internal arcuate fibers). 232 The Human Nervous System bellar, spinothalamic, and spinotectal tracts) lospinal tract from the nucleus reticularis occupy the same general location as at more gigantocellularis of the medulla, and the caudal levels. vestibulospinal tract from the lateral vestibular Three prominent cerebellar relay nuclei of nucleus. The fibers of these tracts are intermin- the medulla, referred to as precerebellar nuclei, gled with other fibers; hence, they are not are the source of fibers, which pass through the clearly delineated. inferior cerebellar peduncle before terminating The reticular nuclei include the nucleus in the cerebellum. The first, the accessory raphe magnus, central reticular nucleus, and cuneate nucleus of the lower medulla, located lateral reticular nucleus; these belong to the lateral to the cuneate nucleus, is the homolog of raphe, central, and lateral nuclear groups, the dorsal nucleus of Clarke in the spinal cord; respectively. Just rostral to this level is the obex it receives proprioceptive input from the cervi- (see Fig. 13.2), located at the most caudal end cal and upper thoracic regions, especially the of the fourth ventricle. upper extremities, via uncrossed fibers ascending in the fasciculus cuneatus. The ipsilaterally Level of the Middle Third of the Inferior projecting cuneocerebellar fibers from the Olivary Complex (see Fig. 13.10) accessory cuneate nucleus are the pathway The distinguishing features of this level are from the upper extremity and are equivalent to the nuclei of the inferior olivary complex, the posterior spinocerebellar tract from the fourth ventricle, inferior cerebellar peduncle, lower extremity. The second relay nucleus, the and cranial nerve nuclei. The olivary complex lateral reticular nucleus, is located in the vicin- comprises the phylogenetically new principal ity of the spinothalamic tract at the level of the inferior olivary nucleus together with phyloge- caudal two thirds of the inferior olivary nuclei. netically old dorsal and medial accessory oli- This nucleus receives afferent input from the vary nuclei. Efferent fibers from the inferior spinal cord via spinoreticular and collateral olivary complex decussate and pass succes- branches of spinothalamic fibers and from sively through the medial lemnisci, the vicinity fibers from the red nucleus of the midbrain. of the contralateral olivary complex, and the The third cerebellar relay group, the inferior inferior cerebellar peduncle before terminating olivary complex, is discussed in the next sub- in the cerebellum. The accessory olivary nuclei section. project primarily to the vermis of the cerebel- Of the descending tracts and fibers, only the lum, whereas fibers from the principal olivary pyramids, composed of corticospinal fibers, are nucleus terminate in the contralateral cerebellar clearly demarcated. The anterior border of the hemisphere. Olivocerebellar fibers carry exci- medial longitudinal fasciculus (MLF) is not tatory input to the deep cerebellar nuclei and clearly defined because its fibers overlap with the entire cerebellar cortex. The input to the those of the medial lemniscus. At this level, the inferior olivary nuclei is derived from the MLF is composed of (1) the pontine reticu- spinal cord, cerebral cortex, red nucleus, peri- lospinal tract from the pars oralis and pars cau- aqueductal gray of the midbrain, and the deep dalis of the pontine reticular formation, (2) the cerebellar nuclei. The spinoolivary fibers interstitiospinal tract from the interstitial ascend in the anterior funiculus. Originating nucleus of Cajal in the midbrain, (3) the tec- from the frontal, parietal, temporal, and occip- tospinal tract from the midbrain tectum, and (4) ital lobes, corticoolivary fibers descend with vestibulospinal fibers from the medial vestibu- the corticospinal tract before terminating lar nucleus. bilaterally. Fibers from the red nucleus and Just posterior to the inferior olivary nuclear periaqueductal gray descend in the central complex, within the reticular formation, are tegmental tract. Some of the fibers from the fibers of the rubrospinal tract from the red deep cerebellar nuclei, after emerging from the nucleus in the midbrain, the medullary reticu- cerebellum via the superior cerebellar peduncle, Chapter 13 Brainstem 233

Figure 13.10: Transverse section of the medulla at the level of the middle of the inferior olive. The arcuate nuclei are minor nuclei projecting to the cerebellum.

decussate in the lower midbrain and descend in The paramedian reticular nuclei (nuclei lat- the central tegmental tract to the inferior oli- eral to medial lemniscus in vicinity of inferior vary complex. olivary nucleus) and the nearby arcuate In the tegmentum anterior to the floor of the nucleus relay influences via the inferior cere- fourth ventricle is a row of cranial nerve nuclei. bellar peduncles to the cerebellum. The cells of Two motor nuclei, located medial to the fovea the raphe nuclei (nucleus raphe magnus) con- (sulcus limitans), are the hypoglossal general tain serotonin (5-hydroxytryptamine) and proj- somatic efferent (GSE) and dorsal vagal general ect to the spinal cord. visceral efferent (GVE) nuclei. Two sensory The central reticular nuclear group at upper nuclear groups, located laterally to the fovea, are medullary levels consists of the gigantocellular the nucleus solitarius (GVA and SVA) and the reticular nucleus, which is located posterior to medial and inferior vestibular special somatic the inferior olivary complex. This large-celled afferent (SSA) nuclei. The nucleus ambiguus nucleus occupies the medial two-thirds of the special visceral efferent (SVE) is a motor reticular formation as far rostral as the nucleus located in the middle of the tegmentum. medullary–pontine junction. Input to this The spinal nucleus of n.V is a sensory nucleus in nucleus is derived largely from (1) widespread the dorsolateral tegmentum. The vagus nerve is areas of the cerebral cortex via crossed and associated with the nucleus ambiguus, dorsal uncrossed corticoreticular fibers, (2) higher vagal nucleus, nucleus solitarius, and the spinal brainstem levels via the central tegmental tract, nucleus of n.V. (3) neurons from the parvicellular nucleus of 234 The Human Nervous System the lateral nuclear group, and (4) spinoreticular cerebellar peduncle. Fibers of the cochlear fibers ascending in the anterolateral funiculus nerve branch in an organized sequence so that of the spinal cord. The output from the gigan- each fiber is distributed in a precise pattern to tocellular reticular nucleus projects (1) ros- both the dorsal and ventral cochlear nuclei. At trally via the central tegmental tract to higher a slightly higher level (right side of Fig. 13.11), brainstem levels and to the intralaminar nuclei fibers of the vestibular nerve pass at right of the thalamus and via the median forebrain angles among the fibers of the inferior cerebel- bundle to the hypothalamus and (2) caudally lar peduncle enroute to the four vestibular via the medullary (lateral) reticulospinal tract nuclei (medial, inferior, and lateral vestibular to the spinal cord. nuclei are illustrated). The lateral reticular zone consists of the lat- In Fig. 13.11, the large inferior cerebellar eral reticular nucleus and parvicellular reticular peduncle (left side) is illustrated as it passes nucleus. Input to the parvicellular reticular (right side) into the cerebellum. The peduncle nucleus is derived from (1) widespread areas of contains the following fibers passing to the the cerebral cortex via crossed and uncrossed cerebellum: posterior spinocerebellar, cuneo- corticoreticular fibers, (2) collateral fibers from cerebellar, and olivocerebellar tracts, along with the auditory, vestibular, trigeminal, and visceral fibers from such nuclei as the lateral reticular pathways, and (3) spinoreticular fibers from the and paramedian reticular nuclei. A portion of spinal cord. The output from the parvicellular the inferior cerebellar peduncle, called the reticular nucleus is directed medially to the juxtarestiform body, is composed of fibers asso- gigantocellular reticular nucleus. Except for pos- ciated with the vestibular system conveying sible minor changes, the locations of the ascend- influences to and from the vestibulocerebellum ing and descending tracts and pathways are and the fastigial nuclei of the cerebellum. similar to those described in the Level of Decus- The reticular nuclei at this level include the sation of the Medial Lemniscus subsection. The raphe magnus, gigantocellularis and parvicel- posterior spinocerebellar tract is close to the infe- lularis. rior cerebellar peduncle, which it is about to join. The four deep cerebellar nuclei, oriented in order from medial to lateral, are the fastigial, Tangential Section at the Levels of the globose, emboliform, and dentate nuclei. The Glossopharyngeal and Vestibulocochlear globose and emboliform nuclei are collectively Nerves (see Fig. 13.11) called the nucleus interpositus. The fibers of This medullary level is in the vicinity of the the inferior cerebellar peduncle pass lateral to medullopontine junction. It is different from the dentate nucleus. The juxtarestiform body is the midolivary level in several respects. Among located between the deep cerebellar nuclei and these are the absence of the hypoglossal and the lateral border of the fourth ventricle. dorsal vagal nuclei, the presence of cranial nerve nuclei associated with the glossopharyn- Level of Nuclei of Sixth and Seventh geal, cochlear, and vestibular nerves, and the Cranial Nerves (see Fig. 13.12) presence of the inferior cerebellar peduncle, The general pattern of organization at this which can be seen extending from the medulla level differs from that of the levels of the into the cerebellum. medulla primarily because of the massive size The nuclei associated with the glossopha- of the ventral or basilar pons relative to the dor- ryngeal nerve include the nucleus solitarius, sal or tegmental pons. The ventral pons repre- spinal nucleus of n.V, inferior salivatory sents a modified, rostral continuation of the nucleus, and nucleus ambiguus. These nuclei pyramids of the medulla. The tegmentum of the are discussed in Chapter 14. pons represents a rostral continuation of the The dorsal and ventral cochlear nuclei are medulla exclusive of the pyramids. The bound- situated on the outer surface of the inferior ary between the dorsal and ventral pons is a Chapter 13 Brainstem 235 plane located just anterior to the medial lem- Except for a few significant modifications, niscus. The fourth ventricle is large. the dorsal pons resembles the medulla. The The basilar pons consists of the corti- MLF is still located anterior to the fourth ven- cospinal tract, pontine nuclei, terminal branches tricle and just lateral to the midline, whereas of the descending corticopontine fibers to the the spinal tract and nucleus of the trigeminal pontine nuclei, and pontocerebellar fibers; the nerve are in the dorsolateral tegmentum. How- latter pass from the pontine nuclei through the ever, the medial lemniscus has shifted from middle cerebellar peduncle to the cerebellum. a ventromedial tegmental location (vertical

Figure 13.11: Transverse section (slightly oblique) of the upper medulla at the level of the cochlear and glossopharyngeal nerves (left) and the vestibular nerve (right). Section includes the cerebellum and its deep cerebellar nuclei. 236 The Human Nervous System

Figure 13.12: Transverse section of the lower pons at the level of the sixth and seventh cranial nerves. orientation) in the medulla to a ventral tegmen- before emerging medially at the pon- tal location (horizontal orientation) in the pons. tomedullary junction. After emerging from the The central tegmental tract is prominent in the facial nucleus, the lower motoneurons form a middle of the reticular formation. bundle that follows a circuitous course. The The cranial nerve nuclei present at this level facial nerve passes posteromedially, ascends have their equivalents in the medulla. The for a short distance medial to the abducent abducent nucleus, motor nucleus of the facial nucleus, and then, as the genu of n.VII, passes nerve, and the superior salivatory nucleus are posterior to the abducent nucleus; finally, it located within the tegmentum in sites similar to turns laterally before continuing anterolaterally those occupied within the medulla by the through the lateral tegmentum before emerging hypoglossal nucleus, nucleus ambiguus, and from the brainstem at the cerebellopontine dorsal vagal nucleus, respectively. The superior angle (see Fig. 13.3). The hillock in the floor of vestibular nucleus is found in the posterolateral the fourth ventricle at the site of the abducent tegmentum. The course of the fibers of the nucleus and the internal genu is called the abducent and facial nerves is characteristic and facial or abducent colliculus. The nervus inter- significant. The lower motoneurons of the sixth medius is a part of n.VII (Chap. 14); some of its nerve emerge from the abducent nucleus and fibers originate in the superior salivatory pass ventrally through the medial tegmentum nucleus and others terminate in the spinal and basal pons lateral to the pyramidal tract nucleus of n.V and the nucleus solitarius. Chapter 13 Brainstem 237

The superior and inferior salivatory nuclei Level of the Trigeminal Nerve (see Fig. 13.13) are diffuse and confluent groups of cells The characteristic features at this midpon- located within and close to the parvicellular tine level are (1) the principal sensory nucleus reticular nucleus (see Figs. 13.11 and 13.12). and motor nucleus of the trigeminal nerve and Components of the auditory pathways found at (2) the superior cerebellar peduncle on the lat- this level are the superior olivary complex and eral aspect of the narrowing fourth ventricle. the lateral lemniscus, which is located in the The principal nucleus of n.V is a nucleus of ventrolateral tegmentum. Auditory fibers termination of the sensory root of the trigemi- decussating between the olives constitute the nal nerve; other fibers of this root have their trapezoid body (see Figs. 13.12 and 16.6). cell bodies in the mesencephalic nucleus of The reticular nuclei at this level and those of n.V, which is located lateral to the fourth ven- the lower pons caudal to the principal nucleus tricle. The motor nucleus of n.V, located medial of the trigeminal nerve are the nucleus raphe to the principal nucleus, contains the cell bod- pontis (a raphe nucleus), the nucleus reticularis ies of the lower motoneurons that form the pontis caudalis (a central reticular group motor root of the trigeminal nerve. nucleus), and the nucleus parvicellularis (a lat- The superior cerebellar peduncle is prima- eral reticular nucleus). rily composed of cerebellar efferent fibers orig-

Figure 13.13: Transverse section of the midpons at the level of the entrance of the trigeminal nerve. 238 The Human Nervous System inating in the dentate, emboliform, and globose fibers of the lateral lemniscus and from nuclei; these fibers decussate in the lower mid- descending fibers from the medial geniculate brain tegmentum and (1) ascend to the nucleus body; it projects influences (1) rostrally to the ruber and to the rostral intralaminar and ven- medial geniculate body via the brachium of the trolateral thalamic nuclei and (2) descend in the inferior colliculus and to the superior colliculus brainstem tegmentum to the reticulotegmental and (2) caudally to auditory nuclei via the lat- nucleus of the pons and the inferior olivary and eral lemniscus. The bilateral nuclei of the paramedian nuclei of the medulla. The anterior inferior colliculi are interconnected by fibers in spinocerebellar tract courses posteriorly in the the commissure of the inferior colliculus. As a superior cerebellar peduncle; its fibers termi- group, the medial lemniscus, spinothalamic nate in the anterior vermal cortex. tract, and lateral lemniscus have shifted later- The medial lemniscus has shifted somewhat ally and dorsally along the outer margin of the laterally and the spinothalamic tract and lateral reticular formation of the tegmentum. In this lemniscus have shifted slightly dorsolaterally shift, the lateral lemniscus approaches the infe- along the outer margin of the reticular forma- rior colliculus; its fibers enter and terminate in tion. The medial longitudinal fasciculus, cen- the nucleus of the inferior colliculus. The rostral tegmental tract, rubrospinal tract, and the trally projecting fibers from the latter form the structures of the basilar pons have the same brachium of the inferior colliculus, which is topographic relations to one another as those located in the dorsolateral tegmentum of the described in the previous section. The lateral upper midbrain. lemniscus contains a small diffuse aggregation The posterior trigeminothalamic tract, from of neurons called the nucleus of the lateral lem- the ipsilateral principal nucleus of n.V, is niscus. located in the tegmentum posterior to the cen- The reticular nuclei extending from this tral tegmental tract. The anterior trigeminothal- level up to the lower midbrain are (1) the supe- amic tract, from the contralateral spinal and rior central nucleus (a raphe nucleus), (2) the principal nuclei of n.V, is located between the reticulotegmental nucleus (actually an exten- medial lemniscus and spinothalamic tract. The sion of the pontine nucleus of the basilar pons MLF is notched posteriorly by the nucleus of into the tegmentum [as do the pontine nuclei, the trochlear nerve. The fibers of the trochlear the reticulotegmental nucleus projects its fibers nerve (IV) pass as a dorsocaudally directed arc to the cerebellum]), and (3) the nucleus reticu- from this nucleus along the outer edge of the laris pontis oralis and locus ceruleus (see Fig. periaqueductal gray matter; they decussate 13.14) (central reticular nuclei). The cells of completely in the superior medullary velum the locus ceruleus are noradrenergic neurons and emerge from the posterior tectum caudal to whose axons are distributed to the (1) cerebel- the inferior colliculus. The locus ceruleus is lum, (2) cerebrum, including directly to the located deep to the inferior colliculus. cerebral cortex, (3) brainstem, and (4) spinal The reticular nuclei at this level include (1) cord. the dorsal and ventral raphe tegmental nuclei (raphe nuclei), (2) the rostral portion of the Level of the Inferior Colliculus (see Fig. 13.14) nucleus reticularis pontis oralis and locus The distinguishing features at this level ceruleus (central reticular nuclei), and (3) include the inferior colliculi and the decussa- pedunculopontine and cuneiform nuclei (lat- tion of the superior cerebellar peduncle. The eral reticular group nuclei). The dorsal ventricular system is represented by the narrow tegmental nucleus (supratrochlear nucleus) is cerebral aqueduct. located dorsal to the trochlear nucleus in the The large nucleus of the inferior colliculus is periaqueductal gray matter; it receives input a major processing station in the auditory path- from the mammillary body. The ventral ways. It receives input from ascending auditory tegmental nucleus is present ventral to the Chapter 13 Brainstem 239

Figure 13.14: Transverse section of the lower midbrain at the level of the inferior colliculus and nucleus of the fourth cranial nerve. medial longitudinal fasciculus; it is apparently The laminated superior colliculus and the a rostral extension of the superior central rostrally located pretectum (see Fig. 13.16) are nucleus. The pedunculopontine nucleus lies in reflex centers. The superficial layers of the the caudal midbrain lateral to the superior superior colliculus receive direct input from the cerebellar peduncle and medial to the medial retina and the visual cortex. The deep layers lemniscus. It is the only brainstem nucleus receive inputs from the auditory and that receives direct input from the globus pal- somatosensory systems. The superior collicu- lidus (see Fig. 24.3). lus has roles in orienting the head and eyes toward a visual stimulus. The pretectum is part Section Through Midbrain at Level of of the circuitry involved in the direct and con- Superior Colliculus (see Fig. 13.15) sensual light reflexes (Chap. 19). The major characteristic features at this The red nucleus is a large oval nucleus in the level are the superior colliculus, nucleus of the medial tegmentum. It is composed of a caudal oculomotor nerve, red nucleus, substantia magnocellular part and a rostral parvicellular nigra, and crus cerebri. The medial geniculate part. Some fibers of the superior cerebellar body, marking the most caudal nucleus of the peduncle terminate within the nucleus, whereas diencephalon (or thalamus), is present. others pass through it and along its outer 240 The Human Nervous System

Figure 13.15: Transverse section of the upper midbrain at the level of the superior colliculus and the third cranial nerve. The medial region between the bilateral substantia nigra is called the ventral tegmental area (VTA). The VTA contains dopaminergic neurons that project rostrally to the forebrain, including the nucleus accumbens, a component of the limbic system (Chap. 22). margins as a “capsule,” on their way to the ven- The substantia nigra is located between the tral lateral, ventral anterior, and some intralam- tegmentum and the crus cerebri. It is divided inar thalamic nuclei. into a pars compacta and a pars reticularis. The The rubrospinal tract originates from cells in large cells of the compact (or black) part contain the caudal one-fourth of the red nucleus; its melanin pigment and primary catecholamines; fibers cross as the ventral tegmental decussa- these cells synthesize and convey dopamine, via tion before descending as the rubrospinal tract nigrostriatal fibers, to the neostriatum (caudate in the anterior tegmentum. nucleus and putamen). The cells of the reddish The oculomotor nuclear complex is located brown pars reticularis contain iron, but no in a V-shaped region formed by the paired melanin pigment. medial longitudinal fasciculi. The fibers of the The crus cerebri is the basilar part of the oculomotor nerve (III) arise in this nucleus and midbrain. It is composed of descending corti- course anteriorly through the medial tegmen- cofugal fibers, which originate in the cerebral tum, including the red nucleus, on their way to cortex. The corticospinal and corticobulbar emerge as rootlets from the interpeduncular fibers are located in the middle two-thirds (see fossa. Fig. 13.15). They are said to be somatotopi- Chapter 13 Brainstem 241 cally organized at this level with the head minothalamic tract is located in the dorsome- andupper-extremity and lower-extremity mus- dial tegmentum. The interpeduncular nucleus is culature influenced by nerve fibers arranged located at the midline just dorsal to the interpe- from medial to lateral within the crus. Fronto- duncular fossa. Dorsal to this nucleus is the pontine fibers are located in the medial portion, ventral tegmental area (VTA, not labeled) and corticopontine fibers from the parietal, (Chap. 15). Neurons of VTA have been impli- temporal, and occipital cortical areas are in the cated with the reward properties of cocaine lateral portion of the crus. The most medial and addiction (Chap. 22). lateral portions of the crus may contain some Reticular nuclei at this level include nuclei corticobulbar fibers. linearis (raphe nuclei), nucleus ruber, which The medial lemniscus, anterior trigemi- is considered to be a specialized central retic- nothalamic tract, and spinothalamic tract have ular nucleus, and cuneiform nuclei (lateral shifted to a slightly more dorsal location in the reticular nuclear group). Nonreticular nuclei tegmentum. The brachium of the inferior col- include the interpeduncular nucleus, mesen- liculus (auditory tract) is located dorsolateral to cephalic nucleus of the trigeminal nerve, the spinothalamic tract; it is heading to the interstitial nucleus of Cajal, and the nucleus medial geniculate body. The posterior trige- of Darkschewitsch.

Figure 13.16: Transverse section at the junction of the upper midbrain and diencephalon. 242 The Human Nervous System

Transverse Section Through Junction of SUGGESTED READINGS Midbrain and Thalamus (see Fig. 13.16) In this section are structures of the upper Brodal A. The Reticular Formation of the Brain midbrain and the adjoining cerebrum. The Stem; Anatomical Aspects and Functional Corre- midbrain is only slightly changed from the lations. Henderson Trust Lectures, No. 18. Edin- previous section (Fig. 13.15). The pulvinar burgh: Oliver and Boyd; 1957. and medial and lateral geniculate bodies DeMyer W. Neuroanatomy. Malvern, PA: Harwal; belong to the thalamus (Chap. 23). Also illus- 1998, p. 170. trated are the caudate nucleus (a basal gan- Felten DL, Sladek JR, Jr. Monoamine distribution in glion, Chap. 24), stria terminalis (a tract of the primate brain V. Monoaminergic nuclei: anatomy, pathways and local organization. Brain limbic system, Chap. 22), internal capsule Res. Bull. 1983;10:171–284. (fibers of the cerebrum; Chap. 23), and pineal Garver DL, Sladek JR Jr. Monoamine distribution in body (Chap. 22). primate brain. I Catecholamine-containing peri- The brachium of the inferior colliculus karya in the brain stem of Macaca speciosa. J (auditory pathways) terminates in the medial Comp. Neurol. 1975;159:289–304. geniculate body of the thalamus. Note that the Garver DL, Sladek JR Jr. Monamine distribution in fibers in the optic tract end either in the lat- primate brain. II. Brain stem catecholaminergic eral geniculate body of the thalamus or in the pathways in Macaca speciosa (arctoides). Brain superior colliculus and pretectum (Chap. 19). Res. 1976;103:176–182. The ascending reticular pathway fibers of Hobson JA, Brazier MAB, eds. The Reticular For- the central tegmental tract terminate in the mation Revisited: Specifying Function for a Non- specific System. New York: Raven; 1980. intralaminar nuclei of the thalamus (see Fig. Olszewski J, Baxter D. Cytoarchitecture of the Human 22.1). Brain Stem. 2nd ed. New York: Karger; 1982. Refer to the previous section for a discus- Peterson BB. The reticulospinal system and its role sion of the superior colliculus, pretectum in the control of movement. In: Barnes C, ed. (pretectal area), oculomotor nerve (n.III), sub- Brainstem Control of Spinal Cord Function. New stantia nigra, and crus cerebri. York: Academic; 1984. 14 Cranial Nerves and Chemical Senses

Classification of Cranial Nerves Ganglia in the Head Cranial Nerve Nuclei Within the Brainstem Some Functional and Clinical Considerations Chemical Senses (Olfaction and Gustation)

Twelve pairs of cranial nerves are periph- efferent (GVE). In addition, many cranial eral nerves of the brain (see Fig. 14.1). The nerves have special components: special olfactory and optic nerves are nerves of the somatic afferent (SSA), special visceral affer- cerebrum (telencephalon). The other 10 pairs ent (SVA), and special visceral (branchial) are nerves of the brainstem (and in one case, efferent (SVE). The terms defining the com- partially of the cervical spinal cord). They ponents are used as follows: somatic refers to supply structures of the head and neck and, in head, body wall, and extremities; visceral the case of the vagus nerve, structures of the refers to viscera; afferent refers to sensory trunk. Some cranial nerves contain almost (input); efferent refers to motor (output); gen- exclusively afferent fibers, others almost eral refers to wide areas of the head and body; exclusively efferent fibers, and a third group special refers to the specialized functions of contains substantial proportions of both affer- olfaction (smell), gustation (taste), vision, ent and efferent fibers (see Table 14.1). The audition, equilibrium (vestibular system), and afferent fibers arise with one exception, those branchiomeric (gill arch) muscles. Cranial that mediate unconscious proprioception, nerves are classified into one of three groups, from cell bodies located in peripheral ganglia; depending on the main function component: their central processes enter the brainstem and special afferent, general efferent, and bran- end in sensory nuclei of termination (see Fig. chiomeric or mixed (see Table 14.1). 14.2). Efferent fibers arise from cell bodies located in brainstem motor nuclei (see Fig. Special Afferent Nerves 14.3). Cranial nerves pass to and from the cra- These sensory nerves serve the special nial cavity through foramina, canals, and fis- senses (i.e., smell, sight, hearing, and balance sures in the skull. [equilibrium]). Included are two special somatic afferent (SSA) nerves:

CLASSIFICATION OF Optic (II) CRANIAL NERVES Vestibulocochlear (VIII) and a special visceral afferent (SVA) nerve Many of the cranial nerves have the same Olfactory (I) general functional components as occur in spinal nerves: general somatic afferent (GSA), Taste, also SVA, is mediated by components general visceral afferent (GVA), general of three branchiomeric nerves: cranial nerves somatic efferent (GSE), and general visceral VII, IX, and X.

243 244 The Human Nervous System

Figure 14.1: Basal surface of the brain and roots of the cranial nerves. The cerebellum and rostral portion of the temporal lobe are removed on the right side of the figure to better show nerves located at the cerebellopontine angle and some unrelated components of the cerebrum.

General Somatic Efferent Nerves Branchiomeric (Visceral) Nerves These are motor nerves that supply volun- The nerves in this category are mixed (both tary muscles derived from embryonic somites, afferent and efferent) in function. specifically skeletal muscles, except bran- It includes motor components that inner- chiomeric ones: vate branchiomeric muscles (i.e., striated muscles that arise from branchial arches of the Oculomotor (III) embryo). (Branchial arches are a series of ele- Trochlear (IV) vations, separated by clefts, on the walls of Abducent (VI) the primitive pharynx. The clefts are so Hypoglossal (XII) clearly homologous to those found in lower vertebrates such as fish that they are believed They innervate the voluntary somatic mus- to be phylogenetically related to gills. In cles of the eye and tongue. In addition to GSE embryonic development, muscle-forming fibers, the oculomotor nerve contains parasym- cells called myoblasts congregate in the pathetic (GVE) fibers to the involuntary mus- branchial arches, where they give rise to much cles of the eye (Chap. 19). of the head and neck musculature.) The fibers Chapter 14 Cranial Nerves and Chemical Senses 245

Table 14-1: Cranial Nerves and Their Functional Components Name Components Functions (major) I. Olfactory nerve Special visceral afferent Smell II. Optic nerve Special somatic afferent Vision III. Oculomotor nervea General somatic efferent Movement of eyes General visceral efferent Pupillary constriction and accommodation (parasympathetic) IV. Trochlear nervea General somatic efferent Movements of eyes V. Trigeminal nerve Special visceral efferent Muscles of mastication and eardrum tension General somatic afferent General sensations from anterior half of head including face, nose, mouth, and meninges VI. Abducent nervea General somatic efferent Movements of eyes VII. Facial nerveb Special visceral efferent Muscles of facial expression and tension on ear bones General visceral efferent Lacrimation and salivation (parasympathetic) Special visceral afferent Taste General visceral afferent Visceral sensory VIII. Vestibulocochlear nerve Special somatic afferent Hearing and equilibrium IX. Glossopharyngeal Special viscera] efferent Swallowing movements nerveb General visceral efferent Salivation (parasympathetic) Special visceral afferent Taste General visceral afferent Visceral sensory Special visceral efferent Swallowing movements and laryngeal control X. Vagus nerveb and General visceral efferent Parasympathetics to thoracic and abdominal cranial root of XI (parasympathetic) viscera Special visceral afferent Taste General visceral afferent Visceral sensory XI. Spinal accessory nerve Special visceral efferent Movements of shoulder and head (spinal root) XII. Hypoglossal nervea General somatic efferent Movements of tongue a In addition, there are GSA fibers for proprioception from the muscles of the eye (III, IV, VI) and tongue (XII). b In addition, there are GSA fibers for cutaneous sense from just behind the external ear (VII, IX, and X).

innervating branchiomeric muscles are classi- Vagus (X) fied as visceral because of their association Spinal accessory (XI) with the visceral functions of eating and breathing, not because they are part of the The SVE components of these nerves are autonomic nervous system. The lower distributed amongst the branchial arches as fol- motoneurons are morphologically and func- lows: the first arch (jaw) by n.V, the second tionally identical to motoneurons that supply (hyoid) arch by n.VII, the third arch by n.IX, the somatic musculature. The nerves with spe- and the remaining arches by nerves X and XI. cial visceral efferent fibers are as follows: Three of the nerves (facial, glossopharyngeal, and vagus) also contain parasympathetic fibers Trigeminal (V) (GVE), SVA fibers subserving taste, and gen- Facial (VII) eral visceral afferent fibers (GVA) (see Table Glossopharyngeal (IX) 14.1). Although the accessory nerve contains 246 The Human Nervous System only lower motoneurons categorized as SVE, (n.VIII), which are located in the posterolateral and thus technically is not a mixed nerve, it is tegmentum of the upper medulla and lower regarded as part of the vagus system. pons. The general somatic afferent column includes the mesencephalic nucleus of n.V (proprioception), consisting of scattered clus- GANGLIA IN THE HEAD ters of first order neurons in the posteromedial midbrain tegmentum, the principal (chief or The named ganglia in the head are of two main) sensory nucleus of n.V (touch), located types: (1) sensory ganglia containing the cell in the lateral midpontine tegmentum, and the bodies of neurons of the first order (equivalent spinal trigeminal nucleus (pain and tempera- to dorsal root ganglia of the spinal cord), and ture), located in the lateral tegmentum of the (2) parasympathetic ganglia. The sensory gan- lower pons, medulla, and the upper two cervi- glia, including their associated cranial nerves cal spinal cord segments (fibers from nerves V, and functional components, are the trigeminal VII, IX, and X terminate in these nuclei). The (Gasserian, semilunar) ganglion and mesen- visceral afferent column consists of the nucleus cephalic nucleus of n.V (GSA), geniculate gan- solitarius located in the midposterior tegmen- glion of n.VII (GVA, SVA, and GSA), tum of the medulla; its components include vestibular and spiral ganglia of n.VIII (SSA), taste (SVA) and other visceral fibers (GVA) superior (GSA), and inferior (SVA) ganglia of that enter the brainstem via cranial nerves VII, n.IX; and superior (GSA) and inferior (SVA) IX and X. ganglia of n.X (see Fig. 14.2). The mesencephalic nucleus of n.V is unique in that it con- Motor Nuclei of Origin (see Fig. 14.3) sists of cell bodies of the trigeminal ganglion The general somatic efferent column that are displaced to the brainstem. includes nuclei of the oculomotor nerve (mid- The parasympathetic ganglia (GVE), where brain), trochlear nerve (lower midbrain), abdu- preganglionic fibers synapse with postgan- cent nerve (lower pons), and hypoglossal nerve glionic neurons, include the ciliary ganglion of (medulla). These nuclei, located in the postero- n.III, pterygopalatine (sphenopalatine) and medial tegmentum, are composed of lower submandibular ganglia of n.VII, and the otic motoneurons innervating the voluntary muscles ganglion of n.IX (see Fig. 14.3). The numerous of the eye and tongue. ganglia of the vagus nerve (n.X) are located in The special visceral (branchial) efferent col- or near organs of the body (e.g., heart and gas- umn includes the motor nucleus (masticator trointestinal tract; see Fig. 20.3). nucleus) of the fifth nerve (midpons, n.V), motor nucleus of the seventh nerve, usually CRANIAL NERVE NUCLEI referred to as the facial nucleus (lower pons, WITHIN THE BRAINSTEM n.VII), and nucleus ambiguus (medulla, nerves IX, X, and XI). The nuclei of lower motoneu- Sensory nuclei where afferent fibers terminate rons to branchiomeric muscles are located in (called terminal nuclei) and the nuclei of origin the middle of the tegmentum. The fact that of motor fibers of the cranial nerves are organ- these alpha motoneurons are morphologically ized in discontinuous nuclear “columns” within identical to those of the general somatic effer- the brainstem. The olfactory nerve (n.I, SVA) and ent nerves cannot be overemphasized the optic nerve (n.II, SSA) are telencephalic The general visceral efferent column derivatives, not brainstem cranial nerves. includes the accessory oculomotor nucleus of Edinger–Westphal (midbrain, n.III), the supe- Sensory Nuclei of Termination (see Fig. 14.2) rior salivatory nucleus (posterior tegmentum The special somatic afferent column of lower pons, n.VII), the inferior salivatory includes the vestibular and cochlear nuclei nucleus (posterior tegmentum of upper Chapter 14 Cranial Nerves and Chemical Senses 247 medulla, n.IX), and the dorsal motor nucleus of the vagus nerve (posterior tegmentum of SOME FUNCTIONAL AND medulla, n.X). These nuclei are composed of CLINICAL CONSIDERATIONS cell bodies of preganglionic parasympathetic neurons of the autonomic nervous system. The Olfactory Nerve (n.I) salivatory nuclei are intermixed with other neu- The olfactory nerve (SVA) is composed of rons in the tegmentum and identifiable only by unmyelinated axons that extend from the nasal physiologic techniques. mucosa to the olfactory bulb. Villi, with recep-

Figure 14.2: Location of the afferent (sensory) cranial nerve nuclei within the brainstem, which form three columns. The superior and inferior ganglia of the ninth and tenth cranial nerves are unlabeled. 248 The Human Nervous System

Figure 14.3: Scheme of the efferent (motor) cranial nerve nuclei within the brainstem, which form three columns. Arabic numerals indicate parasympathetic ganglia: (1) ciliary ganglion, (2) pterygopalatine and submandibular ganglia, (3) otic ganglion and (4) terminal ganglia. tors, protrude from the dendrites of the olfac- of axons of retinal ganglion cells, and as a tory receptor neurons (ORNs) into the olfactory tract it does not regenerate when interrupted portion of the nasal mucosa. The axons of the (Chap. 19). olfactory nerve are grouped into bundles wrapped by a single neurolemma cell (see Fig. Oculomotor (n.III), Trochlear (n.IV) and 2.8B). The ORNs are unique in that each serves Abducent (n.VI), Nerves (see Fig. 14.4) as a chemoreceptor, transducer, and as a first- These cranial nerves have lower motoneu- order neuron. As a receptor, it responds directly rons (GSE) that innervate the extraocular vol- to environmental chemicals that are sensed as untary muscles and the levator palpebrae odors; as a transducer, it evokes graded poten- muscle (eyelid). The integrated actions of these tials; as a first-order neuron, it conducts nerve nerves are responsible for conjugate move- impulses to neuronal complexes within the ments of the eye (called gaze; simultaneous olfactory bulb (see Figs. 1.9 and 22.2). movement of the two eyes in the same direction). Each nerve contains proprioceptive Optic Nerve (n.II) (GSA) fibers, which can have cell bodies along Bipolar cells of the retina are the SSA first- the nerve, in the trigeminal ganglion or in the order neurons of the visual pathway. The optic mesencephalic nucleus of n.V. The third nerve nerve is actually a tract of the brain composed contains preganglionic parasympathetic (GVE) Chapter 14 Cranial Nerves and Chemical Senses 249 fibers that synapse with postganglionic neurons lowing account is schematic. Nerve III inner- in the ciliary ganglion. They are part of the vates the levator palpebrae, superior rectus, pathway for accommodation and pupillary con- inferior rectus, medial rectus, and inferior striction (Chap. 19). oblique muscles. Nerve IV innervates the superior oblique muscle, and nerve VI innervates Functional Role of the Extraocular Muscles. the lateral rectus muscle. The integrated activ- Control of eye movements is complex, the ity of these muscles results in horizontal, verti- action of an individual muscle varying with the cal, oblique, and convergence movements position of the eyeball within the orbit. The fol- (Chap. 19). The levator palpebrae elevates the

Figure 14.4: Scheme of the nuclei (nu) and distribution of the general somatic efferent cranial nerves: oculomotor, III; trochlear, IV; abducent, VI; and hypoglossal, XII. The extraocular muscles innervated by the oculomotor nerve are the inferior oblique (IO), inferior rectus (IR), medial rectus (MR), and superior rectus (SR). In addition, the oculomotor nerve supplies the levator palpebrae superioris (LP), which elevates the upper eyelid. Parasympathetic preganglionic fibers from the Edinger–Westphal subdivision of the oculomotor nucleus go to the ciliary ganglion; postganglionics innervate the sphincter of the iris (constriction of pupil) and the ciliary muscles (accommodation). The trochlear nerve innervates the superior oblique (SO) and the abducent nerve innervates the lateral rectus (LR). The hypoglossal nerve innervates the intrinsic muscles (longitudinal, vertical and transverse) of the tongue, and the styloglossus innervates hypoglossus and genioglossus muscles. 250 The Human Nervous System eyelid. The medial rectus is an adductor of the (3) pupils of unequal size (anisocoria); (4) eye (pupil directed to nose), and the lateral rec- external strabismus, with the eye abducted and tus is an abductor (pupil directed to temple); unable to move inward, upward, and down- these muscles move the eyeball in the horizon- ward. This horizontal diplopia is the result of tal plane. In lateral gaze, the medial rectus of the unopposed action of the lateral rectus and one eye and the lateral rectus of the other eye the superior oblique muscle. The eye cannot be contract synergistically. During convergence, adducted or elevated. both medial recti contract simultaneously (Chap. 19). In contrast, the action of the mus- Lesion of the Trochlear Nerve. A complete cles responsible for vertical eye movements— lesion of the trochlear nerve results in a verti- superior and inferior recti and superior and cal diplopia, head tilt, and limitation of ocular inferior oblique muscles—are influenced by movement on looking down and in. Diplopia the position of the eyeball in the orbit. The is maximal when the eyes are directed down- superior rectus elevates the eye (pupil up); the ward; this makes it difficult for the subject to elevation increases with abduction. The inferior descend stairs. To align the eyes in order to rectus depresses (pupil down); the depression minimize or eliminate the diplopia, the patient increases with abduction. tilts his head to the shoulder of the side oppo- The superior oblique intorts (rotation of site the paralyzed muscle. Because the upper portion of eye medially toward the mid- trochlear nerve decussates within the brain- line) the abducted eye and depresses (moves stem, the trochlear nucleus is located on the pupil down) the adducted eye. Intorsion side opposite to that of its nerve; hence, a increases with greater abduction, and depres- lesion of a nucleus of the trochlear nerve is sion increases with greater adduction. The infe- expressed in the contralateral eye. rior oblique extorts (lateral rotation of the upper portion of the eye away from the mid- Lesion of the Abducent Nerve. A complete line) the abducted eye and elevates the lesion of the abducent nerve results in a hori- adducted eye. zontal diplopia, with the ipsilateral eye adducted, because of the unopposed action of Lesion of the Oculomotor Nerve. Ocular the normal medial rectus muscle. The diplopia convergence occurs when viewing a close is maximal when the subject attempts to gaze to object; it keeps the image precisely aligned on the side of the lesion (because the eye with the the fovea of both eyes (Chap. 19). Except for paralyzed lateral rectus muscle cannot be ade- convergence, all normal eye movements are quately abducted). It is minimal with gaze to conjugate, i.e., the two eyes turn so that their the normal side because the visual axis of the visual axes remain parallel. The paralysis of normal eye can be aligned with that of the one or more extraocular muscles results in affected eye. diplopia (double vision) as a result of faulty conjugate movements. A complete lesion of an Trigeminal Nerve (n.V) (see Fig. 14.5) oculomotor nerve produces the following: (1) The trigeminal nerve branches into three drooping of the eyelid (ptosis) and inability to divisions: ophthalmic, maxillary, and mandibu- elevate it because of unopposed action of the lar (see Fig. 14.5). Each division supplies a dis- orbicularis muscle, which closes the eyelid tinct region; there is no overlap in contrast with (innervated by n.VII); (2) dilated pupil (mydri- the dermatomal overlap of spinal roots (see asis) and unresponsiveness of eye reflexes to Figs. 9.5 and 10.6). light (pupillary constrictor and ciliary muscle The sensory fibers enter at the midpons level paralysis from third nerve injury and the unop- as the sensory root (portio major), whereas the posed action of pupillary dilator muscle, which motor fibers emerge through the adjacent is innervated by the intact sympathetic fibers); motor root (portio minor). Chapter 14 Cranial Nerves and Chemical Senses 251

Figure 14.5: The cranial nerve nuclei and distribution of the trigeminal nerve (n.V). The nerve has three divisions: ophthalmic (I), maxillary (II), and mandibular (III). The three sensory nuclei (mesencephalic, principal, and spinal) of the nerve form a continuous column from the level of the superior colliculus to spinal cord level C2. The sensory nuclei are somatotopically organized. Because of rotation of the nerve root, mandibular fibers are most dorsal and ophthalmic fibers most ventral. The spinal trigeminal nucleus, divided into pars, oralis, interpolaris, and caudalis, also receives input from primary fibers that innervate the region of the external ear via the seventh nerve (geniculate ganglion) and nerves IX and X (superior ganglia).

Sensory Root. The sensory input (GSA) is mandibular nerve from the muscles of mastica- conveyed via first-order fibers (with cell bodies tion and from pressure receptors in the peri- in the trigeminal ganglion) from the skin of the odontal ligaments of the teeth. There is a scalp anterior to the coronal plane through the monosynaptic relay to the lower motoneurons ears. The innervated region comprises the face, of the motor nucleus of n.V to complete a two- orbit, mucous membranes of the nasal cavity, neuron arc that mediates the jaw reflex (similar nasal sinuses and oral cavities, teeth, and most to the knee jerk reflex). The mesencephalic of the dura mater. These first-order neurons ter- nucleus also receives proprioceptive input from minate in the principal sensory nucleus and the the extraocular muscles. spinal trigeminal nucleus of n.V (see Figs. 9.5, 10.6, and 14.5). Motor Root. The lower motoneuron fibers Cell bodies of first-order neurons mediating from the motor nucleus of n.V (SVE) pass proprioception form the mesencephalic nucleus through the motor root and the mandibular of n.V. This nucleus receives input via the division before innervating the jaw muscles of 252 The Human Nervous System mastication (masseter, pterygoids, and tempo- nuclear (upper motoneuron) lesions usually do ralis muscles), tensor tympani and some other not impair trigeminal motor activity. muscles. The jaw jerk reflex is evoked by tapping the chin of the slightly opened mouth with Facial Nerve (n.VII) (see Fig. 14.6) a reflex hammer (see Fig. 10.6). The facial nerve consists of (1) the facial nerve proper or motor division comprised of Lesion of the Trigeminal Nerve. Interrup- lower motoneurons (SVE) and (2) the nervus tion of all trigeminal nerve fibers unilaterally intermedius with sensory (GSA and SVA) and results in (1) anesthesia and loss of general parasympathetic components (GVE). All cell senses in the regions innervated by n.V and (2) bodies of first-order sensory neurons are in a lower motoneuron paralysis (loss of jaw the geniculate ganglion. The GVA input from reflex and fibrillations, weakness and atrophy the viscera in the soft palate and tonsillar of jaw muscles). The sensory changes include region and the SVA (taste) input from the loss in the ipsilateral nostril of the sensitivity of anterior two-thirds of the tongue terminate in the nasal mucosa to ammonia and other volatile the nucleus solitarius (see “Gustatory chemicals (smarting effect) and a loss of Nucleus”). Fibers from the motor nucleus of corneal sensation on the same side. The inter- n.VII (SVE) take a hairpin course through the ruption of sensory fibers from the cornea (oph- lower pons (they recurve as the internal genu thalmic division) produces a loss of the around the nucleus of n.VI) before emerging ipsilateral and contralateral (consensual) into and passing through the cerebellopontine corneal reflex (Chap. 19). Fibers forming the angle. These fibers innervate the muscles of afferent limb of the corneal reflex terminate in facial expression, including the orbicularis the spinal trigeminal nucleus, pars oralis (see oculi (closes eyelid and protects eye), bucci- Fig. 9.5), which projects bilaterally to the facial nator (moves cheek), and stapedius (moves nucleus (n.VII). The latter innervate the orbic- stapes bone) muscles. Parasympathetic pre- ularis oculi muscles that close the eyes (both ganglionic fibers from the superior salivatory eyes blink). The loss of proprioceptive input nucleus make synaptic connections with post- can result in the relaxation of the ipsilateral ganglionic neurons in the pterygopalatine and muscles of facial expression (innervated by submandibular ganglia; these fibers stimulate n.VII). The loss of the jaw jerk results from the the lacrimal, nasal, oral, submaxillary and interruption of both the afferent and efferent sublingual glands, and blood vessels. limbs of the arc. Because of the action of the contracting pterygoid muscles on the normal Lesion of the Facial Nerve. A lesion inter- side, the jaw, when protruded, will deviate and rupting the facial nerve (e.g., Bell’s palsy) is point to the paralyzed side. primarily expressed as a lower motoneuron Sharp, agonizing pain localized over the dis- paralysis of the muscles of facial expression. tribution of one or more branches of the trigem- The paralysis of Bell’s palsy can occur sud- inal nerve is known as trigeminal neuralgia or denly, followed within a few months by a spon- tic douloureux. This condition (of unknown taneous recovery. On the ipsilateral side, the cause) can be accompanied by muscle twitch- forehead is immobile, the corner of the mouth ing (tic) and disturbances in salivary secretion. sags, the nasolabial folds of the face are flat- The stimulation of a region, called a trigger tened, facial lines are lost, and saliva can drip zone, can initiate an attack. from the corner of the mouth. The patient is The supranuclear influences upon the motor unable to whistle or puff the cheek because the nucleus of n.V are outlined in Chapter 11. buccinator muscle is paralyzed. When smiling, Because the motor nucleus of n.V is influenced the normal muscles draw the contralateral cor- by both crossed and uncrossed corticobulbar ner of the mouth up while the paralyzed corner and corticoreticular pathways, unilateral supra- continues to sag. Corneal sensitivity remains Chapter 14 Cranial Nerves and Chemical Senses 253

Figure 14.6: The cranial nerve nuclei and distribution of the facial nerve (n. VII).The superior salivatory nucleus is embedded within the reticular formation and cannot be identified in normal brainstem sections.

(n.V), but the patient is unable to blink or close lid on the same side as that stimulated is known the eyelid (n.VII). To protect the cornea from as the direct corneal reflex, whereas the closure damage (e.g., drying), therapeutic closure of of the contralateral eyelid is known as the eyelids or other measures are taken (e.g., consensual corneal reflex. Stated otherwise, if patient wears an eye mask or lids are closed by the facial nerve on one side is completely sutures). Lacrimation and salivation on the destroyed, the sensitive cornea cannot evoke a lesion side can be impaired. Taste will be lost direct corneal reflex but can evoke a consensual on the ipsilateral anterior two-thirds of the corneal reflex. If the fibers of the nervus inter- tongue. An increased acuity to sounds (hypera- medius on both sides are intact and motor cusis) results from paralysis of the stapedius fibers of the facial nerve destroyed on one side, muscle, which normally dampens the ampli- then the direct corneal reflex is absent on that tude of the vibrations of the ear ossicles. side; however, lacrimal secretion can increase Hyperacusis occurs only to loud sounds, which on both sides because of parasympathetic activate the acoustic reflex (Chap. 16). activity. When the cornea is touched, the eyelid immediately closes (the corneal reflex). The Supranuclear Facial Palsy. A unilateral trigeminal nerve forms the sensory limb from supranuclear lesion of the upper motoneurons the cornea of the eye, and the facial nerve is the (corticobulbar and corticoreticular fibers) to the motor limb causing the orbicularis oculi mus- facial nucleus results in a marked weakness of cle to close the eyelid. The closure of the eye- the muscles of expression of the face below the 254 The Human Nervous System eye on the side contralateral to the lesion. The lar nuclei in the brainstem, and uniquely in the frontalis muscle (wrinkles forehead) and the cerebellum (Chap. 18). orbicularis oculi muscle (closes eyelid) are unaffected. The accepted explanation states Glossopharyngeal Nerve (n.IX) (see Fig. 14.7) that (1) bilateral upper motoneuron projections The GVA input of n.IX from the palatine, from the cerebral cortex terminate on the lower tonsillar, and pharyngeal regions and from the motoneurons, innervating the frontalis muscle carotid sinus (pressoreceptor, arterial pressure) and orbicularis oculi, and (2) only unilateral, and carotid body (chemoreceptor, CO2 and O2 crossed upper motoneuron projections go to the concentration in blood) is conveyed via first- lower motoneurons, innervating the muscles of order fibers (cell bodies in inferior ganglion) to facial expression of the lower face. Hence, after the nucleus solitarius. The SVA input (taste) unilateral supranuclear lesions, the contralat- from the posterior third of the tongue is relayed eral muscles are deprived of upper motoneuron via first-order neurons (cell bodies in inferior influences. In some patients with supranuclear ganglion) to the gustatory portion of the lesions, the weak, lower facial muscles will nucleus solitarius, which is located at its rostral remain paralyzed to volitional control, but will end. Some GSA afferents from the tympanic respond to emotional or mimetic stimuli (joke, cavity and external auditory meatus with cell distress). The influences that evoke this invol- bodies in the superior ganglion terminate in the untary response are not known. For more spinal trigeminal nucleus. The SVE lower details, refer to Chapters 11 and 17. motoneurons from the nucleus ambiguus inner- Note the distinction between a lower vate pharyngeal and palatine muscles (effect motoneuron lesion and an upper motoneuron swallowing) and the stylopharyngeal muscle lesion involving the muscles of facial expres- (elevates upper pharynx). The preganglionic sion. In a lower motoneuron paralysis, all of the parasympathetic (GVE) component from the muscles of facial expression on the same side inferior salivatory nucleus is relayed via the as the lesion are paralyzed. In an upper otic ganglion to the parotid gland. motoneuron paralysis following a lesion of the Disturbances associated with lesions of corticobulbar fibers, for example, in the inter- n.IX, include (1) unilateral loss of taste in the nal capsule, the muscles of facial expression in posterior third of the tongue, (2) unilateral loss the lower face below the angle of the eye on the of the gag (pharyngeal) reflex, and (3) unilat- side opposite the lesion are paralyzed. eral loss of the carotid sinus reflex. Glosso- pharyngeal neuralgia (similar to trigeminal Vestibulocochlear Nerve (n.VIII) neuralgia) can be triggered by chewing or swal- The cochlear nerve, an exteroceptive nerve lowing. concerned with hearing, consists of fibers of bipolar neurons with cell bodies in the spiral Vagus Nerve (n.X) (see Fig. 14.8) ganglion (Chap. 16). Its peripheral fibers inner- The vagus nerve has not only general and vate the hair cells in the spiral organ of Corti special visceral afferent components, but gen- and the central fibers terminate in the dorsal eral and special visceral efferent components as and ventral cochlear nuclei. The vestibular well (see Table 14.1). In addition, there is a nerve, a proprioceptive nerve concerned with general somatic afferent component. The GVA equilibrium and orientation of the head in input is from the respiratory system (larynx, space, consists of fibers of bipolar neurons with trachea, and lungs), cardiovascular system cell bodies in the vestibular ganglion (Chap. (carotid sinus and body, heart, and various 16). Its peripheral processes innervate the blood vessels), gastrointestinal tract, and dura cristae (in ampullae of the semicircular ducts) mater in the posterior fossa. The peripheral and in the maculae (of utricle and saccule); the processes extend from the organs to the cell central processes terminate in the four vestibu- bodies located in the inferior ganglion located Chapter 14 Cranial Nerves and Chemical Senses 255

Figure 14.7: The cranial nerve nuclei and distribution of the glossopharyngeal nerve (n. IX). This nerve supplies motor innervation to the stylopharyngeus muscle, the muscles (*) of the anterior and posterior pillars of the fauces, and, possibly, some superior pharyngeal muscle fibers involved in deglutition. The inferior salivatory nucleus is embedded within the reticular formation. ‡, auditory tube.

adjacent to the medulla; the central processes SVE output takes origin from lower motoneu- terminate in the nucleus solitarius. The SVA rons in the nucleus ambiguus that innervate the fibers mediate taste. Their peripheral processes voluntary muscles of the soft palate, pharynx, originate in the epiglottis and extend to cell and intrinsic laryngeal muscles (some of the bodies in the inferior ganglion adjacent to the fibers from the nucleus ambiguus course via medulla; central processes terminate in the gus- n.XI before joining the vagus nerve). tatory portion of the nucleus solitarius. The GSA component consists of fibers from The GVE component consists of pregan- the tympanic cavity (middle ear) and the exter- glionic parasympathetic fibers from the dorsal nal auditory meatus (with cell bodies in the vagal nucleus that project to terminal ganglia superior ganglion) that terminate in the spinal close to their target structures. From there, trigeminal nucleus. postganglionic neurons go to the cardiovascular, respiratory, and gastrointestinal systems of Lesion of the Vagus Nerve. A complete uni- the thorax and abdomen. A GVE influence to lateral lesion of the vagus nerve results in the the heart itself is conveyed over preganglionic following symptoms: (1) the soft palate is flac- parasympathetic neurons from cells that might cid, producing a voice with a twang (dyspho- be located close to the nucleus ambiguus. The nia); (2) swallowing is difficult (dysphagia) 256 The Human Nervous System

Figure 14.8: The cranial nerve nuclei and distribution of the vagus (n.X) and accessory (n.XI) nerves.

because of a unilateral paralysis of pharyngeal Accessory (Spinal Accessory Nerve (n.XI) constrictors (the pharynx is shifted slightly to (see Fig. 14.8) the normal side); (3) difficult or labored The accessory nerve consists of two roots, breathing (dyspnea). A transient tachycardia spinal and bulbar (cranial). The fibers of the (increased heartbeat) occurs because of the spinal root originate from anterior horn cells in interruption of some parasympathetic stimula- cervical levels 1 through 5, emerge and ascend tion (see subsection Lesion of the Accessory alongside the spinal cord (dorsal to the dentic- Nerve). Bilateral lesions of the vagus nerve are ulate ligament) and medulla, and join the cra- fatal unless a tracheotomy is done immediately; nial root in the jugular foramen; the spinal root the larynx is paralyzed and the vocal cords innervates the ipsilateral sternomastoid and the become adducted. upper half of the trapezius muscles. The fibers Chapter 14 Cranial Nerves and Chemical Senses 257 of the cranial root originate from the nucleus the glossopharyngeal nerve to the nucleus soli- ambiguous course, with n.XI a short distance tarius. This nucleus sends fibers to (1) the dor- before branching and joining n.X, and, eventu- sal vagal (parasympathetic) nucleus and (2) the ally, form the recurrent laryngeal nerve, which “vasomotor center” in the rostral ventrolateral innervates the intrinsic laryngeal muscles. reticular formation of the medulla. The motor limb of the reflex arc, acting Lesion of the Accessory Nerve. A lower through inhibitory efferent fibers of the vagus motoneuron paralysis of the spinal root fibers is nerve, decreases the heart rate and the cardiac revealed by a weakness in the ability to rotate output. In contrast, the “vasomotor center” the head so that the chin points to the side oppo- sends inhibitory signals via the reticulospinal site the lesion (paralyzed sternomastoid mus- tract to sympathetic preganglionic neurons cle). There is a downward and outward rotation (levels T1–T5) of the intermediolateral cell of the upper scapula together with impaired columns of the spinal cord (Chap. 20). This ability to shrug the shoulder and elevate the arm diminishes sympathetic tone, also resulting in a over the head (paralyzed upper trapezius mus- decreased heart rate and cardiac output and, in cle). After a unilateral lesion of the cranial root, addition, decreases blood pressure by lowering the ipsilateral vocal cord becomes fixed and peripheral resistance through vasodilation of partially adducted; the voice is hoarse (dyspho- the peripheral blood vessels. nia) and reduced to a whisper. Unilateral injury Attacks of syncope (fainting) occur in indi- to the recurrent laryngeal nerve causes partial viduals with hypersensitive carotid sinus abduction because of sparing of the motor fibers reflexes when light external pressure (tight col- to the cricothyroid muscle, which travel in the lar) is applied to the sinus. superior laryngeal nerve. Carotid Body Reflex. The carotid body Reflexes Involving Nerves VII, IX, X, and XI (located near the carotid sinus) can initiate a Taste–Salivary Gland Reflex. Following sequence of neural events affecting the respira- stimulation of the taste receptors, gustatory tory cycle. The activation of the chemoreceptors impulses are conveyed to the rostral end of the of the carotid body (responding to CO2,O2, and nucleus solitarius (gustatory nucleus) from the pH levels in the blood) increases the frequency anterior two-thirds of the tongue, via the facial of action potentials conveyed via the glossopha- nerve, and from the posterior third of the ryngeal nerve to the nucleus solitarius. From tongue, via the glossopharyngeal nerve. Projec- this nucleus, interneurons project to the “respi- tions from the gustatory nucleus terminate in ratory center complex” within the brainstem the parasympathetic neurons of the superior reticular formation. This center, transmits sig- and inferior salivatory nuclei. From these nals via reticulospinal fibers to the lower nuclei, preganglionic fibers course through the motoneuron of the phrenic and intercostal facial and glossopharyngeal nerves to the nerves, resulting in inspiratory movements. The sphenopalatine, submandibular, and otic gan- accompanying inflation of the lungs stimulates glia. Postganglionic fibers innervate the sali- the stretch receptors in the bronchiolar walls to vary glands and stimulate secretion (Chap. 20). increase the frequency of impulses conveyed via the vagus nerve to the nucleus solitarius. Carotid Sinus Reflex. Baroreceptors, which Inhibitory influences from this nucleus to the are mechanorecptors in the wall of the carotid “respiratory center complex” finally end the sinus (located at the bifurcation of the common inspiratory phase of respiration. carotid artery into the external and internal carotid arteries), respond to an increase in Gag (Pharyngeal) Reflex. Stimulation of the blood pressure by increasing the firing rate of pharyngeal region activates the contraction and nerve impulses in the visceral afferent fibers of elevation of the pharynx. The afferent limb of 258 The Human Nervous System this reflex is in the glossopharyngeal nerve to sites have evolved to detect the diversity of the nucleus solitarius. Interneuronal connec- chemical stimuli in the environment. Chemical tions to the nucleus ambiguus stimulate the sensitivity and chemical senses are universal efferent limb of lower motoneurons, traveling expressions of living organisms. The most con- over fibers of the glossopharyngeal and vagus spicuous sensory response of bacteria and nerves to the voluntary muscles of the palate primitive protozoans, called chemotaxis, is the and pharynx. use of chemical receptors to locate food and adequately oxygenated water and to avoid nox- Cough Reflex. Generally, coughing occurs ious substances. Vertebrates have chemorecep- following the irritation of the larynx, trachea, tors for monitoring chemical conditions of both and/or bronchial tree. The afferent limb con- the internal and external environments. Intero- veys impulses via the vagus nerve to the ceptive sensors monitor such physiologically nucleus solitarius. Interneuronal connections significant molecular variables in the blood as are made with the “respiratory center complex” carbon dioxide, oxygen, and pH, as well as and with the nucleus ambiguus. The “center” nutrients (e.g., glucose). The activated recep- activates the rest of the arc, resulting in forced tors initiate the processing of neural signals, expiration. The nucleus ambiguus and its lower resulting in release of neurotransmitters at motoneuron axons stimulate the pharyngeal nerve terminals that control the appropriate and laryngeal musculature to participate in the responses. The original chemical communica- act of coughing. tion of bacteria and primitive protozoa has not been replaced, but, rather, augmented, acceler- Hypoglossal Nerve (n.XII) (see Fig. 14.4) ated, and localized. The external environment Lower motoneurons originating in the in vertebrates is sensed by exteroceptive sen- hypoglossal nucleus innervate the ipsilateral sors and expressed as olfaction (smell), gusta- tongue musculature, including the intrinsic tion (taste), and chemesthesis (common muscles and the genioglossus, styloglossus, and chemical senses, Chap. 9). hyoglossus muscles. Interruption of the fibers Olfaction is of great adaptive importance, of n.XII produces an ipsilateral lower motoneu- sampling odorant information coming from ron paralysis of the tongue. The fibrillations that great distances via air currents. Olfactory occur during early stages are followed by atro- receptors, located within respiratory structures, phy of the muscles, which results in a wrinkled are associated with the olfactory nerve and tongue surface on the side of the lesion. When vomeronasal nerve. Gustation is less sensitive protruded, the tongue deviates to the paralyzed and more restrictive in responses. Taste recep- side. The deviation is the result of the unop- tors, located with feeding structures, are asso- posed contraction of the contralateral ciated with oral and pharyngeal regions genioglossus, which pulls the root of the tongue innervated by the facial, glossopharyngeal, and forward while the paralyzed ipsilateral muscle vagus nerves. acts as a pivot. The proprioceptive fibers (GSA) In light of the significant responses to, and from the tongue muscles are presumed to have roles of, odorants and tastants, substances stim- cell bodies scattered along the nerve. ulating respectively the senses of smell and taste, it is somewhat puzzling that there are no vernaculars for anosmia, the clinical absence of CHEMICAL SENSES (OLFACTION smell, or for ageusia, the clinical lack of, or AND GUSTATION) impairment of, taste.

Frankinsense and myrrh, as the scent of Olfaction God, is a testament to the biblical significance The olfactory system includes the olfactory of our chemical senses. A plethora of receptive nerves, olfactory pathways, and a complex of Chapter 14 Cranial Nerves and Chemical Senses 259 processing centers within the brain. The olfac- unmyelinated axon synapses in the olfactory tory receptor neurons (ORNs) are embedded in bulb within a single glomerulus (see Fig. 14.9). the olfactory neuroepithelium, roughly 5 cm2, There is assumed to be a gene for every recep- in the roof of each nasal cavity. tor type. Olfactory receptor neurons with the An olfactory receptor neuron is bipolar. A same odorant receptor occupy small zones of single dendrite is directed toward the mucosal the olfactory mucosa scattered among other surface, where it forms a knoblike expansion ORNs expressing different receptor types. All from which several mobile cilia extend into the ORNs of the same receptor type in a zone proj- olfactory epithelium coated with serous fluid ect to the same glomerulus, where they synapse that serves as a solvent for the odoriferous on dendrites of mitral and tufted cells. This stimuli (see Fig. 14.9). The nonolfactory part of maximizes the functional–collecting role of the the nasal mucosa is coated with mucus. The olfactory epithelium unmyelinated axon of the ORN terminates in a Sensory information is extensively processed spherical synaptic unit called a glomerulus and refined in the olfactory bulb before it is within the olfactory bulb (see Fig. 2.2). Every sent to the olfactory cortex. Glomeruli are the ORN functions as a chemoreceptor, transducer, receptive sites for the first stage in the analysis and a transmitter of impulses to a glomerulus and modulation of olfactory information (see (see Fig. 14.9). Olfactory receptor neurons Fig. 14.9). The axons of the approximately 2 have a life-span of only 4–8 weeks. The million ORNs converge within 2000 glomeruli; unmyelinated axons are grouped into discrete it is estimated that the axons of 25,000 ORNs bundles, wrapped by a single neurolemma terminate on individual glomeruli. Following cell, that collectively constitute the olfactory neural processing within the olfactory bulb, an nerve. These neurons are continuously replaced estimated 20–50 relay neurons (mitral and throughout life by basal cells, which, like those tufted cells) project to higher centers, including of the taste buds, are stem cells that differenti- the olfactory cortex, reflecting an approximately ate into new functional neurons. The receptor 100–fold convergence. The primary dendrites gene family acts (1) to either upregulate or of each mitral neuron are also confined to a sin- downregulate the rate of replacement of ORNs gle glomerulus. Each mitral neuron responds to in response to functional needs and (2) to guide multiple sets of odorants; mitral neurons of newly generated ORN axons to a designated other glomeruli respond to different sets of site in the same glomerulus as its predecessor. odorants. The thousands of different volatile odorants The first of three levels of neural processing (odorous molecules) in the air are dissolved in referred to as refinement sites occur within the the compatible organic molecular and ionic olfactory bulb. Each spherical glomerulus con- environment of the serous secretion of Bow- tains synaptic triads comprised of synapses man’s glands that bathe the cilia of the ORNs. among ORNs, periglomerular interneurons, The interactions between the odorant mole- and mitral neurons interacting as signal refine- cules and the receptor sites of the ORN cilia ment sites: (1) The axons of the ORNs branch activate G-protein-coupled second-messenger profusely and have axodendritic synapses with systems that lead to graded potentials and dendrites of the periglobular interneurons and action potentials in the axons. Odorant receptor with the primary dendrites of the mitral cells genes of the olfactory receptor neurons form within the glomeruli and (2) the dendrites of the largest gene family of the vertebrate the periglomerular interneurons have inhibitory genome (Buck and Axel, 1991). This large dendrodendritic synapses with the dendrites of multigene family (1000 or so different odorant the mitral neurons. These synaptic activities receptor types) permits discrimination of a play a role in sharpening and refining sensory wide variety of odorants. Each ORN expresses information. (3) The periglomerular interneu- only one unique type of odorant receptor. Its rons, which encircle a glomerulus interconnect 260 The Human Nervous System

Figure 14.9: Pathways of the olfactory system. The olfactory system is organized for the perception and conscious discrimination of chemical odorants and for activating the limbic system, which is involved in acts of self-preservation and emotive aspects of behavior. (1) When stimulated, receptors of the villi of each odorant receptor neuron (ORN) of the olfactory mucosa generate neural signals that are transmitted via its axon to one glomerulus of the olfactory bulb (see Fig. 2.2A). (A) A glomerulus, the initial signal refinement site where neural processing occurs within each neuronal triad, consists of (a) axodendritic synapses of axon terminals of ORNs on the dendritic arbors of periglobular interneurons (PNs) and mitral neurons (MNs) and (b) reciprocal dendrodendritic synapses between the dendritic arbors of the PNs and MNs. This is succeeded by a second signal refinement site located outside the glomerulus that involves reciprocal dendrodendritic synapses between the dendritic arbors of MNs and granule interneurons (GNs). Input to both of these signal refinement sites within the olfactory bulb is derived from centripetal axons arising in centers of the brain and the anterior olfactory nucleus. A similar sequence of synaptic processing applies to the tufted neurons. (2) The output of the olfactory bulb is projected via the olfactory tract by the axons of MNs and their branches to five neuronal centers. These centers include the anterior olfactory nucleus that projects to the contralateral olfactory bulb, the olfactory tubercle of the anterior perforated substance, piriform cortex, entorhinal cortex, and the amygdala. (The axons of tufted neurons terminate in the anterior olfactory nucleus and the olfactory tubercle.) Each of these five higher centers projects directly to the frontal lobe and indirectly to it via a relay in the dorsomedial nucleus of the thalamus, which projects to orbitofrontal cortex. The indirect input is akin to other sensory pathways that reach the cortex via the thalamus. Both frontal cortex and orbitofrontal cortex have roles in the conscious discrimination of odors. Some physiologic, emotional and behavioral responses, expressed in the functional roles of the limbic system, are derived from odorants that activate the olfactory system’s projections from the amygdala to the hippocampus and from entorhinal cortex to the hypothalamus (Chaps. 21 and 22). (B) Numbers 1 though 10 locate structures in the brain involved with olfaction: (1) anterior olfactory nucleus, (2) olfactory tubercle (3), piriform cortex, (4) entorhinal cortex, (5) amygdala, (6) frontal cortex, (7) thalamus, (8) orbitofrontal cortex, (9) hippocampus, (10) hypothalamus. Chapter 14 Cranial Nerves and Chemical Senses 261 by axodendritic synapses and thereby form a forated space, amygdala, piriform cortex, and screen maintaining the functional integrity of entorhinal cortex. The tufted neurons project each glomerulus. However, some synaptic only to the anterior olfactory nucleus and the communication occurs through a screen to an olfactory tubercle. The anterior olfactory adjacent glomerulus. The axodendritic synapses nucleus has connections with the contralateral between the input ORN and the principal mitral olfactory bulb. The other four regions have relay cell is the essential linkage for input– connections with neural centers likely to be output transmission, whereas the inhibitory involved with either (1) perception and dis- dendro-dendritic microcircuit synapses between crimination of odors or (2) emotional and moti- the mitral and tufted relay neurons and the vational aspects of smell; they give rise to two intrinsic periglobular interneurons are involved pathways; one that bypasses the thalamus and in control and elaboration of the input–output projects directly to frontal cortex and a second transfer. that goes to the orbitofrontal cortex via a relay The second level of signal refinement occurs in the dorsomedial nucleus of the thalamus. deep in the bulb by negative feedback circuits Note that the direct projection to the cortex located outside of the glomerulus, between the reflects the olfactory system’s ancient origin granule interneurons and the secondary den- and is unique among sensory systems. The dor- drites (basal dendrites). These dendrodendritic somedial thalamic nucleus can have a compa- synapses from the mitral neuron to granule rable role in olfaction to the ventral lateral interneuron are excitatory, and those from the thalamic nucleus in somesthesis (Chaps. 10 granule interneuron to mitral neuron are inhib- and 11). itory (see Fig. 14.9). This also serves to The discrimination of odors involves neo- sharpen and refine olfactory information prior cortex (orbitofrontal and frontal cortices). to its transmission via the olfactory tract to the Human subjects with lesions of the orbito- olfactory cortex. In addition, other dendroden- frontal cortex are unable to discriminate odors dritic synapses are present between the second- (Buck, 2000). The amygdala and entorhinal ary dendrites of the mitral cells and dendrites cortex, which have connections with the hypo- of some periglobular neurons on the periphery thalamus and hippocampus, respectively, are of glomeruli, These inhibitory synapses can components of the limbic system (Chap. 22). form another curtain of inhibition encircling They are associated with emotional and moti- each glomerulus and the region of the second- vational aspects of smell and the behavioral ary dendrites of the mitral neurons. and physiological effects of odors. The third level of neural processing involves Olfactory hallucinations or seizures, referred the modulatory influences of different centrifu- to as uncinate fits, occur in association with gal fiber systems arising from the olfactory cor- other features of epilepsy such as involuntary tex (e.g., basal forebrain), locus ceruleus and movements and altered or complete loss of midbrain raphe nuclei to the activity of the consciousness. They are called uncinate fits periglobular interneurons and the granule because of abnormal electrical activity in the interneurons, These connections can modulate uncus (see Figs. 1.7 and 14.1) generally pro- bulb function, signal refinement, and behav- ducing an unpleasant olfactory reminiscence, ioral responses. For example, these influences which begins the epileptic attack. The uncus can enhance the perception of an aroma when encompasses most of primary olfactory cortex searching for food as a response to relieve including the entorhinal and piriform areas as hunger pangs. well as the amygdala. The mitral cells, regarded as the principal relay neurons, convey information to higher Accessory Olfactory System. Many mam- regions, including the anterior olfactory mals have an accessory olfactory system nucleus, olfactory tubercle of the anterior per- known as the vomeronasal system (VNS) com- 262 The Human Nervous System prising paired epithelial vomeronasal organs in Japanese), which is the flavor of MSG (VNOs) located adjacent to the nasal septum, (monosodium glutamate) used in cooking. vomeronasal nerves, accessory olfactory bulbs, However, many taste sensations cannot be and the amygdala that provide inputs to the described in terms of four or five modalities or hypothalamus and frontal cortex. Chemical combinations thereof. Among these are the communication between members of some qualities of numerous spices, fruits, and veg- species occurs via odors called pheromones, etables. In fact, a truly objective classification which exert important roles in endocrine has not been developed; probably, there are no responses associated with sexual and social primary taste modalities. All are chemically behaviors and reproductive physiology (i.e., induced sensations. In addition, a form known mating, maternal activities, and establishing as “intravascular taste” occurs when certain territorial boundaries). Relatively few phero- nutrients such as sugars are injected intra- mones have been chemically identified. The venously. The subjective sensation of taste can vomeronasal system is described as rudimen- be readily modified by many factors, including tary or absent in humans. The lack of convinc- state of health and hormone levels. The nervous ing evidence for a functional vomeronasal system has a remarkable capacity to recognize system in Old World monkeys and apes support a deficiency of certain key nutrients. For exam- the claim that the system as a separate entity ple, to correct for a NaCl deficiency, an does not exist in humans. appetite for salt is induced, resulting in a crav- ing for salty foods (e.g., animals at a saltlick). Gustation (Taste) Taste buds are microscopic sensors, similar The sense of taste acts at the gateway moni- in size to the cell body of an alpha motoneuron toring both volatile and nonvolatile compo- of the spinal cord, and are visible to the nents of food and drink. Taste combines the unaided eye. Each of the some 10,000 taste bud recognition and response to a diverse repertory consists of from 40 to 60 elongated bipolar of chemical entities comprising salts, sugars, taste (neuroepithelial) receptor cells arranged acids, and a wide array of toxic substances. like the segments of an orange and a smaller Taste and smell interact to produce chemosen- basal (stem) cell (see Fig. 14.10). Currently, sory experiences and perceptions such as fla- elongated dark cells, intermediate cells, and vor, which can be modified and enhanced by light cells are candidates as representing either trigeminal “common chemical sense” input and three different taste cell types or the develop- temperature. Gustation is initiated by the mental phases of one receptor type. Each taste response of chemoreceptors of the taste cells of cell has chemoreceptors on several apical organelles called taste buds (see Fig. 14.10) microvilli that extend through the common that are innervated by the facial, glossopharyn- taste pore at the surface of a taste bud into the geal, and vagus nerves. Ambient chemicals microenvironment of saliva-containing tastants. called tastants mediate taste perceptions. Even At the present time, it is not known whether a “water sense” is indicated; distilled water each taste cell responds to only one tastant or to applied to taste buds evokes discharges in a composite of tastants. Each taste cell is inner- “taste nerve fibers”. In humans, taste sensations vated at its base by branches of several afferent can be elicited following appropriate stimula- gustatory nerve fibers and each primary nerve tion of chemoreceptors on the taste cells of fiber has branches that innervate several cells thousands of taste buds distributed over the within a taste bud. tongue, palate, pharynx, laryngeal surface of Saliva, containing proteins, can contribute to the epiglottis, and the upper esophagus. The taste sensation by binding to a tastant and expe- four taste modalities classically recognized in diting its delivery to chemoreceptors in the humans are salty, sweet, sour, and bitter. A fifth membranes of the microvilli of the taste cells. putative modality is called umami (‘delicious’ The saliva then removes the taste stimulant. Chapter 14 Cranial Nerves and Chemical Senses 263

Figure 14.10: Pathway of the gustatory system. (A) Chemical molecules stimulate the receptors of the villi of the gustatory receptor cells of taste buds that activate first-order neurons of cranial nerves V, VII, and IX. The axons of these neurons terminate in the “gustatory nucleus,” which is within the solitary nucleus. Second-order fibers from the gustatory nucleus ascend ipsilaterally within the reticular formation in the central tegmental tract and terminate in the ventral posterior medial (VPM) nucleus of the thalamus. Third-order fibers from VPM terminate in (1) several centers in the forebrain (e.g., ventral striatum and amygdala) and (2) in primary taste cortex (frontal operculum, rostral insula, and lower postcentral gyrus. (B) The flask-shaped taste bud contains a basal cell and three types of receptor cell. Basal cells serve as stem cells that generate a replacement supply of receptor taste cells. The different shading of illustrated receptor taste cells represents either (1) different developmental stages or (2) three separate types of differentiated taste cell. 264 The Human Nervous System

The mechanisms that serve to transduce sen- with their cell bodies in the geniculate gan- sory stimulation of taste cells to salty, sour, glion (CN VII) and the inferior ganglia of CNs sweet, and bitter are of two categories: (1) IX and X. With regard to taste, CN VII inner- those involved with specific membrane recep- vates the anterior two-thirds of the tongue and tors and (2) those based on direct permeation the palate, CN IX innervates the posterior (passing through) or blockage of ion channels. third of the tongue, and CN X innervates the The detection of salty taste stimuli is medi- epiglottis, pharynx, and upper esophagus. The ated by Na+ ion influx through Na+ channels taste buds in different parts of the mouth are (direct depolarization by Na+ ions) and that of differentially sensitive to each of the taste sour taste stimuli is mediated either by (1) qualities. Sweet taste is best detected at the direct depolarization by H+, (2) direct perme- anterior tip of the tongue, salt in the anterior ation of Na+ channels by protons, or (3) proton half of the tongue, sour along the lateral part blockage of K+ channels. The detection of of the tongue and bitter in the hard palate and sweet stimuli can result from activation of spe- the posterior tongue. The gustatory nerves ter- cific G-protein-coupled receptors on taste cells. minate in the rostral nucleus solitarius, which Bitter tastants are detected in some cases by is called the gustatory nucleus located in the interactions with ion channels and in other rostral part of the medulla (see Fig. 14.10). cases by specific G-protein-coupled receptors. The caudal portion of the nucleus solitarius is Umami, the tastant of monosodium glutamate, the visceral or cardiovascular nucleus. The is considered to trigger the fifth type of taste branches of a single nerve taste fiber can stimulus. Umami taste is presumed to be asso- innervate the taste cells in more than one taste ciated with a specific type of metabotropic glu- bud; this constitutes the receptive field of that tamate receptor. The receptors for most taste nerve fiber. Each taste bud can be innervated sensations exhibit a wide range of molecular by several different afferent fibers and, thus, specificity (e.g., broad tuning), as exemplified can contribute to several receptive fields; the by the synthetic sweeteners saccharin and taste buds innervated by a single taste neuron aspartane that are effective in stimulating sweet can be located on different papillae distributed receptor taste cells. over a distance of several millimeters. In addi- Taste cells have a short-life span (Apop- tion, a taste bud can be innervated by several totic Death, Chap. 6) and are replaced about nerve fibers and thereby be a component of a every 6–12 days from the basal cells of each complex receptive field. taste bud. During this cell turnover, the nerve fibers appear to be guided by chemical mark- Central Taste Pathway. The central taste ers to make synaptic contact with specific pathway differs from those of other sensory types of taste receptor cell. Although the systems in that it is exclusively ipsilateral (does innervation by the taste nerve fibers is essen- not decussate). Axons of the second-order neu- tial to maintain the structural and functional rons of the gustatory nucleus ascend within the integrity of the taste bud, the taste sensibilities ipsilateral central tegmental tract (see Figs. of the receptor cells appears to be pro- 13.12 to 13.14) and terminate in the ventral grammed in the gustatory epithelium itself, posteromedial nucleus (parvicellular part, not by the afferent nerves. Taste buds degen- VPM pc) of the thalamus. Axons from VPMpc erate after transection of their sensory inner- pass through the ipsilateral posterior limb of vation; they subsequently reappear following the internal capsule to the primary taste cortex the regeneration of new sensory nerve fibers. (frontal operculum at anterior end of lateral fis- This trophic maintenance of each taste bud is sure, lower end of postcentral gyrus and rostral apparently dependent on a trophic factor from insula, mainly area 43). A secondary taste cor- the nerve. Cranial nerves VII, IX, and X con- tex has been described in parts of the tain the special visceral afferent taste fibers orbitofrontal cortex. The various populations of Chapter 14 Cranial Nerves and Chemical Senses 265 taste buds express somewhat different sensibil- taste stimuli. This neural center can be a part of ities. They are represented in topographically a system that interfaces reward signals to the overlapping patterns throughout the taste path- motor system where the initiation for action is way. Neurons at all levels of the gustatory path- generated (Chap. 22). way are broadly tuned and typically respond to stimuli derived from diverse taste qualities. They respond optimally to one of the four basic SUGGESTED READINGS taste qualities, but are not specific to just one stimulus. Gustatory neurons readily adapt to Axel R. The molecular logic of smell. Sci. Am. constant stimulation. The neurons of the taste 1995;273:154–159. pathways become more finely tuned at the Brodal A. The Cranial Nerves: Anatomy and Anatomico-Clinical Correlations. 2nd ed. higher levels. The multimodal representations Oxford: Blackwell; 1965. of tastes are realized after these finely tuned Brodal A. Neurological Anatomy in Relation to representations (e.g. ‘flavors’) are processed in Clinical Medicine. 3rd ed. New York: Oxford the primary taste cortex, orbitofrontal cortex, University Press; 1981. and secondary gustatory cortex. The sensation Buck L, Axel R. A novel multigene family may of flavors result from combinations of gusta- encode odorant receptors: a molecular basis for tory, olfactory, and somatosensory inputs. The odor recognition. Cell 1991;65:175–187. cerebral cortex mediates the appreciation of Buck LB. Information coding in the mammalian these representations of taste. The loss of taste olfactory system. Cold Spring Harbor Symp. perception (ageusia) can result following a Quant. Biol. 1996;61:147–155. Buck LB. The molecular architecture of odor and stroke involving the VPM of the thalamus or pheromone sensing in mammals. Cell 2000;100: the primary taste cortex. 611–618. Doty RL. Olfaction. Annu. Rev. Psychol. 2001; Other Neuronal Centers Associated with 52:423–452. Taste. The gustatory nucleus also projects to Doty RL, ed. Handbook of Olfaction and Gustation. nuclei within the brainstem that are associated 2nd ed. New York: Marcel Dekker; 2003. with such visceral reflexes as salivation, swal- Finger TE, Silver WL, Restrepo D. The Neurobiol- lowing, vomiting, digestion, and respiration. ogy of Taste and Smell. 2nd ed. New York: Wiley- Taste areas of the cortex project to other centers Liss; 2000. of the brain. The perception of the sensations of Gilbertson TA, Boughter JD Jr. Taste transduction: saltiness, sweetness, sourness, and bitterness appetizing times in gustation. NeuroReport 2003; 14:905–911. generate information that exerts strong influ- Gilbertson TA, Damak S, Margolskee RF. The ences on the lateral hypothalamus, amygdala, molecular physiology of taste transduction. Curr. and ventral striatum (nucleus acccumbens). To Opin. Neurobiol. 2000;10:519–527. the tastes of food and drink, the lateral hypo- Hildebrand JG, Shepherd GM. Mechanisms of thalamus has a role in the generation of auto- olfactory discrimination: converging evidence nomic responses associated with ingestion and for common principles across phyla. Annu. Rev. digestion. It can be involved with the reward Neurosci. 1997;20:595–631. value food has for hungry animals. The amyg- Kareken DA, Mosnik DM, Doty RL, Dzemidzic M, dala, with its reciprocal connections with the Hutchins GD. Functional anatomy of human cortical taste areas, presumably is integrated odor sensation, discrimination, and identification in health and aging. Neuropsychology 2003;17: with learning associations between initially 482–495. derived visual stimuli (e.g., sight of food) and Kauer JS, White J. Imaging and coding in the the primary rewards and reinforcement pro- olfactory system. Annu. Rev. Neurosci. 2001;24: vided by taste. The ventral striatum receives 963–979. influences from the orbitofrontal cortex and the Korsching S. Olfactory maps and odor images. Curr. amygdala and some neurons responding to Opin. Neurobiol. 2002;12:387–392. 266 The Human Nervous System

Leblanc A. The Cranial Nerves: Anatomy, Imaging, Seiden A. Taste and Smell Disorders. Stuttgart: Vascularisation. 2nd ed. New York: Springer- Georg Thieme Verlag; 1997. Verlag; 1995. Strausfeld NJ, Hildebrand JG. Olfactory systems: Malnic B, Godfrey PA, Buck LB. The human olfac- common design, uncommon origins? Curr Opin tory receptor gene family. Proc. Natl. Acad. Sc.i Neurobiol.1999;9:634–639. USA 2004;101:2584–2589. Wilson-Pauwels L, Akesson E, Stewart P, Spacey S. Matsunami H, Montmayeur JP, Buck LB. A family Cranial Nerves in Health and Disease. 2nd ed. of candidate taste receptors in human and mouse. Hamilton Ontario: BC Decker; 2001. Nature. 2000;404:601–604. Witkin JW. Nervus terminalis, olfactory nerve, and Mombaerts P, Wang F, Dulac C, et al. The molecu- optic nerve representation of luteinizing hor- lar biology of olfactory perception. Cold Spring mone-releasing hormone in primates. Ann. NY Harbor Symp. Quant. Biol. 1996;61:135–145. Acad. Sci. 1987;519:174–183. Ranganathan R, Buck LB. Olfactory axon pathfind- Zou Z, Horowitz LF, Montmayeur JP, Snapper S, ing: who is the Pied Piper? Neuron. 2002;35: Buck LB. Genetic tracing reveals a stereotyped 599–600. sensory map in the olfactory cortex. Nature Savic I. Imaging of brain activation by odorants in 2001;414:173–179. humans. Curr. Opin. Neurobiol. 2002;12:455–461. 15 Neurotransmitters as the Chemical Messengers of Certain Circuits and Pathways

Role of Inhibition by Interneurons in Information Processing Acetylcholine Amino Acid Transmitters Biogenic Amines (Monoamines) Neuropeptides (Neuroactive Peptides) Nitric Oxide, Carbon Monoxide, and Adenosine

Communication between neurons occurs membrane. The agent can act as a neurotrans- primarily through the release of neuroactive mitter when the receptor protein is directly chemical messengers called neurotransmitters linked to an ion channel protein. Then, the ion or neuromodulators (Chap. 3). For a chemical selected by the channel determines whether the agent to be called a neurotransmitter, it must be response is excitatory or inhibitory. Thus, it is synthesized in the presynaptic neuron (acetyl- possible for a specific transmitter to excite one choline and the monoamines are produced in neuron and inhibit another neuron. Although a the axon terminals), be stored in presynaptic variety of agents act as neurotransmitters, the vesicles and released into a synaptic cleft, bind action in the postsynaptic cell depends not on to a receptor binding site on the postsynaptic the chemical properties of the transmitter but, membrane of another neuron or effector (mus- rather, on the properties of the receptors that cle fiber or gland cell) where it regulates ion recognize and bind transmitters. For example, channels, and alter the membrane potential. acetylcholine (ACh) produces postsynaptic Finally, it must be removed from the synaptic excitation at the neuromuscular junction by cleft by reuptake into the presynaptic neuron or acting on a special type of excitatory ACh by biochemical degradation. Those neuroactive receptor. In contrast, ACh slows the heart by substances that have not been demonstrated to acting on a special type of inhibitory ACh fulfill all of these requirements are often called receptor. putative neurotransmitters. Some investigators Transmitters at ionotropic receptors pro- define transmitters as chemical messengers that duce rapid phasic responses by altering the interact with receptors directly linked to chan- state of ion channels in the postsynaptic mem- nel proteins, and neuromodulators as chemical brane. The agent can act as a neuromodulator messengers that interact with a receptor linked or as a neurotransmitter when the receptor to a G-protein and a second-messenger system protein to which it binds on the postsynaptic (Chap. 3). The term neurotransmitter is com- membrane is linked to a G-protein. The subse- monly used to include neuromodulators. quent interactions of the G-protein and the Whether a neuroactive chemical agent elic- second-messenger system with the ion chan- its an excitatory or an inhibitory response or nels will then designate the response (Chap. whether it acts as a neurotransmitter or a neu- 3). Transmitters at metabotropic (G-protein- romodulator is dependent on the receptor pro- coupled) receptors evoke slowly responding tein to which it binds on the postsynaptic longer-lasting effects.

267 268 The Human Nervous System

the biogenic amines and neuropeptides. Some ROLE OF INHIBITION chemical messengers can belong to both classes BY INTERNEURONS IN depending on the receptor. For example, ACh INFORMATION PROCESSING acts as neurotransmitter interacting with nicotinic ACh receptors that elicit fast excitatory Lateral inhibition is an important physiolog- responses through the neuromuscular junction ical process that is utilized in information pro- on voluntary muscles. In contrast, ACh acts as cessing by all sensory systems. In this process, a neuromodulator interacting with muscarinic inhibition (e.g., by inhibitory interneurons) ACh receptors that elicit slow inhibitory reduces (modulates) the intensity of a strongly responses on cardiac muscle. excited response (the signal) relatively less Some mature neurons release only one than a weakly excited response (the noise) and, transmitter or modulator at all of its synapses. thus, enhances the signal-to-noise ratio. For Others release multiple chemical messengers, example, lateral inhibition (Chap. 3) enhances small-molecule transmitters, as well as neu- odor sensitivity by granule cells in the olfactory roactive peptides. The coexistence of multiple bulb (Chap. 14) and luminance contrast by messengers in different vesicles in an axon ter- amacrine cells in the retina (Chap.19). Two minal is still a matter of considerable discus- transmitters involved in these processes are sion. In a broad context, this dual presence GABA and dopamine. expands the means by which a neuron can con- The chemical messengers that are presumed vey complex messages with subtle signal con- to be neurotransmitters or neuromodulators tent. The neuropeptide can act to augment what comprise more than 50 neuroactive substances. the primary transmitter is programmed to They have been classified as (1) small-molecule accomplish, as, for example, by strengthening transmitters and (2) neuropeptides (neuroac- or prolonging the action of the transmitter. The tive peptides). The former are of three types: responses of a postsynaptic neuron to a combi- (1) Acetylcholine is the only low-molecular- nation of transmitters can vary depending on weight transmitter not derived from an amino the amounts and proportions of the messengers acid; (2) the four amino acids are gamma released. amino butyric acid (GABA), glycine, gluta- Chemical synapses are characterized both mate, and aspartate; (3) the four biogenic by their agents and by the receptor type or monoamines include the three catecholamines various subtypes on which they act. Fourteen norepinephrine (noradrenaline), epinephrine serotonergic receptor subtypes have been (adrenalin), and dopamine, all derived from the described on one postsynaptic membrane that amino acid tyrosine, and serotonin, derived interacts with an agent. Some axon terminals from the amino acid tryptophan. The numerous can have their own receptors, called autorecep- neuropeptides include such putative neuromod- tors, that respond to the chemical messenger ulators as (1) opioid peptides, (2) gastrointesti- released at the terminals; they have a role in nal (gut–brain) peptides, and cardiac/renal and regulating transmitter release (see Fig. 3.10). tachykinins, such as substance P, and (3) hypo- Transmitters and modulators identify chemical thalamic releasing peptides and neurohypophy- systems that delimit complex neural pathways seal peptides, which act as stress regulatory (see Figs. 15.1 to 15.3). hormones. Neurotransmitters, neuromodulators, and receptors have been categorized in several ACETYLCHOLINE ways. In one classification, the neuroactive messengers that usually act (1) as neurotrans- Acetylcholine is a small-molecule transmit- mitters are acetylcholine and the amino acids ter synthesized from acetylcoenzyme A and listed earlier, and (2) as neuromodulators are choline and catalyzed by the enzyme choline Chapter 15 Neurotransmitters 269 acetyltransferase. It is degraded in the synaptic Broca, and the septal nuclei; (2) the brainstem cleft by the enzyme acetylcholine esterase tegmental group consists of the laterodorsal (Chap. 3). Neurons that release ACh are known tegmental nucleus of the central gray and the as cholinergic neurons. Both of these enzymes subjacent pedunculopontine nucleus. The stria- are synthesized in the cell body and conveyed tum also contains a small number of cholinergic by fast axoplasmic transport to the axon termi- interneurons (Chap. 24). The output from these nal, where the production of ACh takes place two groups of nuclei is distributed predomi- (Chap. 3). nately to neurons with muscarinic receptors. About 10,000 molecules of ACh are packaged into each synaptic vesicle. Upon release Roles of the Projections from the Cholinergic from the presynaptic terminal into the synaptic Basal Forebrain Group (see Fig. 15.1) cleft, some ACh diffuses rapidly to reach post- The orderly widespread cholinergic projec- synaptic receptors. The remaining ACh is tions to the cerebral cortex and hippocampus quickly hydrolyzed by the enzyme acetyl- enhance the responsiveness to inputs of sensory cholinesterase or removed by diffusion from the information involved in cognition, attention, synaptic cleft. Some choline is recycled in the learning, and memory. Defects in the choliner- terminal. There are two basic types of receptor gic projections are implicated in the patho- for ACh. The nicotinic receptor is an ionotropic physiology of neuropsychiatric disorders in receptor, whereas the muscarinic receptor is perinatal development and during aging. A metabotropic. Certain drugs that simulate ACh decrease in the density of these axonal termi- and bind exclusively to either nicotinic or mus- nals is a normal occurrence during aging, as carinic receptors can further differentiate the well as degenerative changes in neurons of the two types. Seven different subtypes of nicotinic frontoparietal cortex and hippocampus and is receptors have been described in muscle, auto- seen in Alzheimer’s disease. The projections to nomic ganglia, and central nervous system the cingulate gyrus, hippocampus, and amyg- (CNS) neurons. Five different subtypes of mus- dala contribute to the functional expressions of carinic receptor also have been distinguished. the limbic system (Chap. 22). Acetylcholine is synthesized by all spinal cord and brainstem motoneurons. Roles of Projections from the Cholinergic In the peripheral nervous system, ACh is Brainstem Tegmental Group (see Fig. 15.1) the principal transmitter of motor neurons. All Rostrally directed pathways to the basal alpha and gamma motoneurons release ACh at ganglia are integrated into the organized motor the neuromuscular junctions. All pregan- behavior circuits of the striatopallidal systems, glionic sympathetic and parasympathetic neu- the substantia nigra (pars compacta), and the rons also release Ach. In autonomic ganglia, frontal lobe and also with the cholinergic the primary cholinergic receptors are nico- interneurons of the striatum. Disproportionate tinic. All postganglionic parasympathetic neu- activation by cholinergic neurons relative to rons (and postganglionic sympathetic fibers to diminished dopaminergic activation is associ- sweat glands of the skin) are cholinergic. At ated with parkinsonism (Chap. 24). Some ros- these postsynaptic sites, muscarinic receptors tral connections are links in the functional predominate. activity of the reticular activating system, In the CNS, major concentrations of cholin- which participates in arousal and wakefulness ergic projection neurons are located in two (Chap. 22). Other cholinergic projections from major nuclear clusters referred to as the basal the pedunculopontine and dorsolateral tegmen- forebrain group and the brainstem tegmental tal nuclei pass into the cerebellum. group (see Fig. 15.1): (1) The basal forebain Descending cholinergic projections to the group comprises magnocellular neurons of the lower brainstem core of the pontine and basal nucleus of Meynert, the diagonal band of medullary reticular formation have key roles in 270 The Human Nervous System sensory processing and autonomic control. Tar- coupled with a virtual paralysis of somatic body gets include the solitary nucleus, the “medial musculature (Chap.20). Projections to the region vasodepressor region” (MDR in Fig. 20.6) of the of the solitary nucleus contribute to the process- tegmentum, and the vasopressor region of ros- ing of sensory input. Projections to the medial troventrolateral reticular nucleus (N.RVL). vasodepressor region and to preganglionic sym- Cholinergic projections within the reticular for- pathetic neurons via the rostral ventrolateral mation initiate the rapid eye movement (REM) reticular nucleus are involved in cardiovascular phase of sleep during which dreaming occurs control mechanisms (Chap. 20).

Figure 15.1: Cholinergic pathways. Cholinergic pathways are widely distributed throughout the CNS. Central cholinergic transmission is involved with cognition, attention, memory, and reflex visceral control. A major concentration of cholinergic cells is located in the basal forebrain in the septal nuclei (SE), the diagonal band of Broca (DBB), and the magnocellular part of the basal nucleus of Meynert (M). These nuclei emit extensive orderly cholinergic projections to the fron- totemporal lobes and to the hippocampal formation. Subsets of cholinergic cells in the medial septal nuclei and diagonal band of Broca project via the fornix to the hippocampal formation and via the cingulate bundle to the cingulate gyrus of the limbic cortex. A second major group of cholinergic cells is concentrated in the contiguous complex comprised of the lateral dorsal tegmental nucleus (Ldt) and the pedunculopontine nucleus. They project rostrally to the limbic cortex, thalamus, and tectum, posteriorly to the cerebellum, and caudally to the lower brainstem central autonomic core of visceral reflex circuits and to spinal cord sympathetic centers. Visceral reflex circuits, including the solitary nucleus and the rostral ventrolateral reticular nucleus of the medulla, are modulated by acetylcholine, a transmitter that is involved in cardiovascular control along with programmed motor behavior and homeostatic adjustments. Chapter 15 Neurotransmitters 271

cardiovascular reflex function and endocrine AMINO ACID TRANSMIITTERS control, and in the regulation of emotional behavior. The movement disorder Huntington’s Amino acid transmitters are ubiquitous cel- disease is associated with a loss of GABAergic lular components of the CNS. Of the known striatal cells, which normally inhibit the globus putative transmitters, they are the most numer- pallidus and other nuclei of the basal ganglia ous and act on the greatest number of synapses. (Chap. 24). The four designated amino acid transmitters Distributed throughout the brain, the GABA are gamma amino butyric acid (GABA), receptors mediate the sedative effects of benzo- glycine, glutamate, and aspartate. On the basis diazepines, and the actions of barbiturates. In of their chemical structure alone, these four are addition, they appear to be a major site for related. GABA acts by opening the chloride anesthetic action. Benzodiazepines (e.g., Lib- channels and thus produces hyperpolarizing rium and Valium) are drugs used for alleviating currents and inhibitory postsynaptic potentials such generalized anxiety disorders as restless- (IPSPs). Glycine usually exerts inhibitory ness, difficulty in concentration, and feeling on responses, but it can produce excitatory effects. edge. The effect on specific neurons produced Glutamate and possibly aspartate act by pro- by these drugs results from the enhancement by ducing excitatory (depolarizing) postsynaptic the action of GABA. The benzodiazepines bind potentials (EPSPs). Glutamate always produces to GABA receptors and, by so doing, enhance EPSPs on ionotropic receptors, whereas activa- the inhibitory effects of GABA by increasing tion of metabotropic receptors can produce the affinity of the receptors for GABA. The either excitation or inhibition. resulting increase in chloride influx through chloride channels acts to reduce anxiety and Gamma Amino Butyric Acid provide for muscle relaxation. Gamma amino butyric acid (GABA) is widely distributed in inhibitory interneurons Glycine and projection neurons of the CNS. GABA is This transmitter, with a restricted distribu- enzymatically converted from glutamate tion in the CNS, is present in interneurons of within presynaptic terminals. Following its the spinal cord (Renshaw cells) (see Fig. 3.11). release and action, GABA is returned via These neurons exert inhibitory effects by membrane transporter reuptake to provide an opening the Cl– channels of the lower motor additional source for GABA synthesis by the neurons (Chaps. 3 and 6). In the cerebral cor- presynaptic neuron. It also enters glial cells for tex, small amounts of glycine have excitatory deactivation. effects at glutamatergic synapses. By inhibit- Gamma amino butyric acid, involved in the ing the release of glycine, tetanus toxin evokes mechanisms of lateral inhibition, occurs at all violent muscle spasms. The blocking of levels of the CNS, including but not limited to glycine receptors is the likely explanation for interneurons of the cerebral cortex, granule the production of muscle spasms following cells of the olfactory bulb (Chap. 14), amacrine strychnine poisoning. cells of the retina (Chap. 19), Purkinje cells and basket cells of the cerebellum (Chap. 18), bas- Glutamate (Glutamic Acid) ket cells of the hippocampus (Chap, 22), Glutamate (glutamic acid) is the most com- interneurons and projection neurons of the cau- mon excitatory transmitter in the central nerv- date nucleus and putamen (Chap. 24) and ous system. Estimates suggest that over interneurons in the sensory gating, and auto- one-half of brain synapses release glutamate. It nomic control centers in the hypothalamus, does not readily cross the blood–brain barrier. reticular formation, and raphe. GABAergic Glutamate, synthesized within the neuron from interneurons are critical in the spinal cord, in glucose, exerts its role by opening Na+ and K+ 272 The Human Nervous System channels. Following its release and action, These amino acid transmitters, in excess, func- glutamate is, by uptake, conveyed from the tion as excitotoxins that cause neuronal cell synaptic cleft by membrane transporters either death. Elevated extracellular glutamate concen- directly to adjacent neurons or into the sur- trations in the CNS have been implicated in rounding glial cells. Within astrocytes, it is neuronal death in head injury, stroke, and enzymatically converted to glutamine, which is epilepsy. Reduced uptake by glial cell gluta- released and taken up by transporters into the mate transporters can be an important mecha- axonal presynaptic endings, where it is metab- nism underlying excitotoxicity involved in olized by the mitochondrial enzyme glutamase amyotrophic lateral sclerosis (Lou Gehrig’s back to glutamate. Glutamate supply within disease). presynaptic terminals is continuously replen- ished by the glutamate–glutamine cycle by the Aspartate active linkage between neurons (glutamate) That aspartate can act as an excitatory amino and the glia (glutamine). acid neurotransmitter was first suggested by Glutamate receptors are both ionotropic and recorded membrane depolarization of centrally metabotropic. (1) There are three types of activated neurons and subsequently by involve- ionotropic receptor involved in direct gating of ment of N-methyl-D-aspartate (NMDA) gluta- ion channels. More than a dozen genes encode mate receptors. In recent years, its presence in subunits of the ionotropic receptors. (2) There and release from presynaptic vesicles has been are eight metabotropic receptors involved in demonstrated, fulfilling the most important cri- the indirect gating via G-proteins and second teria for inclusion as a transmitter. Aspartate messengers. Thus, like other transmitter has been found in many loci, including excita- systems, glutamate interacts with a variety of tory nerve terminals of Schaffer collateral– receptors. commissural projections in the hippocampus, High concentrations of glutamate synapses corticostriate fibers, striatal interneurons, are present in the cerebral cortex, dentate gyrus olivocerebellar climbing fiber synapses, dorsal of the hippocampus, striatum, and the spinal root ganglia, the cochlea and retinal photore- cord. Essentially, all of the major efferent pro- ceptors, and bipolar cell terminals. In some jections from the cerebral cortex are compo- hippocampal neurons, aspartate and glutamate nents of glutamatergic systems. These are colocalized in the same nerve endings. comprise the corticobulbar, corticothalamic, corticostriate, and corticopontine pathways. The mossy fibers projecting to the cerebellum BIOGENIC AMINES (MONOAMINES) also are glutamatergic The striatum, a major component of the The biogenic amines comprise (1) the cate- basal ganglia, receives substantial excitatory cholamines norepinephrine, epinephrine, and glutamatergic inputs from all areas of the cere- dopamine and (2) the indolamine serotonin bral cortex (Chap. 24). Suggestions have been (5-hydroxytryptamine [5-HT]). They are chemi- made that alterations in the glutamatergic cortical messengers used by neurons as well as by costriatal projection system might be one of the endocrine and other cells. A catecholamine is an initial events leading to the development of organic compound that contains a catechol Huntington’s and other neurodegenerative nucleus and an amino group. Catecholamines diseases. are synthesized by neurons of the brain and sym- Excitotoxicity by glutamate is the phenome- pathetic ganglia by a sequence of steps from the non by which excess amounts of glutamate essential amino acid tyrosine. The initial and destroy neurons. The hyperactivity of excita- rate-limiting step in this synthesis requires the tory amino acid systems or the failure of nor- presence of tyrosine hydroxylase to produce mal reuptake mechanisms can be deleterious. dopamine. In turn, in the presence of dopamine Chapter 15 Neurotransmitters 273 beta-hydroxylase, dopamine can be converted to These major modulatory biogenic systems norepinephrine, and in the presence of phen- and the cholinergic system have extensive lyethanolamine-N-methyl-transferace (PNMT) connections encompassing most areas of the norepinephrine can be converted to epinephrine. brain. Each has a significant role in modulat- Serotonin is synthesized within the neuron in the ing sensory and motor activities and states of presence of tryptophan hydroxylase from the arousal. amino acid tryptophan. Reuptake into the presynaptic terminal and Norepinephrine (Noradrenaline) (see Fig. 15.2) enzymatic degradation constrain the fate of the In the peripheral nervous system, norepi- released monoamine neurotransmitters within nephrine is synthesized by all postganglionic the synaptic cleft. (1) Reuptake by transporters sympathetic nerves, except those that innervate leads to the recycling of the transmitter into the sweat glands, which are cholinergic (Chap. synaptic vesicles of the presynaptic terminals for 20). Cell groups which synthesize norepineph- later release (see Fig. 3.10). (2) The degradation rine or epinephrine, are located within the pon- is accomplished by two enzymes. Catechol-O- tine and medullary tegmentum (see Fig. 15.2). methyl transferase deactivates transmitters The most prominent of these nuclei is the locus within the synaptic cleft and monoamine oxi- ceruleus. Epinephrine neurons (C 3) provide a dase does so on the inside of the presynaptic ter- major source of input to the locus ceruleus. minal and on the postsynaptic membrane. These Many of the cells contributing fibers to the processes are integrated for maintaining a steady tegmental circuitry are not adrenergic. Adren- supply of transmitters. ergic receptors for norepinephrine (mediators Neurons that release norepinephrine and epi- of adrenal hormone actions) comprise two nephrine are called adrenergic neurons; those groups of metabotropic receptors called alpha- that release dopamine are called dopaminergic and beta-adrenergic receptors. Each consists of neurons; those that release serotonin are called several subgroups coupled to different G-pro- serotonergic neurons. The activity of these teins. Of these, the beta-receptors predominate monoamine transmitters is limited by their in the brain. reuptake via transporters into the presynaptic Adrenergic neurons throughout the brain- ending, where they are recycled into vesicles for stem are strongly influenced by sensory inputs future use (Chap. 3). In the human brain, from somatic and visceral sources and by dopaminergic and adrenergic neurons contain bodily states and mental-stress-related infor- melanin pigment and, thus, can often be visual- mation. These cells also integrate signals from ized macroscopically without special stains. higher-ordered neural centers and the internal These catecholamine cell systems (the solitary and external milieu from sensory relay nuclei tract nucleus and ventrolateral medulla synthe- in the dorsal horn of the spinal cord (e.g., stim- size norepinephrine, designated as the A1-2 and uli evoking pain), from vagal and glossopha- C1-3 cell groups, respectively) communicate ryngeal inputs (e.g., from the carotid sinus, stress-related information bidirectionally to carotid body, and thoracic and abdominal vis- specific behavioral, endocrine, and autonomic cera to the nucleus solitarius) (see Fig. 20.5). control centers in the brain and spinal cord. These myriads of sensory inputs drive The major biogenic pathway systems in the responses generated in the locus ceruleus. brainstem are (1) the dopaminergic pathways, The axons projecting from the locus ceruleus originating from the substantia nigra and ventral and other adrenergic cells groups of the reticular tegmental area of the midbrain, (2) the nora- formation join several pathways: namely the drenergic pathways, originating from the locus central tegmental tract, dorsal longitudinal fas- ceruleus and several tegmental nuclei, and (3) ciculus, and the medial forebrain bundle (see the serotonergic pathways, originating from the Fig. 15.2). These pathways terminate rostrally in raphe nuclei (see Figs. 15.2 and 15.3). the tectum, thalamus, hypothalamus, hippocam- 274 The Human Nervous System

Figure 15.2: Noradrenergic and adrenergic pathways. The ascending pathways on the left originate from medullary and pontine reticular nuclei and terminate in the cerebrum. The ascending A1 noradrenergic pathway terminates in the magnocellular hypothalamus, synapsing with cells that synthesize arginine, vasopressin, and oxytocin; its rostral extension, the C1 adrenergic column, ascends to terminate in the locus ceruleus, amygdaloid nucleus, and parvocellular hypothalamic cells that synthesize corticotrophin-releasing hormone, the visceral thalamus, and preoptic (stress) axis. The descending pathway on the right from A5 norepinephrinergic and C1 adrenergic neurons synapse with thoracolumbar and sacral cholinergic preganglionic motoneurons, and with local A2 and C2 norepinephrine and epinephrine interneurons from local fiber plexuses in the solitary tract. The locus ceruleus (on right) gives rise to widespread noradrenergic projections. Ascending fibers are distributed to the inferior and superior colliculi and continue rostrally into the forebrain. Locus ceruleus efferents in part traveling in the median forebrain bundle terminate in the thalamus, hypothalamus, hippocampus, amygdala, nucleus accumbens, and cerebral cortex. Other fibers project to the cerebellum. Descending fibers go to all levels of the spinal cord and to nuclei in the lower brainstem. Chapter 15 Neurotransmitters 275 pus, amygdala, and cerebral cortex, dorsally in responsiveness to novel, unfamiliar, and sur- the cerebellum, and caudally in the lower brain- prising stimuli. Thus, the LC influences behav- stem and spinal cord. ioral arousal and the level of the forebrain and sensory perception (e.g., inputs to the solitary Locus Ceruleus (LC). The locus ceruleus, nucleus and the dorsal horn of the spinal cord) located in the upper pons, has the largest collec- and muscle tone. tion of norepinephrine neurons (see Fig. 13.14). In humans, the LC contains about 10,000 neu- Epinephrine (Adrenalin) (see Figs. 15.2 rons on each side, with axons that project to and 20.5) every region of the brain and spinal cord. The Epinephrine is a stress transmitter hormone “almost universal” distribution of output from synthesized on physiological demand by a the LC is consistent with the belief that the LC small number of nuclei in the lower brainstem acts as a modulator, which sets background tone including in the dorsal vagal complex (solitary within the brain. It is the largest source of wide- nucleus, area postrema, dorsal motor nucleus spread norepinephrine innervation to the cere- of the vagus) and the rostral ventrolateral retic- brum. Stimulation of the LC does not yield any ular nucleus (n. RVL) (C1 group). Ascending well-defined specific effect. Rather, the LC is projections go to the norepinephrinergic locus conceived as having a role in enhancing the sig- ceruleus, the raphe, amygdala, visceral parts of nal-to-noise ratio (lateral inhibition) (i.e., sup- the thalamus, hypothalamus, septal area, and to pressing irrelevant stimuli [background noise] the preoptic region. These neurons can exert and highlighting relevant stimuli). LC projec- inhibitory or excitatory influences. The n. RVL tions apparently modify behavioral arousal and sends fibers caudally to the intermediolateral cause increased alertness as indicated by elec- cell column of the thoracolumbar spinal cord, troencephalograms. which contains preganglionic sympathetic neu- The LC is remarkable in that its axons are rons (Chapter 20). Activation of this pathway extensively branched and project directly with- increases heart rate and blood pressure, and out interruption until each branch makes stimulates release of catecholamines by the synaptic connections through varicosities and adrenal medulla. synapses in essentially every major region of the CNS. The LC projections are bidirectional, Dopamine (see Fig. 15.3) simultaneously influencing widespread central Dopaminergic neurons, wholly confined to neural activity, behavioral arousal, and sympa- the CNS, are concentrated in small groups and thetic response patterns. Axons of the LC proj- give rise to projections generally classified by ect (1) rostrally via the central tegmental tract, length as short, intermediate, or long systems, dorsal longitudinal fasciculus and medial fore- which terminate in discrete targets (see Fig. brain bundle to the tectum, periventricular 15.3). This is in contrast to the more centralized hypothalamic, and thalamic nuclei, hippocam- groups of noradrenergic and serotonergic neu- pus and the cerebral cortex, (2) via the superior rons, which give rise to relatively longer pro- cerebellar peduncle to the cerebellum, (3) to jections to diffuse sites. many regions of the brainstem, and (4) cau- Receptors, identified as dopamine receptors, dally to the spinal cord (see Fig. 15.2). comprise two groups of metabotropic receptor Wide-ranging projection fields of the LC is coupled to G-proteins that affect the activity of a feature consistent with its suggested actions adenylyl cyclase second-messenger systems. as a modulator setting (brain tone) background. Activation of one subgroup results in excitatory The LC is conceived as having the role of sup- responses and of another in inhibitory responses. pressing irrelevant stimuli (background noise) A special group functions as autoreceptors that and enhancing relevant stimuli. LC projections are involved with the reduction of dopamine modulate behavioral arousal, vigilance, and synthesis and release. 276 The Human Nervous System

Short Systems. Dopaminergic interneurons Intermediate-Length Systems. There are wholly confined to the olfactory bulb (granule three intermediate-length dopaminergic path- cells) and retina (amacrine cells) selectively ways. (1) Tuberohypophyseal projections from enhance the signal-to-noise ratio by lateral the hypothalamus to the anterior and interme- inhibition. diate lobes of the pituitary are involved in

Figure 15.3: Some dopaminergic pathways (left) and the serotonergic pathways (right) are illustrated. The long dopaminergic pathway from the substantia nigra, pars compacta projecting to the putamen, and caudate nucleus is involved in motor control (Chap. 24), whereas that from the ventral tegmental area (VTA) projecting to the nucleus accumbens, amygdala, and hippocampus is involved in emotional responsiveness (Chaps. 22 and 24). One intermediate-length pathway from the hypothalamus to the hypophysis is shown. Reciprocal GABAergic strionigral connections are shown on the right. Serotonergic pathways arise from the raphe. Rostral raphe nuclei send fibers via the medial forebrain bundle to the thalamus, hypothalamus, striatum, and cerebral cortex, particularly the limbic cortex involved in emotions. The nucleus raphe magnus in the medulla projects to the spinal cord and is involved in pain modulation. Chapter 15 Neurotransmitters 277 inhibiting release of prolactin and melanocyte- tors. The numerous serotonin receptor subtypes stimulating hormone; (2) incertohypothalamic are grouped into families. All, except one are projections from the zona incerta, which is a G-protein coupled with second-messenger rostral extension of the brainstem reticular pathways. formation, terminate in the hypothalamus; (3) The raphe nuclei project diffusely through- dopamine cells are involved in the regulation of out the brain and spinal cord. Neurons of the autonomic and endocrine control, release of rostral raphe nuclei have axons that ascend in pituitary hormones, and the expression of sex- the median forebrain bundle and terminate in ual and other social behaviors. the hypothalamus, striatum, cerebral cortex (e.g., limbic cortical areas and primary cortical Long Systems. The largest groups of dopa- areas such as primary visual cortex), and the minergic neurons in the brain are in the sub- ependyma lining the ventricles. The centrally stantia nigra, pars compacta, and the ventral located pontine and immediately adjacent tegmental area (VTA) in the midbrain, which raphe cell groups innervate the brainstem give rise to separate pathways (see Figs. 13.15 nuclei of the reticular formation and the cere- and 15.3). The former emits the nigrostriatal bellum. The caudal medullary raphe nuclei pathway to the caudate nucleus and putamen, project to the spinal trigeminal nucleus and to which has an important role in motor control the spinal cord where they terminate in the (Chap. 24). Progressive degeneration of these intermediolateral cell column and also parts of neurons deprives the striatum of dopamine and the dorsal and ventral horn. causes Parkinson’s disease. Neurons of the Serotonergic pathways have a significant VTA form the mesolimbic pathway to the role in modulating the responsiveness of the nucleus accumbens, amygdala, and hippocam- cerebral cortical neurons, in the control of pus (Chap. 22). This projection is involved in hypothalamic, cardiovascular, and thermoregu- mechanisms of reward; rats choose electrical latory centers, and in modulating by inhibition self-stimulation of the VTA and its dopaminer- afferent input from pain fibers. gic neurons over food and sex. The dopaminer- The rostral serotonergic projections have gic mesocortical system from the VTA to active roles in the functioning of the primary neocortex, especially the prefrontal areas, is sensory cortical areas of the neocortex and in thought to gate signals that regulate biological the maintenance of limbic cortical tone for drives and motivation associated with initiation coping with emotion and anxiety. Following of behavioral responses. its release from mast cells and other damaged cells, serotonin is the agent that activates and Serotonin (5-hydroxytryptamine [5-HT]) sensitizes the nociceptors of the primary Serotonin is synthesized primarily by “pain” fibers (A-delta and C fibers) (Chap. 9). neurons within the raphe nuclei of the brain- In the nervous system, serotonin is involved stem (see Figs. 9.5 and 15.3), in mast cells with second-messenger systems as a modula- (associated with nociception, Chap. 9), tor. The projections to the spinal trigeminal platelets and enterochromaffin cells of the nucleus and dorsal horn of the spinal cord gut (Chap. 20). modulate perception of pain, and those to the Serotonin is synthesized from the amino ventral horn act to regulate tone of the motor acid tryptophan and released from synaptic system (Chap. 9). In addition, serotonin is vesicles in axonal endings. Rapid active reup- involved in a complex of physiologic activi- take by transporters into the same terminal lim- ties of the hypothalamus, including changes in its the action of serotonin within the synaptic blood pressure, body temperature, food cleft. Enzymatic degradation of serotonin has intake, the sleep–wake cycle, sexual behav- only a secondary role. Except for one subtype, iors, certain psychological and psychotic serotonin receptors are all metabotropic recep- states and responses to certain drugs. 278 The Human Nervous System

Serotonin reuptake inhibitors such as fluox- neuropeptide vesicles are not refilled with etine (Prozac) and a host of more recent agents transmitter by reuptake in the axon terminals. are widely used to help people cope with a The released neuropeptides are removed from range of behavioral symptoms including mild the synaptic cleft via diffusion and degradation to severe depression, deficiency in the ability to by extracellular peptidases. The relatively slow experience pleasure, fear of rejection, and lack removal of neuropeptides contributes to the of self-confidence. They act by blocking the longer duration of their effects. Virtually all serotonin transporter in the axon terminal and neuropeptides mediate their effects by activat- the reuptake of serotonin from the synaptic ing G-protein-coupled metabotropic receptors cleft. The result is an increase in the level and and second-messenger slow postsynaptic duration of the action of serotonin, which is responses. G-protein receptors comprise many translated in a few weeks into therapeutic subtypes. effects on both depression and obsessive– Neuropeptides (peptidergic transmitters) are compulsive disorders. produced in cells derived from embryonic neural precursor structures (neural plate and neural crest); these include neurons, chromaffin cells NEUROPEPTIDES of the adrenal medulla, enterochromaffin cells (NEUROACTIVE PEPTIDES) of the gut (Chap. 20), and islet cells of the pancreas. The neuropeptides comprise the largest The neuropeptides found in the brain can be class of neuroactive substances, functioning grouped into three major families: (1) opioid primarily as neuromodulators. They are pro- peptides (opiates) such as enkephalins, endor- teins composed of short chains of 5–50 amino phins, and dynorphin, (2) gastrointestinal acids. Neuropeptides are synthesized and pack- (gut–brain) peptides such as vasoactive intes- aged by fundamentally different mechanisms tinal polypeptide (VIP), substance P and than utilized for the production of ACh and the neurotensin, and (3) hypophysiotrophic c pep- biogenic amines. The latter transmitters are tides) such as vasopressin and oxytocin (Chap. produced by the activity of enzymes utilizing 21). molecular precursors delivered to the axon Vesicles of small-molecule (classical) trans- terminals. The polypeptides, from which neu- mitters in many neurons are colocalized with ropeptides are derived, are synthesized by an vesicles of neuropeptides in the axon terminals RNA-directed preparation mechanism that (see Fig. 15.4). Two neuropeptides, each in its produces the precursor neuropeptides de novo own vesicles, can also coexist in the same ter- in the cell body of the neuron through the minal. Some examples of colocalization are sequence of ribosomes, endoplasmic reticulum, ACh with enkephalins, ACh with VIP, GABA and Golgi apparatus and finally packaged into with somatostatin, glutamate with substance P, vesicles. The initial stages of peptide neuro- serotonin with substance P, and norepinephrine transmitter processing occur after packaging with enkephalins. The corelease of a fast-acting into vesicles that involve proteolytic cleavage, transmitter with a neuromodulator peptide hav- glycosylation, and disulfide bond formation. ing a long-lasting effect increases the versatil- The neuropolypeptides packaged in the cell ity of synaptic activity. The significance of body as large peptide-filled vesicles are trans- corelease on the functional activity of the nerv- ported by axoplasmic flow to the nerve termi- ous system has yet to be fully evaluated and nals. Neuropeptide synthesis is basically understood. Evidence indicates that neuropep- similar to the synthesis of proteins secreted by tides have a role in some aspects of sensing and non-neural glandular cells such as pancreatic emotion. They seem to modulate the perception enzymes. Unlike the vesicles that contain the of pain and such aspects of emotion as pleasure biogenic amine small-molecule transmitters, and response to stress (Chap. 21). Chapter 15 Neurotransmitters 279

Figure 15.4: Composite illustration of a postganglionic noradrenergic neuron of the sympathetic system. Each varicosity (enlargement) of the axon, called a bouton, contains both large and small vesicles. Neuropeptides are localized in the large vesicles and norepinephrine in the small vesicles. These transmitters, when released, influence the nearby effectors (Chap. 20). The linearly arrayed varicosities along the axon are called boutons en passage and those at the end of the axon are called terminal boutons. Some of the structures innervated are illustrated. The smooth muscle cells are joined together by gap junctions (nexus) to form multicellular functionally integrated units.

The corelease of ACh and VIP by postgan- tained in small synaptic vesicles), causes glionic parasympathetic fibers innervating the increased secretion from the gland and VIP salivary glands illustrates the dual role of these (contained in large vesicles), relaxes smooth two chemical messengers. Each agent acts on a muscles of the blood vessels, resulting in vaso- different target cell. Stimulation of the para- dilation and increased blood flow through the sympathetic nerves, which release ACh (con- organ. 280 The Human Nervous System

Opioid Peptides regions associated with neurons in the pain Opioid denotes being opiatelike in terms of pathways (Chap. 9). In some regions, such as a functional similarity to morphine (a com- the cerebral cortex, there are interneurons con- pound extracted from opium). Opioid peptides taining enkephalins. Enkephalin opioids are are endogenous (originating within the body) believed to reduce sensitivity to pain peripher- or synthetic agents that exhibit pharmacologi- ally (PNS) as well as centrally (CNS) by activating opiate receptors in the periaqueductal cal activity similar to morphine. Because the gray in the midbrain (increase in enkephalins) opioid peptides bind with morphine receptors (Chap. 9). Morphine and other opiates induce of CNS neurons, they are also called morphi- euphoria by activating the receptor sites of the nomimetic peptides. Several subtypes of opiate enkephalin neurons of the amygdala and other receptor exist, all of which are linked to components of the limbic system. The dynor- G-proteins. The endogenous opioids do not phins are enkephalins that are concentrated in cross the blood–brain barrier. Chemical groups the structures of the limbic system and hypo- of opioid peptides include the endorphins and thalamus (Chaps. 21 and 22). enkephalins. Opiates are drugs that are derived Enkephalin opioids are believed to modulate from the opium poppy. They are used therapeu- pain impulses by acting to reduce sensitivity to tically as powerful analgesics by binding to pain peripherally (PNS) as well as centrally opiate receptors. (CNS) by activating opiate receptors in the periaqueductal gray of the midbrain (release of Endorphins (Endogenous Morphine). The enkephalins) (Chap. 9). Morphine-induced endorphin neurons have cell bodies that are euphoria and the euphoric effects of opiates are located in the ventral (arcuate area) hypothala- presumed to be generated by activating the mus. Long axons project from these endorphin receptor sites of the enkephalin neurons of the neurons to the amygdala and to the periventric- amygdala and structures of the limbic system. ular region of the thalamus and brainstem, The relief of pain associated with acupunc- including the raphe nuclei, adjoining reticular ture treatment results from the release, in the formation, and locus ceruleus. The endorphins brain, of enkephalins, which bind to opiate bind to opioid receptors, which produce analge- receptors. Evidence for this conclusion is that sia, sedation, and miosis (pupillary constriction). following the administration of naloxone,a These agents have a central role in controlling potent opiate antagonist, the anesthetic effects the drives for food, water, and sexual activity— of acupuncture are blocked. In the placebo all associated with the limbic system (Chap. 22). effect, pain is often relieved by indifferent The effect of opiates in humans is not so much medications such as saline. In these cases, the as a specific blunting of pain, but, rather, it is placebo effect can be shown to be blocked by an induced state of indifference or emotional naloxone. detachment from the experience of distress. Gastrointestinal (Gut–Brain) Peptides Enkephalins. Enkephalin neurons are These peptides were initially identified in widely distributed in the CNS. Each neuron has the gastrointestinal (GI) tract and were later short axon projections. They are located in the found in the nervous system. hypothalamus, basal ganglia (globus pallidus Secretin/glucogon peptide family, an intes- and substantia nigra), amygdala and some lim- tinal acid calcification hormone, is synthesized bic structures, periaqueductal gray of the mid- by the hypothalamic stress axis and cerebellum brain, raphe nuclei, and reticular formation of and is involved in modulating stress adaptation the brain. Their presence in the spinal nucleus reactions. of the trigeminal nerve and the dorsal horn Vasoactive intestinal peptide (VIP) is widely (substantia gelatinosa) of the spinal cord is in distributed in the CNS and in the intrinsic neu- Chapter 15 Neurotransmitters 281 rons of the gut. It is found in high concentrations release of growth hormone, and thyrotropin- in the cerebral cortex, hippocampus, amygdala, releasing hormone, which stimulates the and hypothalamus and in the intrinsic neurons of release of thyrotropin from the pituitary gland the gut. VIP appears to function as an inhibitory (Chap. 21). modulator to smooth muscle and as an excitatory modulator of glandular epithelial cells. Neurohypophyseal (Pituitary) Substance P is an excitatory modulator Peptide (Hormone) located in the CNS and GI tract. Its effects are Vasopressin (antidiuretic hormone) is a neu- of long duration. Its role in the GI tract is to rohypophyseal peptide hormone involved with influence the constriction of smooth muscles. the reabsorption of water by the kidney and in Substance P is released in the dorsal horn of the the constriction of blood vessels. spinal cord by A-delta and C-pain fibers of dor- Oxytocin is a peptide involved in stimulating sal root ganglia sensory neurons (Chap. 9). (1) the smooth muscles of the uterus to con- Substance P and GABA are colocalized in spe- tract, (2) milk release in lactating women by cific populations of striatal neurons, which the contraction of the myoepithelial cells of the project to the medial segment of the globus pal- mammary gland, and (3) promoting maternal/ lidus and to the substantia nigra (Chap. 24). infant bonding. Substance P also is found in the raphe nuclei of Both vasopressin and oxytocin are synthe- the brainstem and hypothalamus. sized within the cell bodies of hypothalamic Neurotensin is a gut–brain peptide present in neurons of the magnocellular neurosecretory enteric neurons and in the median eminence system and stored in the posterior lobe of the (hypothalamus), substantia nigra, periaqueduc- pituitary gland (Chap. 21). tal gray, locus ceruleus, and raphe nuclei. It can participate in the control of body temperature and regulation of the pituitary gland (Chaps. 21 NITRIC OXIDE, CARBON and 22). MONOXIDE, AND ADENOSINE Neuropeptide Y (NPY) is widely distributed throughout the endocrine and autonomic regu- Nitric oxide (NO) acts as a neuronal mes- latory brain regions and the enteric nervous senger in both the central and peripheral nerv- system. Release of NPY in the hypothalamus ous systems. It is an unconventional nitrergic stimulates food intake, regulates arterial blood transmitter that is not found in vesicles. Rather, pressure, heart rate, and anterior pituitary hor- it readily diffuses from its site of origin in the mone release and, presumably, enhances cell through the cell and its membranes. It is memory. possible that NO can be released from both Cholecystokinen (CCK) in humans stimu- presynaptic and postsynaptic neurons. Note lates gastrointestinal motility, accelerates the that NO is not the nitrous oxide (N2O) used as transit of food, and stimulates and potentiates an anesthetic. actions of pancreatic enzyme secretions and In neurons, NO can be produced in response postprandial gallbladder contractions. CCK is a to the excitatory synaptic transmitter glutamate stress factor called on by mental and physical acting through an NMDA receptor that opens stress and trauma. Its role in the CNS is related Ca2+ ion channels. The resulting influx of Ca2+ to short-term food intake and sensations of sati- ions passing through the channels bind to the ety and modular nociception. intracellular protein calmodulin that activates the enzyme nitric acid synthase. This enzyme Hypophysiotrophic Peptides and converts the amino acid arginine into nitric Other Peptides oxide. This sequence is rapid, taking only mil- Opioid hypothalamic-releasing hormones liseconds. NO is an unstable gas that is include somatostatin, a peptide that inhibits the extremely membrane permeant. It diffuses 282 The Human Nervous System through membranes, bypassing interactions Adenosine (a purine) is a mysterious with synaptic membrane receptors. It acts as a purinergic modulator that is a degradation modulator in which a postsynaptic neuron can product of adenosine triphosphate (ATP). This influence a presynaptic neuron. It is extremely purine acts not only as a chemical messenger, labile and lasts for about 5–10 seconds. The but also, more specifically, as a modulator. mechanisms underlying the actions of NO Adenosine can exert its influences presynapti- remain to be elucidated. cally by inhibiting the release of transmitters Nitric oxide’s role in dilating blood vessels and postsynaptically by its action on some (nitrovasodilator) is indicative of one mode of receptors associated with the second-messen- its activity. The parasympathetic neurotrans- ger systems. It is released by sympathetic neu- mitter ACh binds to the endothelial cells lining rons innervating, for example, the smooth blood vessels to activate the release of NO, muscles of the vas deferens and the GI tract which diffuses across membranes to the (see Neural Control of the Gut, Chap. 20) and smooth muscles of a blood vessel (Chap. 20). cardiac muscle. Nitric oxide causes dilation of the blood vessel as a consequence of the relaxation of the smooth muscle cells. Thus, ACh acts through NO and not directly on the smooth muscles, SUGGESTED READINGS which lack ACh receptors. Nitric oxide relaxes the muscles through the activation of a second- Azmitia EC. Modern views on an ancient chemical: messenger system involving cyclic guanosine serotonin effects on cell proliferation, matura- monophosphate, which is related to cAMP tion, and apoptosis. Brain Res. Bull. 2001;56: (Chap. 3). The dilation is counterbalanced by 413–424. the sympathetic transmitter norepinephrine, Azmitia EC. Serotoninergic chemoreceptive neu- which acts directly with receptor sites on the rons: a search for a shared function. Mol. Inter- smooth muscle whose contraction results in vent. 2004;4:18–21. constriction of the blood vessel. The NO Bredt DS. Nitric oxide signaling specificity—the heart of the problem. J. Cell. Sci. 2003;116:9–15. formed following the absorption of nitroglycer- Burke WJ, Li SW, Zahm DS, et al. Catecholamine ine into the bloodstream relieves the pain monoamine oxidase, a metabolite in adrenergic symptoms of angina caused by the constricted neurons, is cytotoxic in vivo. Brain Res. 2001; blood vessels of the heart. Nitric oxide stimu- 891:218–227. lates the cardiac blood vessels to dilate and, Cooper J, Bloom F, Roth R. The Biochemical Basis thus, restores an adequate blood flow to the of Neuropharmacology. 8th ed. New York: heart muscle. NO is released by neurons of the Oxford University Press; 2003. myenteric plexus of the gut as a nonadrener- Davis KL, Dennis Charney D, Coyle JT, Nemeroff gic–noncholinergic (NANC) agent involved in C, eds. Neuropsychopharmacology: The Fifth smooth muscular relaxation during peristalsis Generation of Progress. Baltimore, MD: Lippin- (Chap. 20). cott Williams & Wilkins; 2002. The NO released at glutamatergic synapses Gundersen V, Chaudhry FA, Bjaalie JG, Fonnum F, is thought to have a role in developmental and Ottersen OP, Storm-Mathisen J. Synaptic vesicu- synaptic plasticity exhibited by neurons (Chap. lar localization and exocytosis of L-aspartate in excitatory nerve terminals: a quantitative immuno- 3). This can be of significance in the synaptic gold analysis in rat hippocampus. J. Neurosci. plasticity underlying learning and memory 1998;18:6059–6070. associated with, for example, the hippocampus Gundersen V, Ottersen OP, Storm-Mathisen J. (Chap. 22). In addition, NO can participate in Aspartate- and glutamate-like immunoreactivi- the acquisition of learned behavior. ties in rat hippocampal slices: depolarization- Carbon monoxide is another membrane-per- induced redistribution and effects of precursors. meant gas formed in the brain. Eur. J. Neurosci. 1991;3:1281–1299. Chapter 15 Neurotransmitters 283

Hall Z, ed. An Introduction to Molecular Neurobiol- Ruggiero DA, Underwood MD, Rice PM, Mann JJ, ogy. Sunderland, MA: Sinauer Associates; 1992. Arango V. 1999. Corticotropic-releasing hor- Hardman J, Limbird L, Gilman A. Goodman & mone and serotonin interact in the human brain- Gilman’s The Pharmacological Basis of Thera- stem: behavioral implications. Neuroscience peutics. 10th ed. New York: McGraw-Hill Med- 91:1343–1354. ical; 2001. Sabatini BL, Oertner TG, Svoboda K. The life cycle Kirchgessner AL. Glutamate in the enteric nervous of Ca(2+) ions in dendritic spines. Neuron system. Curr Opin Pharmacol. 2001;1:591–596. 2002;33:439–452. Kirchgessner AL. Orexins in the brain–gut axis. Siegel G, Agranoff B, Albers R. Basic Neurochem- Endocr Rev. 2002;23:1–15. istry: Molecular, Cellular and Medical Aspects. Kupfermann I. Functional studies of cotransmission. Philadelphia: Lippincott-Raven; 1999. Physiol Rev. 1991;71:683–732. Snyder SH, Bredt DS. Biological roles of nitric Myers RD. Neuroactive peptides: unique phases in oxide. Sci. Am. 1992;266:68–70. research on mammalian brain over three decades. Strand F. Neuropeptides: Regulators of Physiologi- Peptides 1994;15:367–381. cal Processes. Cambridge, MA: MIT Press; 1999. Nestler EJ, Hyman S, Malenka RC. Molecular Neu- Tong Q, Kirchgessner AL. Localization and func- ropharmacology: A Foundation for Clinical tion of metabotropic glutamate receptor 8 in the Neuroscience. New York: McGraw-Hill Medical; enteric nervous system. Am. J. Physiol. Gastroin- 2001. test. Liver Physiol. 2003;285:G992–G1003. 16 Auditory and Vestibular Systems

The Labyrinths Auditory System Vestibular System

The auditory system is exteroceptive and vesicles located within the temporal bone, concerned with perception of sound. The forms the bony framework for the cochlea, vestibular system, in contrast, is proprioceptive vestibule (utricle and saccule), and three semi- and concerned with the maintenance of equi- circular canals (see Fig. 16.1). The membra- librium and orientation of the body in space nous labyrinth is enclosed within the osseous and, hence, involved in motor activities. The labyrinth—analogous to a tube within a tube receptors (mechanoreceptors) are hair cells (see Fig. 16.2). The hair cells are located within located within specialized neuroepithelial the membranous labyrinth. The space within structures. They are responsible for converting the osseous labyrinth (perilymphatic space), mechanical energy in the form of displacement which surrounds the membranous labyrinth, is of their surface elements caused by sound filled with perilymph; the space within the waves (for hearing) and head movements (for membranous labyrinth (endolymphatic space) balance) into electrochemical energy to be is filled with endolymph. The hair cells are transmitted to the auditory (cochlear) or located within the endolymphatic space. The vestibular root of the vestibulocochlear nerve endolymphatic and perilymphatic spaces are (cranial n.VIII), respectively. The hair cells are separate compartments. Their respective fluids located within the membranous labyrinth of the have different chemical compositions similar to inner ear, which is a closed tubular system the differences between an extracellular fluid filled with endolymph. The auditory hair cells (perilymph) and intracellular fluid (endolymph). are in the spiral organ of Corti in the cochlea. Thus, they have different resting potentials The vestibular hair cells are located in the mac- allowing for the passage of charge and stimula- ula of the utricle, the macula of the saccule, and tion of the hair cells. the cristae ampullares of the three semicircular canals. The cochlear and vestibular nerves Osseous Labyrinth merge to form the vestibulocochlear nerve or The osseous labyrinth, located within the eighth cranial nerve, which enters the brain- petrous portion of the temporal bone, consists stem at the cerebellopontine angle (junction of the vestibule, semicircular canals, and between the cerebellum, pons and medulla; see cochlea. It develops from the primitive otic Fig. 13.11). capsule. The utricle and saccule, constituents of the membranous labyrinth, are within the vestibule. Openings into the vestibule include THE LABYRINTHS the vestibular aqueduct, foramina for the passage of vestibular nerve bundles, and the oval There are two labyrinths: an osseous (or window. The three semicircular canals sur- bony) labyrinth and a membranous labyrinth. round the semicircular ducts. The bony cochlea The osseous labyrinth, a network of canals and is a spiral structure that winds two and a half

285 286 The Human Nervous System

Figure 16.1: External ear, middle ear, and inner ear on right side viewed from the front.

turns from base to apex around a bony core, the to the subarachnoid space. Perilymph is there- modiolus, which contains the cell bodies (spiral fore in continuity with cerebrospinal fluid. ganglion) of the afferent auditory nerve fibers as well as efferent fibers from the brainstem Membranous Labyrinth that go to the auditory hair cells. The cochlea The vestibular portion of the membranous portion of the osseous labyrinth is divided into labyrinth on each side consists of (1) three semi- the scala vestibuli and scala tympani, which circular ducts, lateral (or horizontal, actually are separated from each other, except at the tilted with the front higher by 30°), superior (or apex, by the membranous labyrinth (cochlear anterior), and posterior (or inferior), named for duct, scala media). The scala vestibuli and their orientation within the temporal bone, (2) scala tympani communicate at the apex of the the utricle, and (3) the saccule. The three semi- cochlea through a small opening called the circular ducts are in open communication with helicotrema. The scala vestibuli is in continuity the utricle via five openings. Each semicircular with the perilymphatic space of the vestibule, duct has one bulbous portion, the ampulla. The where the oval window is located, sealed with nonampullated ends of the superior and poste- the stapes foot-plate. An opening at the basal rior canals are joined together. The cochlear end of the scala tympani, sealed by a connec- duct or scala media is the portion of the mem- tive tissue membrane, is called the round win- branous labyrinth associated with the auditory dow. It should be noted that the perilymphatic system (see Figs. 16.2 and 16.3). The cochlear space is connected through the narrow cochlear duct is connected to the saccule via the ductus aqueduct at the basal end of the scala tympani reuniens. The utricular duct (from the utricle) Chapter 16 Auditory and Vestibular Systems 287 and the saccular duct (from the saccule) merge osseous labyrinth. The membranous labyrinth to form the endolymphatic duct (within the bony overlying the apical end of the receptor cells vestibular aqueduct), which conveys endolymph (cochlear duct, saccule, utricle, semicircular to the endolymphatic sac (see Fig. 16.2). The ducts, and endolymphatic duct and sac) is filled endolymphatic sac, located between layers of a with endolymph, which is actively formed in well-vascularized region of the dura mater on both the cochlear and vestibular portions of the the posterior face of the petrous bone, is where labyrinth. The receptors (hair cells) have tight endolymph is cleared from the membranous junctions along the apex that block endolymph labyrinth into the venous system and perilymph from reaching basal portions of the cells, which is drained into the subarachnoid space from the are bathed in perilymph.

Figure 16.2: The labyrinth. (A) Right labyrinth, from the front. The perilymphatic space is located between the bony labyrinth and the membranous labyrinth: it extends as the cochlear canaliculus. The endolymphatic space is located within the membranous labyrinth, which includes the three semicircular ducts, utricle, saccule, cochlear duct and endolymphatic duct and sac. (B) Cross-section through a half-turn of the cochlea. The scala vestibuli and scala tympani (containing the perilymph) are connected at the apex of the cochlea through a narrow opening called the helicotrema (not shown). 288 The Human Nervous System

Sensory Receptor Areas AUDITORY SYSTEM There are six specialized areas within the membranous labyrinth on each side that con- Ear Anatomy and Physiology tain sensory epithelial receptors (hair cells) in contact with the terminal endings of the eighth The “ear” consists of the external ear, mid- cranial nerve: three cristae ampullares (one in dle ear, and inner ear (see Fig. 16.1). the ampulla of each semicircular duct), one The external ear (auricle and external audi- macula utriculi, and one macula sacculi, all tory meatus) is separated from the middle ear innervated by vestibular neurons and the spiral by the tympanic membrane (ear drum). The organ of Corti in the cochlea, innervated by external auditory meatus functions as a sound auditory neurons. The organ of Corti is located resonator, increasing the sound pressure level within the cochlear duct (scala media) of the (usually measured in decibels) at the tympanic membranous labyrinth. membrane. The auricle and head have baffle

Figure 16.3: The organ of Corti in the middle turn of the cochlea with four rows of outer hair cells; there are three rows in the basal turn and five in the apical half-turn, reflecting the fact that the basilar membrane is wider at the apex. Inner and outer pillar cells enclose the tunnel of Corti, which contains perilymph and is traversed by cochlear nerve fibers. The pillars have fenestrated stiff processes that cover the apical surface of the hair cells. Chapter 16 Auditory and Vestibular Systems 289 and shadow effects on sound waves that aid in that the decibel scale is logarithmic, so a 10-dB sound localization. increase in intensity has 100 times more The middle ear is an air-filled space energy. Zero decibels is the average threshold bounded laterally by the tympanic membrane for human hearing and 140 dB is the threshold and medially by the inner ear. A chain of three for pain. Normal conversational speech is ear ossicles traverses this space: the malleus, 40–60 dB. Frequencies between 50 and 20,000 which is attached to the tympanic membrane; Hz can be detected as sound. The frequencies the incus in an intermediate position; and the perceived with optimum acuity by most sub- stapes, whose foot-plate is inserted into the jects fall between 2000 and 5000 Hz. Airborne oval window. Two small skeletal muscles are in vibrations (sound waves) pass through the the middle ear: the tensor tympani inserted into external auditory meatus and set the tympanic the malleus and the stapedius, which is membrane vibrating (air conduction). Some attached to the stapes. The latter is responsible vibrations can bypass the ear ossicles and reach for the stapedial or acoustic reflex. The middle the perilymph directly through bone (bone con- ear functions as a mismatch transformer duction). The oscillations of the stapes foot- increasing the sound pressure level at the oval plate in the oval window produce pressure window as compared to that at the tympanic waves within the perilymph of the scala membrane. This is necessary because of the vestibuli that travel variable distances, depend- increased impedance of the cochlear fluids ing on frequency, up the 21/2 turns (approxi- (perilymph) as compared to air in the external mately 35 mm) of cochlea (see Fig. 16.2). auditory canal. A greater amount of pressure is High-frequency waves press down maximally necessary to vibrate the higher-impedance on the basilar membrane near the base of the fluid. If the tympanic membrane and ossicular cochlea, whereas lower-frequency waves chain were not present, sound waves would hit impinge progressively toward the apex. Thus, the oval and round windows simultaneously, each section of the basilar membrane has a canceling out their vibrations. Also, there characteristic tuning curve for which it is most would be insufficient energy to adequately sensitive (this is found in all levels of the audi- stimulate the inner ear. This is important clini- tory system). The waves cause downward, fol- cally in patients with chronic middle ear disease. lowed by upward, deflections of the basilar The narrow auditory (eustachian) tube con- membrane. To allow propagation of the pres- nects the middle ear with the nasopharynx. It is sure (traveling) waves in the inner ear, the mem- important for equalizing air pressure on the two brane of the round window bulges outward and sides of the eardrum. inward in synchrony (equal and opposite) with The inner ear is the cochlea (spiral shell). movement of the stapes. This is necessary Traveling waves within the perilymph, gener- because perilymphatic fluid is incompressible ated by movement of the stapes in the oval within the bony cochlea; traveling waves would window, displace the basilar membrane together not be generated if there were no compensatory with the organ of Corti containing the special- movements at the round window. ized auditory receptors—the hair cells. Cochlear Duct (Scala Media) Sound Reception The vestibular (Reissner’s) membrane forms Vibrations can be perceived as sounds. the roof of the scala media and separates it from Sound travels in the form of waves with a char- the scala vestibuli. This membrane is a single acteristic frequency, measured in hertz (Hz) layer of cells that runs obliquely from the upper (cycles per second) and amplitude, measured in limit of the spiral ligament (attached to the lat- sound pressure level (decibels [dB]). Frequency eral wall of the cochlea) to the limbus on the is a measure of pitch, and amplitude is a meas- osseous spiral lamina. The basilar membrane, ure of loudness. It is important to remember bordering the scala tympani, forms the floor of 290 The Human Nervous System the scala media; it is suspended between the outer (see Figs. 16.3 to 16.5). There is a single osseous spiral lamina and the lower extent of row of inner hair cells and between three (at the spiral ligament. The spiral organ of Corti, the base) and five (at the apex where the basi- containing the auditory receptors, rests on the lar membrane is wider) rows of outer hair cells basilar membrane. The lateral wall of the scala for a total of about 15,500. The inner and outer media is formed by the stria vascularis on the hair cells are separated by the tunnel of Corti. spiral ligament. It contains specialized cells for Both have efferent as well as afferent nerve active transport of ions to maintain the +80-mV endings. However, direct efferent innervation endolymphatic potential; thus, the current nec- goes only to the outer hair cells. Efferents to the essary for hair cell depolarization. inner hair cells synapse on the afferent fibers. Roughly 95% of the bipolar cells in the spiral The Organ of Corti and Auditory Hair Cells ganglion supply afferent innervation selec- The spiral organ of Corti has two types of tively to the inner hair cells. Each innervates hair cell: flask-shaped inner and cylindrical only 1 inner hair cell, which, in contrast, is

Figure 16.4: The hair cells of the organ of Corti. The axis of sensitivity of a cochlear hair cell is bending of the stereocilia in the direction of the basal body. Flask-shaped inner hair cells receive afferent innervation from 95% of the cochlear nerve fibers. Cylindrical outer hair cells have a scant afferent innervation, but a greater efferent innervation from neurons in the brainstem. They change the characteristics of the basilar membrane. Efferents to the inner hair cells synapse on the afferent fibers. Inner hair cells are responsible for all auditory sensations. Chapter 16 Auditory and Vestibular Systems 291

Figure 16.5: Drawing of the organ of Corti viewed from the outer rim of the tectorial membrane. Stereocilia extend from the apical side of hair cells through the stiff reticular membrane, composed of processes (1, 2, 3) of phalangeal cells together with the head plates of inner and outer pillar cells, and are embedded in the tectorial membrane. (From Rivera-Dominquez, et al, 1974.)

connected to axons of as many as 10 ganglion ocilia protrude through a rigid reticular lamina, cells. Auditory perception is attributed exclu- with their distal tips embedded in the gelati- sively to this type cell. The outer hair cells are nous tectorial membrane (see Figs. 16.3 and contractile, and by changing length, they alter 16.5). There are as many as several hundred the tension on the basilar membrane, thereby stereocilia on each of the 3500 inner hair cells maximizing the responsiveness of the inner and 12,000 outer hair cells in the human organ hair cells to the appropriate frequencies. of Corti (see Fig. 16.5). With displacement of The distinctive feature of the hair cells is the basilar membrane, a shearing force is pro- several rows of stereocilia (actually microvilli) duced with an accompanying bending of the called a hair bundle extending from the apical stereocilia that results because the tectorial surface (see Fig. 16.4 and 16.5). The stere- membrane has a different fulcrum and does not ocilia become progressively longer toward the move to the same degree as the hair cells. The outer end of the cell. The basal body, the base hair cells are polarized, with depolarization of a degenerated kinocilium, is located adjacent occurring when the cilia are bent along the axis to the tallest row of stereocilia. All hair cells are of sensitivity (i.e., toward the basal body) (see polarized with the basal body located at the Fig. 16.4). The hair cells act both as transduc- edge furthest from the modiolus. The stere- ers (converting mechanical energy into electro- 292 The Human Nervous System chemical energy) and biologic amplifiers. The cochlear nuclear complex (dorsal, posteroven- organ of Corti is a frequency analyzer, with the tral, and anteroventral cochlear nuclei) located highest pitches mediated at the base of the coil, on the posterolateral surface of the upper the lowest at the apex, and intermediate pitches medulla (see Fig. 13.11). Each subdivision is in an organized topographic pattern between tonotopically organized (has a frequency spe- the highest and the lowest (tonotopic organiza- cific tuning curve) and gives rise to at least par- tion). In addition to different frequencies caus- tially separate second-order ascending fiber ing maximum displacement of the basilar systems. Most fibers decussate in the caudal membrane at given points, the hair cells them- pons and ascend in the contralateral lateral selves have variable mechanical and electrical lemniscus; a smaller number ascend ipsilater- properties: (1) the length of the hair bundle ally. The great majority of second-order fibers increases from base to apex of the cochlea, just arise from the anteroventral cochlear nuclei and as piano strings become longer toward the low- cross to the opposite side in the rather conspic- frequency end, and (2) the membrane potential uous trapezoid body in the anterior pontine resonates at different frequencies along the tegmentum; a large number terminate in the length of the organ of Corti. Perception of superior olivary complex on both sides. Fibers loudness is related to the amplitude of the dis- from the posteroventral and dorsal cochlear placement of the basilar membrane: Louder nuclei decussate more posteriorly in the pon- sounds activate more hair cells. tine tegmentum as the intermediate and dorsal Hair cells at rest have a basal rate of electri- acoustic striae, respectively. Fibers in the for- cal activity or steady-state potential. Potas- mer partially terminate in parts of the superior sium-gated ion channels at the tips of the olivary complex “periolivary nuclei” that give stereocilia are opened or closed by tip links, rise to the olivocochlear bundle, which which connect adjoining stereocilia. At rest, synapses on the receptor cells; fibers of the dorsome channels are open and others closed. sal acoustic stria mainly bypass the superior With displacement of the stereocilia toward the olivary complex. basal body, gates are preferentially opened. Although potassium conductance usually has a Superior Olivary Complex and Localization hyperpolarizing effect, because endolymph, of Sound. The major nuclei of the superior oli- unlike other extracellular fluids, has a high K+ vary complex are the lateral (SOL) and medial concentration, K+ enters the cell, causing depo- (SOM) superior olivary nuclei. Other compo- larization (the generator potential). This opens nents in humans include several periolivary cell voltage-gated calcium channels; entry of Ca2+ groups. In order to localize sounds, cues arriv- triggers transmitter release at the base of the ing at the two ears must be compared. Binaural hair cell, where synaptic contact is made with interaction first occurs at the level of the supe- first-order nerve endings. Thus, each hair cell is rior olivary complex. There are different mech- a mechanoreceptor that transduces mechanical anisms for localizing high- and low-frequency energy of the sound waves into graded poten- sounds. At high frequencies, the head casts a tials, which in turn stimulate the nerve endings sound shadow, producing differences in the of the bipolar cells of the spiral ganglion of the intensity of signals reaching the two ears. This cochlear nerve. disparity is analyzed in the SOL; the anteroventral cochlear nucleus excites the ipsilateral Ascending Pathways (see Fig. 16.6) SOL and inhibits the contralateral SOL via The approximately 30,000 neurons of the fibers that cross in the trapezoid body. At low cochlear nerve have (1) distal branches that ter- frequencies (below about 3000 Hz), the SOM minate on both inner and outer hair cells, but compares time and phase differences of signals primarily the former, and (2) proximal arriving from the anteroventral cochlear nuclei branches that synapse on many neurons in the to localize a sound source. In addition to a Chapter 16 Auditory and Vestibular Systems 293 sound arriving at the two ears at slightly differ- internal capsule (sublenticular portion) and ent times, fibers from the anteroventral continue as the auditory radiations to the trans- cochlear nucleus to the ipsilateral SOM travel a verse gyri of Heschl (areas 41 and 42) on the shorter distance than do the fibers terminating floor of the lateral fissure in the temporal lobe on the same nucleus from the opposite side. (see Fig. 25.5). Data suggest that the cortex involved in auditory processing includes the Higher Levels of the Auditory Pathway. entire superior temporal gyrus as well as por- Several nuclei are intercalated within the tions of the parietal, prefrontal, and limbic ascending auditory pathways to the auditory lobes. The two hemispheres are interconnected cortex; these include the superior olivary com- via the corpus callosum. plex, nuclei of the lateral lemniscus, inferior The complexity of the auditory cortex is colliculus, and medial geniculate body. Com- revealed in studies indicating that it consists of missural fibers interconnect the nuclei of the a tonotopically organized primary cortex (area lateral lemniscus and inferior colliculi. The 41) in the temporal lobe and at least five other portion of the lateral lemniscus between the tonotopically organized auditory cortical areas inferior colliculus and the medial geniculate in the immediate vicinity of the primary audi- body is called the brachium of the inferior col- tory cortex. liculus. Fibers taking origin from the medial Two functionally significant features of the geniculate body enter the posterior limb of the ascending pathways should be emphasized:

Figure 16.6: Diagram of the auditory pathways from one cochlea. 294 The Human Nervous System

(1) the processing centers at each level have a region at the lateral margin of the cerebrum. multiple tonotopic organization and (2) the out- Evidence from animal studies indicates that the put from each ear is conveyed bilaterally, i.e., auditory cortex is not essential for discrimina- via auditory pathways of both sides, with a tion of intensities or frequencies, but is neces- stronger contralateral projection. sary for differentiation of more complex functions such as patterns or rhythms. Descending Pathways An irritative lesion of the organ of Corti or Descending fibers, which accompany the the cochlear nerve can result in tinnitus (the ascending fibers, project downstream from subjective hearing of hissing, roaring, buzzing, auditory cortex and the other nuclei of the audi- and humming sounds). This can occur in tory pathway. They have a role in processing acoustic neuromas of n.VIII in the cerebello- ascending information, enhance signals, and pontine angle. Tinnitus can be followed by suppress noise. This possibly is related to local- nerve deafness as the irritative lesion expands izing functions of the superior olivary complex, and all cochlear nerve fibers are interrupted. enabling a listener to focus on a particular Nerve deafness is also associated with occlu- speaker and inhibit other voices. Fibers from sion of the internal auditory artery, aging, and periolivary portions of the superior olivary Meniere’s disease (see later). complex are integrated into a feedback system Several commonly used drugs are ototoxic. that courses as crossed and uncrossed projec- The most common drugs to cause irreversible tions (called the olivocochlear or cochlear SNHL are the aminoglycosides, such as gen- efferent bundle) via the vestibulocochlear tamicin. Early cessation of treatment will allow nerve, before terminating at the base of the reversal of the damage. This class of antibiotic outer hair cells and at the distal end of afferent causes direct hair cell toxicity to both the audi- fibers that innervate inner hair cells, in the tory and vestibular hair cells. This is usually an organ of Corti. The inhibitory influences con- unwanted side effect of aminoglycoside use, veyed by these efferents act to suppress the but in patients with severe vertigo, it is used to activity of the afferent fibers of the cochlear alleviate symptoms. Other common agents that nerve and to fine-tune the basilar membrane cause ototoxicity include the loop diuretics, through action of the outer hair cells. which cause both permanent and reversible losses, and salicylates, including aspirin, which Functional and Clinical Considerations cause a reversible hearing loss. Cisplatin, a Deafness restricted to one ear is usually common antineoplastic agent, causes a perma- associated with damage to the cochlear nerve nent hearing loss. An early symptom of ototox- or the cochlea itself (sensorineural hearing loss icity from all of these agents is often tinnitus. [SNHL]) or the conducting apparatus within Damage to the eardrum and the ossicles of the middle ear (conductive hearing loss) on the the middle ear is usually followed by a partial side of the deafness. Unilateral lesions of the deafness. This middle-ear deafness (conduction ascending auditory pathways above the level of deafness in otosclerosis) is accompanied by a the cochlear nuclei produce only minor percep- partial loss in the perception of low-pitched tual impairments because of the strong bilater- sounds and a mild loss in the entire auditory ality of the pathway. Evidence indicates that range. unilateral lesions do cause impairments in Presbycusis is the gradual impairment of localizing ability, which also is severely disability to perceive or discriminate sounds in old turbed by lesions involving the trapezoid body. age. This increasing difficulty in hearing high- Bilateral lesions of the central auditory path- pitched sound is associated with degeneration way are rare because the tracts and nuclei are of the hair cells near the base of the cochlear far apart, near the lateral margin of the brain- coil. Conduction deafness can occur as a con- stem; the auditory cortex similarly occupies a sequence of middle-ear disease such as otitis Chapter 16 Auditory and Vestibular Systems 295 media. A tuning-fork test, the Rinne test, can be would be shown on a meter that measures deci- used to distinguish bone-conduction deafness bels. When the reflex is deactivated, hyperacu- from air-conduction deafness. The base of a sis occurs and loud sounds appear louder. This vibrating tuning fork is applied to the mastoid phenomenon occurs in facial nerve palsies as a process of the skull and sound is heard by bone result of paralysis of the stapedius muscle conduction; at the moment the sound ceases, innervated by this nerve (Chap. 14). Although the vibrating fork is placed near the external the tensor tympani also contracts and increases auditory meatus. A subject with normal hearing tension on the eardrum, lesions of the trigemi- will hear the vibrations by air conduction after nal nerve do not elicit hyperacusis. Hyperacu- the bone-conduction hearing ceases. In middle- sis is defined as an increased sensitivity to ear deafness, the vibrating fork cannot be heard sound. A small number of people with other- by air conduction. In partial nerve deafness, wise normal hearing, including the middle-ear air-conduction hearing is better than bone-con- reflex, experience hyperacusis to sounds of all duction hearing, although both are diminished. intensities, particularly high frequencies. This can be quite disruptive. It sometimes accompa- Cochlear Implants. Implantation of multiple- nies migraine headaches. The cochlear nerve array electrodes into the cochlea in cases with acts as the sensory limb of the reflex arc. The nonfunctional hair cells has become relatively cochlear nuclei send fibers to motor neurons in commonplace. The electrodes, which electri- the region of the superior olivary complex adja- cally stimulate the fibers of the eighth nerve, cent to the facial nucleus that project via the receive coded signals that are transmitted tran- facial nerve to the stapedius. scutaneously from a speech processor con- Other auditory reflexes involve various nected to a small microphone positioned brainstem nuclei and their projections to the behind the ear. spinal cord, especially to the motor centers innervating the neck musculature, which Brainstem Auditory Evoked Potentials. rotates the head in the direction of the source of Evoked potentials are employed for diagnostic the sound. purposes. They are recorded from electrodes applied to the scalp utilizing a computer to average multiple responses. Potentials from the VESTIBULAR SYSTEM various portions of the auditory pathway have different latencies and characteristics of wave- The purpose of the vestibular system is to form. Abnormalities in the potentials can be signal changes in the motion of the head used to differentiate between conductive and (kinetic) and in the position of the head with sensorineural hearing loss and to aid in deter- respect to gravity (static). The information mining the presence and location of injury to from the periphery required by the nervous sys- the auditory pathways, as in multiple sclerosis, tem to perform these roles is obtained from strokes, tumors, and so forth. three afferent sources: the eyes, general proprioceptive receptors throughout the body, and the Middle-Ear Reflex. The middle-ear reflex vestibular receptors in the inner ear. These (contraction of the stapedius and tensor tym- three afferent sources are integrated into three pani muscles) is activated by loud sounds systems (visual, proprioceptive and vestibular above about 80 dB. This dampens the ampli- systems) known as the equilibrial triad. tude of movement of the ear ossicles and of the The vestibular system is a special proprio- oscillations of the stapes in the oval window, ceptive system that functions to maintain equi- thus protecting the organ of Corti from dam- librium, to direct the gaze of the eyes, and to age. Under normal physiological conditions, preserve a constant plane of vision (head posi- loud sounds are perceived as less intense than tion), primarily by modifying muscle tone. 296 The Human Nervous System

The Utricle, Saccule, Cristae Ampullares, osseous labyrinth (continuous with the scala and Vestibular Hair Cells vestibuli and scala tympani of the cochlea). The many stereocilia and single kinocilium The receptor end organs in each ear of the of a hair cell in each crista are embedded in a vestibular system include the three cristae gelatinous matrix (cupula) that abuts against ampullares (one crista located in the ampulla of the roof of the ampulla; the kinocilium of each each semicircular duct) and the maculae of the hair cell is located on one side of all stereocilia utricle and saccule (see Fig. 16.7). The three (see Fig. 16.8). The kinocilium is a true cilium semicircular ducts, oriented at right angles to and the stereocilia, as in the organ of Corti, are each other, represent the three dimensions of microvilli. Each vestibular hair cell is depolar- space. The membranous labyrinths of the semi- ized when the stereocilia bend in the direction circular canals, utricle and saccule, are filled of the kinocilium and is hyperpolarized when with endolymph (continuous with the cochlear deflected in the opposite direction; evidence duct) and surrounded by perilymph in the indicates that the axis of sensitivity is retained

Figure 16.7: (A) The right membranous labyrinth as viewed from the front. Neuroepithelial areas (in black) include a crista ampullaris in the ampulla of each semicircular duct, the macula of the utricle, the macula of the saccule, and the spiral organ of Corti of the cochlear duct. (B) The crista ampullaris in a semicircular duct. Stereocilia are embedded in the gelatinous cupula, which extends to the wall of the ampulla. (C) The macula. Stereocilia and the kinocilium of hair cells protrude through the gelatinous cover; their tips contact the otoliths on the surface. Chapter 16 Auditory and Vestibular Systems 297

Figure 16.8: Schematic drawing of type I and type II vestibular hair cells in the macula (utricle and saccule) and in the crista ampullaris of each semicircular canal. Vestibular receptors have a true kinocilium; bending of the hair bundle toward the kinocilium elicits depolarization, whereas bending in the opposite direction produces hyperpolarization. The type I cell is enveloped by a primary afferent nerve fiber, and as in the cochlea, efferents from the brainstem form axo-axonal synapses on the afferent fibers. Vestibular efferents terminate directly on type II hair cells. The maculae have a central band called the striola. The axis of sensitivity is toward the striola in the utricle and away from it in the saccule. 298 The Human Nervous System in the absence of kinocilia. The mechanisms of organs, are really linear accelerometers. The transduction are the same as for the auditory saccular macula responds to vertically directed receptors. All hair cells in a crista are polarized acceleratory and deceleratory linear displace- in the same direction. The cristae ampullares ments and gravity (e.g., movements up and respond to angular movements and only to down in an elevator). The utricular macula acceleration and deceleration, not constant responds to horizontally directed forces and movement of the head. Thus, these receptors gravity. act as angular accelerometers that respond to The role of the vestibular receptors in the the twists and turns of the head. orientation of the head and body in space is The movement of endolymph within the expressed through muscle actions that coordi- semicircular ducts as the head turns and rotates nate eye reflexes, head position and body results in the bending of the cupula and cilia. movements. These specialized proprioceptors Semicircular ducts of the two sides operate in tend to (1) reinforce the tonic activity of mus- pairs: the two horizontal ducts are yoked, as are cles while in a stationary position (e.g., main- the anterior duct of one side with the posterior tain balance while standing in a moving duct of the opposite side. The kinocilia of the vehicle) and (2) trigger muscle reflexes in horizontal ducts, in contrast to those of the other response to changes in position of the head, ducts, face the utricle (i.e., toward the midline). body, and extremities (e.g., sustain balance Thus, rotation to the left causes (1) deflection while walking a tightrope). of the stereocilia in the left horizontal duct toward the kinocilium and in the right duct away Input to the Vestibular Nuclei from the kinocilium, (2) depolarization of hair (see Figs. 16.9 and 18.5) cells in the crista ampullaris of the left horizon- The sensory neurons of the vestibular nerve tal duct and hyperpolarization in the right crista, (cell bodies in the vestibular ganglion) are and (3) increased frequency of impulses in the bipolar with distal branches that terminate on left vestibular nerve leading from the horizontal the hair cells of the vestibular receptors (macu- duct and decreased frequency in the right nerve. lae and cristae ampullares). Most of the cen- The vestibular nerve has a spontaneous firing trally directed axons terminate ipsilaterally rate of about 100 impulses per second. within the brainstem in precise synaptic pat- The macula of the saccule is oriented with terns within each of the four vestibular nuclei its long axis essentially in a vertical plane, and (superior, lateral, medial, and inferior). In gen- the macula of the utricle in a horizontal plane. eral, the fibers originating from the cristae The stereocilia and kinocilium of each hair cell, ampullares end in the medial and superior similar to those in the crista ampullares, are nuclei; the fibers originating in the maculae of embedded in a gelatinous matrix (see Fig. the utricle and saccule terminate primarily in 16.7). However, in the maculae, there is a layer the lateral, inferior, and medial vestibular of calcareous crystals (otoliths) that amplify nuclei. Other fibers of the vestibular nerve the force caused by deflection of the stere- course through the juxtarestiform body (medial ocilia. Additionally, the stereocilia are polar- part of the inferior cerebellar peduncle; see Fig. ized in relation to a curved band, the striola, 18.5) and end directly in the ipsilateral cerebel- which passes through the central portion of the lar cortex, chiefly in the flocculonodular lobe, maculae. In the utricle, all kinocilia face the which is referred to as the vestibulocerebellum. striola, whereas in the saccule, they face in the In addition, this cortex and the fastigial nuclei opposite direction (away from the striola). of the cerebellum send crossed and uncrossed Thus, unlike the crista ampullares, individual fibers to the vestibular nuclei. In summary, the receptors contain some hair cells that are depo- vestibular nuclei receive their main input both larized at the same time others are hyperpolar- from the vestibular receptors and the cerebel- ized. The two maculae, also called otolith lum. In addition, the vestibular nuclei have Chapter 16 Auditory and Vestibular Systems 299

Figure 16.9: Principal vestibular pathways in the brainstem and spinal cord. Interconnections between the vestibular system and the vestibulocerebellum are illustrated in Fig. 18.5. The inset shows a vestibular hair cell whose axis of sensitivity is in the direction of the kinocilium.

reciprocal connections with the flocculonodu- (see Chap. 23) via a relay in the ventral poste- lar lobe and nuclei fastigii of the cerebellum. rior inferior thalamic nucleus. Output From the Vestibular Nuclei Postural Pathways The influences from the vestibular nuclei are The (lateral) vestibulospinal tract, originat- projected (1) to the spinal cord via the (lateral) ing from the lateral vestibular nucleus, is an vestibulospinal tract and medial vestibulospinal uncrossed, somatotopically organized bundle tract (within medial longitudinal fasciculus of fibers terminating all levels of the spinal [MLF]) (see Fig. 16.9), (2) to the cerebellum cord mainly in laminae VII and VIII (see Figs. via fibers in the juxtarestiform body (see Fig. 7.5 and 16.9). It conveys excitatory influences 18.5), (3) to the brainstem primarily via the for extensor muscle tone and extensor reflexes. MLF (vestibulomesencephalic fibers), and (4) The much smaller medial vestibulospinal tract, to the postcentral gyrus between areas 2 and 5 originating from the medial vestibular nucleus, 300 The Human Nervous System is primarily an uncrossed fascicle that descends MLF with the PPRF (see Fig. 16.10). Through in the MLF and terminates mainly at cervical these, the PPRF is associated with lateral gaze levels. It participates in coordination of head movements and horizontal saccades. position in equilibratory responses and with Vestibular influences are conveyed cephali- eye movements to maintain fixation. These cally via relays in the ventral posterior inferior descending vestibular tracts act mainly through thalamic nucleus (part of the ventral posterior spinal interneurons on both alpha and gamma nucleus) that project to the postcentral gyrus, as motoneurons that go to axial and proximal limb noted previously. This pathway is involved in muscles. Their influence in concert with local perception of subjective sensations (e.g., dizzi- myotatic reflexes is to maintain the tonus of the ness) associated with the vestibular system. extensor muscles of the trunk (back musculature) and the limbs. These neural activities are Vestibular Tests and Disorders critical for the support of the body against Nystagmus. Nystagmus refers to involun- gravity (i.e., for the maintenance of upright tary rhythmic movements of the eyes with a posture). rapid movement in one direction (called a saccade) followed by a slow movement in the Vestibuloocular Pathways opposite direction. It is related to an imbalance One of the most important tasks of the of synchronized impulses from vestibular vestibular system is its role in influencing the sources. Nystagmus can be elicited and used in conjugate (i.e., coupled) movements of the tests of vestibular function; when it occurs eyes. These conjugate movements are con- spontaneously, it can be a symptom of a lesion. trolled by inputs from many sources (e.g., from Nystagmus in the normal individual has the areas 8, 18, and 19 of the cerebral cortex) and following basis. As the head and body pivot by means of inputs to the vestibular system. and circle, the eyes attempt to fixate on an The paramedian pontine reticular formation object in space (slow component); as the head (PPRF; also called pontine gaze center), and body continue to circle, the eyes snap located medially in the reticular formation, and quickly in the direction in which the head is its rostral continuation in the midbrain is a circling (fast or quick component). The action critical staging region in the central control of is similar to what happens when watching tele- eye movements. It acts as a nuclear processing graph poles from a moving train (the fast com- complex and contains a variety of cell types ponent is in the direction in which the train is whose activity determines the form of many moving). These eye movements repeat eye movements. Input to neuronal pools within throughout the duration of the circling. By con- the PPRF is derived from the cerebral cortex, vention, nystagmus is named by the direction superior colliculus, cerebellum, auditory and of the fast saccade component. Horizontal nys- vestibular systems, and the spinal cord. Output tagmus is the commonest form. Vertical and from the PPRF is conveyed by circuits utilizing rotatory nystagmus occur less frequently. the MLF and the reticular formation and termi- Nystagmus can occur following irritative or nating in the motor nuclei of cranial nerves III, destructive lesions of a vestibular end organ, IV, and VI, which innervate the extraocular vestibular nerve, vestibular pathways, brain- muscles. The vestibulomesencephalic circuit stem or cerebellum. Certain toxic substances for conjugate eye movements comprises the can also cause nystagmus. vestibular nuclei to PPRF to the nucleus of n. Sudden recurrent attacks of vertigo and VI (in lower pons) and via MLF to the nuclei of nystagmus occur in Meniere’s disease. This is n.III and n.IV (in the midbrain). The abducens usually accompanied by tinnitus, unilateral and oculomotor nuclei also are reciprocally deafness, and varying degrees of nausea and interconnected directly via fibers that travel in vomiting. The condition is thought to be a con- the MLF and by way of linkages through the sequence of increased pressure and dilatation Chapter 16 Auditory and Vestibular Systems 301

Figure 16.10: Conjugate eye movements associated with the horizontal semicircular ducts and ampullae. Rotational acceleration of the head in a clockwise direction to the right (outlined arrows outside the ampullares) results in a relative movement of endolymph in the paired semicircular ducts to the left (solid arrows in the ducts). Movement of the endolymph toward the utricle results in excitatory activity (+) in the hair cells of the right ampulla and away from the utricle results in inhibitory activity (–) in the hair cells in the left ampulla. These activities result in excitation (+) and inhibition (–) in the medial and superior vestibular nuclei and fibers of the MLF; this produces excitatory and inhibitory influences in appropriate motoneurons in the abducens (lateral rectus muscles) and oculomotor (medial rectus muscles) nuclei to elicit conjugate eye movement to the left (solid arrow). 302 The Human Nervous System of the membranous labyrinth resulting from response to an excess of accelerations and edema. decelerations as monitored by the vestibular receptors and projected to the brain. Deaf Rotation Test. The paired horizontal semi- mutes, who lack receptors in the membranous circular canals can be tested by placing the sub- labyrinths, do not experience motion sickness. ject in a rotating (Bárány) chair and tilting the Drugs such as Dramamine raise the threshold head forward by 30° to bring the horizontal of vestibular stimulation and, thereby, amelio- canals parallel to the ground. The chair is rate the symptoms of motion sickness. Four out quickly rotated 10–12 turns before being of every 10 astronauts experience motion sick- abruptly stopped. The endolymph continues to ness during space missions. This affliction is “flow” in the same direction, deflecting the thought to be related to a discordance of signals crista ampullaris of each horizontal canal. A monitored by the eyes, proprioceptors in the whirling sensation follows. The impulses from body, and the vestibular receptors in the head the vestibular source stimulate the eye move- and projected to the brain during the novel ments, and the visual impulses from the eyes, conditions of weightlessness. in turn, create the conscious spinning sensation Central influences are conveyed via vestibu- (vertigo). During the spin of the chair to the lar efferent fibers from the brainstem, which right, the fast component (saccade) in the nor- pass through the vestibular nerve and terminate mal individual is to the right. Immediately after on the hair cells of the vestibular end organs. the spin is stopped, each saccade (postrotatory Vestibular efferent fibers probably exert nystagmus) is reversed and is now directed to inhibitory effects, which ameliorate influences the left (called nystagmus to the left). By plac- that might result in motion sickness and nys- ing the head in appropriate planes, the other tagmus. pairs of semicircular canals can be tested. The In a general way, the vestibular system helps right anterior and the left posterior semicircular us appreciate a sense of motion and assists in canals are paired, as are the right posterior and keeping our balance. Perhaps its finest expres- the left anterior semicircular canals. sion is in such maneuvers as gymnastics, but even when running up a spiral staircase the Caloric or Thermal Test. The semicircular vestibular system is fully engaged in its canals can be tested calorically by irrigating the remarkable coordination of the movements of external auditory meatus with warm (or cold) the eyes, head, trunk, and extremities. water. This elicits convection currents in the endolymph, deflecting the crista ampullaris. Each side of the vestibular apparatus can be SUGGESTED READINGS tested separately. For example, each horizontal semicircular canal is examined by having the Fernandez C, Lysakowski A, Goldberg JM. Hair-cell patient sit with the head tilted backward about counts and afferent innervation patterns in the 60°, bringing the horizontal semicircular canal cristae ampullares of the squirrel monkey with a to the vertical plane. Normally, the nystagmus is comparison to the chinchilla. J. Neurophysiol. to the tested side after warm water is used (and 1995;73:1253–1269. to the opposite side after cold water is used). Goldberg JM. Afferent diversity and the organization of central vestibular pathways. Exp. Brain Res. 2000;130:277–297. Dizziness, feeling of Motion Sickness. Goldberg JM, Brichta AM. Evolutionary trends in lightheadedness, headache, nausea, and vomit- the organization of the vertebrate crista ampul- ing are symptoms associated with motion sick- laris. Otolaryngol. Head Neck Surg. 1998;119: ness (seasickness and airsickness). Motion 165–171. sickness, whether on the sea, in the air, or on Griffiths TD. Central auditory pathologies. Br. Med. the ground (highway), is apparently the Bull. 2002;63:107–120. Chapter 16 Auditory and Vestibular Systems 303

Griffiths TD, Bates D, Rees A, Witton C, Gholkar A, Moore JK. Maturation of human auditory cortex: Green GG. Sound movement detection deficit implications for speech perception. Ann. Otol. due to a brainstem lesion. J. Neurol. Neurosurg. Rhinol. Laryngol. 2002;189(Suppl.):7–10. Psychiatry 1997;62:522–526. Poremba A, Saunders RC, Crane AM, Cook M, Griffiths TD, Green GG, Rees A, Rees G. Human Sokoloff L, Mishkin M. Functional mapping of brain areas involved in the analysis of auditory the primate auditory system. Science 2003;299: movement. Hum. Brain Mapping 2000;9:72–80. 568–572. Highstein SM, Fay RR, Popper AN, eds. The Vestibu- Warren JD, Zielinski BA, Green GG, Rauschecker lar System. New York: Springer-Verlag; 2004. JP, Griffiths TD. Perception of sound-source Hudspeth AJ. How the ear’s works work: mechano- motion by the human brain. Neuron 2002;34: electrical transduction and amplification by hair 139–148. cells of the internal ear. Harvey Lect. 2001;97: Rivera-Dominguez M, Agate FJ Jr, Noback CR. 41–54. Scanning electron microscope observation of the Hudspeth AJ, Logothetis NK. Sensory systems. organ of Corti of the rhesus monkey. Brain Res. Curr. Opin. Neurobiol. 2000;10:631–641. 1974;65:159–164. Jones EG. Chemically defined parallel pathways in Wong D, Pisoni DB, Learn J, Gandour JT, the monkey auditory system. Ann. NY Acad. Sci. Miyamoto RT, Hutchins GD. PET imaging of 2003;999:218–233. differential cortical activation by monaural Minor LB, Goldberg JM. Vestibular-nerve inputs to speech and nonspeech stimuli. Hear. Res. 2002; the vestibulo-ocular reflex: a functional-ablation 166:9–23. study in the squirrel monkey. J. Neurosci. 1991; Zhang LI, Tan AY, Schreiner CE, Merzenich MM. 11:1636–1648. Topography and synaptic shaping of direction Moore JK. Organization of the human superior olivary selectivity in primary auditory cortex. Nature complex. Microsc. Res. Tech. 2000;51:403–412. 2003;424:201–205. 17 Lesions of the Brainstem

General Statement Blood Supply of the Brainstem Medial Zone of the Medulla Posterolateral Medulla Region of the Cerebellopontine Angle (CPA Syndrome) Medial and Basal Portion of the Caudal Pons Medial Longitudinal Fasciculus Lateral Half of the Midpons Basal Region of the Midbrain (Weber’s Syndrome) Upper Midbrain Tegmentum (Benedikt’s Syndrome) Lesions of Both Superior Colliculi (Parinaud’s Syndrome)

The effects of a lesion depend on the III and IV; pons, V; pons–medulla junction, VI, anatomic and physiologic roles of the neurons VII, VIII; medulla, IX, X, XI, XII; and one and tracts damaged. In general, tracts passing from the cervical spinal cord, spinal XI. They through or commencing within the brainstem express their roles on the same side of the body, are oriented in a plane parallel to the long axis with the exception of the ipsilateral trochlear of the brainstem; long tract signs alone are of nerve, which decussates within the substance limited value in determining the level of injury. of the midbrain. Thus, depending on location, a Examples are the spinothalamic tract, medial unilateral lesion can result in signs on the lemniscus, and pyramidal tract. Cranial nerves, opposite side of the body (lesion of a pathway) however, course in a plane perpendicular to the and the same side of the head (lesion of one or long axis. For this reason, they are helpful in more cranial nerves). localizing the level of a lesion, and together Depending on the level, a unilateral lesion with long tract signs, the precise site of a lesion of the brainstem can result in (1) contralateral can be determined. Thus, these orientations, loss of position and vibratory sense (medial longitudinal and transverse, should be kept in lemniscus in medulla or pons), (2) contralateral mind in the following account (see Figs. 13.7 hemiplegia (corticospinal tract in medulla, to 13.16, 14.2, and 14.3). pons, or midbrain), and (3) ipsilateral lower- motoneuron paralysis of the tongue (cranial nerve XII, medulla), lateral rectus (VI, pons– GENERAL STATEMENT medulla junction), and the other extraocular muscles, not including the superior oblique, The long ascending (sensory) and descend- together with the elevator of the eyelid (III, ing (motor) pathways are generally involved midbrain). with sensory and motor expressions of the A unilateral lesion in the lateral medulla opposite side of the body. Ten pairs of cranial can result in (1) contralateral loss of pain and nerves emerge from the brainstem: midbrain, temperature from the body (lateral spinothala-

305 306 The Human Nervous System mic tract), (2) ipsilateral loss of pain and tem- proximity to the descending corticospinal tract. perature from the face (spinal tract and nucleus Injury to one of these nerves and the corti- of n.V), (3) ipsilateral Horner’s syndrome (see cospinal tract results in an alternating hemiple- later, descending sympathetic fibers), (4) nys- gia—the lesion to the nerve produces a lower- tagmus (vestibular nuclei; Chap. 16), and (5) motoneuron (LMN) paralysis on the same side unsteady ipsilateral extremities (input to cere- of the head, and the lesion to the corticospinal bellum; Chap. 18). The combination of the loss tract produces an upper-motoneuron (UMN) of pain and temperature on the ipsilateral side paralysis on the opposite side of the body of the head and the contralateral side of the (because the lesion is rostral to the level of the body is called alternating hemianesthesia. tract’s decussation). A partial paralysis of vol- Lesions of the following pathways within untary muscles innervated by lower motoneu- the brainstem result in signs on the opposite rons is known as a paresis or palsy and that of side of the body and occiput because the tracts muscles supplied by motoneurons of the bulb are crossed: spinothalamic (decussates in (medulla) is known as a bulbar palsy. Usually, spinal cord), medial lemniscus (decussates in unless damage to corticobulbar fibers is bilat- lower medulla), and corticospinal (decussates eral, unilateral lesions lead to little, if any, in lower medulla). In their course through the motor disturbances, with the exception of the brainstem, (1) the spinothalamic tract is located lower facial muscles. The motor and premotor in the lateral tegmentum, (2) the medial lem- cortices emit substantial bilateral projections to niscus shifts as it ascends from a position in the the lower motor neurons of the muscles of anteromedial tegmentum in the medulla to the facial expression above the level of the eyes. In posterolateral tegmentum in the midbrain contrast, cortical projections to LMNs that before terminating in the ventral posterior lat- innervate the muscles of facial expression eral thalamic nucleus, and (3) the corticospinal below the eyes are mainly crossed with only a tract descends through the medial portion of modest uncrossed component. Thus, a unilat- the brainstem. eral lesion of the corticobulbar fibers causes an A unilateral lesion of the auditory pathway UMN paralysis on the contralateral side limited above the level of the cochlear nuclei results in to the muscles of facial expression below the only subtle changes in most auditory percep- level of the eye (see Chap. 11, corticobulbar tions because of the strongly bilateral nature of tract). When the corticobulbar tracts (upper the auditory pathway. The ability to localize motor neurons) are bilaterally interrupted (e.g., sound direction is diminished. The thresholds as can occur in multiple sclerosis), the resulting for sound intensity are unaffected. Unilateral muscle paralysis is known as a pseudobulbar lesions destroying the cochlear nuclei produce palsy. Signs associated with pseudobulbar deafness on the ipsilateral side because audi- palsies include dysphagia (difficulty in swal- tory fibers are interrupted prior to their decus- lowing), dysarthria (difficulty in articulating sation. Deafness in one ear more commonly is speech), and hyperreflexia of the jaw jerk caused because of inner-ear disease. reflex (evoked by tapping the chin gently with A unilateral lesion of the anterior the jaw slightly opened). trigeminothalamic tract in the pons and mid- The branchiomeric nerves (V, VII, IX, X, brain is accompanied by loss of pain and tem- and XI) pass close to the spinothalamic tract perature on the forehead, face, nasal cavity, and before emerging on the lateral side of the brain- oral cavity on the opposite side. This occurs stem. Injury to one of these nerves, the because the lesion is above the level where the spinothalamic tract, and the spinal tract and fibers of this tract decussate in the medulla. nucleus of nerve V results in (1) ipsilateral sen- Cranial nerves III (midbrain), VI (pons– sory loss from the face and a LMN paralysis of medulla junction), and XII (medulla) emerge the muscles, innervated by that nerve and (2) on the anterior aspect of the brainstem in close loss of pain and temperature on the opposite Chapter 17 Lesions of the Brainstem 307 side of the body and back of the head because denervation sensitivity; later, the muscles atro- of the interruption of the decussated fibers of phy and that side of the tongue appears wrin- the spinothalamic tract. kled. When protruded, the tongue deviates to the paralyzed side due primarily because of the unopposed action of the contralateral genio- BLOOD SUPPLY OF THE BRAINSTEM glossus muscle. The contralateral side of the body exhibits signs of an UMN paralysis (cor- The sequence of vertebral arteries, basilar ticospinal tract) and loss of position, muscle artery, and posterior cerebral arteries forms the and joint sense, impaired tactile discrimination, main trunk system supplying arterial blood to and loss of vibratory sense (medial lemniscus), the medulla, pons, midbrain, cerebellum, and because the lesion interrupts these tracts above posterior medial cerebrum (see Figs. 4.1 and the level of their decussation. 4.2). The paired vertebral arteries ascend along Immediately after the vascular occlusion, the the anterolateral aspect of the medulla and join upper and lower limbs on the contralateral side at the pons–medulla junction to form the single exhibit a hypotonus with weakness, decreased midline basilar artery, which ascends and then stretch reflexes (deep tendon reflexes), dimin- divides in the midbrain region into the paired ished resistance to passive manipulation, loss of posterior cerebral arteries. Branches of these superficial reflexes, and loss of response to arteries supply the brainstem in patterns that plantar stimulation of the foot. This is known as can be generalized as follows: paramedian spinal shock. After a month or so following the branches are distributed to a medial zone on stroke, the contralateral limbs develop a spastic either side of the midsagittal plane, short cir- paralysis, hypertonia with weakness, clasp- cumferential branches are generalized to an knife resistance to passive movement, hyper- anterolateral zone, and long circumferential reflexia, loss of superficial reflexes, and the branches are generalized to a posterolateral Babinski (extensor plantar) reflex. zone and to the cerebellum (see Fig. 17.1).

POSTEROLATERAL MEDULLA MEDIAL ZONE OF THE MEDULLA Failure of the posterior inferior cerebellar The occlusion of an anterior spinal artery artery (PICA), a long circumferential artery, can and its paramedian branches to the medial zone cause a lesion resulting in the lateral medullary of the medulla can cause a lesion that involves syndrome (Wallenberg’s syndrome) (see Fig. the hypoglossal nerve (n.XII), corticospinal 17.2B). Damage to the following structures pro- tract in the pyramid, and medial lemniscus (see duces the symptoms: spinothalamic tract; spinal Fig. 17.2A). The resulting alternating hemiple- trigeminal tract and nucleus; fibers and possibly gia combines a lower-motoneuron (LMN) nuclei associated with the glossopharyngeal paralysis of the tongue on the ipsilateral side nerve, vagus nerve, spinal portion of the acces- (n.XII) with an upper-motoneuron (UMN) sory nerve (including the nucleus ambiguus, paralysis and a loss of discriminatory general dorsal vagal nucleus, tractus, and nucleus soli- senses (medial lemniscus) on the contralateral tarius), and portions of the reticular formation, side of the body and both limbs. Recall that the vestibular nuclei, and the inferior cerebellar corticospinal tract decussates at the junction of peduncle. Symptoms include the following: the medulla and cervical spinal cord and that the posterior column–medial lemniscus path- 1. Loss of pain (analgesia) and temperature way decussates in the lower medulla. During sensation (thermoanesthesia) on the oppo- the first few weeks after the lesion, the ipsilat- site side of the body, including the back of eral half of the tongue fibrillates because of the head (crossed spinothalamic tract). 308 The Human Nervous System

Figure 17.1: The patterns of arterial supply of the branches of the vertebral–basilar system within the (A) caudal medulla, (B) midmedulla, and (C) pons. (Refer to Fig. 4.1.)

2. Loss of pain and temperature on the same combination of symptoms 1 and 2 is an side of the face and nasal and oral cavities in alternating hemianesthesia. all three trigeminal divisions (uncrossed 3. Difficulty in swallowing and a voice that is spinal trigeminal tract and nucleus). The hoarse and weak. This is caused by damage Chapter 17 Lesions of the Brainstem 309

to the nucleus ambiguus. A lesion of the thoracic sympathetic outflow are disrupted. Tac- nucleus ambiguus on one side results in an tile and discriminative general senses from the ipsilateral paralysis of the palatal, pharyn- face are normal because the principal sensory geal, and laryngeal muscles, all innervated nucleus of n.V and its ascending pathways are by cranial nerves IX, X, and the cranial divi- above the level of the lesion. sion of XI. Difficulty in the initial stage of swallowing is the result of paralysis of some palatal muscles and adjacent regions. Diffi- REGION OF THE culty in later stages of swallowing (dyspha- CEREBELLOPONTINE ANGLE gia) is the result of paralysis of the (CPA SYNDROME) pharyngeal muscles. The palate and uvula deviate to the nonparalyzed side during Acoustic neuromas are slow-growing vocalization. The hoarseness occurs because tumors that originate from neurolemmal of paralysis of the musculature controlling the ipsilateral vocal cord. 4. Loss of gag reflex on the ipsilateral side and absence of sensation on the ipsilateral side of the fauces (glossopharyngeal nerve). 5. Disturbances in equilibrium because of damage to part of the inferior cerebellar peduncle. 6. Nausea and vertigo because of damage to the vestibular nuclei and vestibulocerebellum.

A bulbar palsy occurs following degeneration of motoneurons of the medulla. A transient tachycardia (increase in heartbeat) can result from sudden withdrawal of some parasympathetic innervation; compensatory mechanisms, including influences from the contralateral vagus nerve, restore normal heartbeat. The absence of afferent stimulation from some visceral receptors (e.g., carotid body and carotid sinus) to the solitary nucleus is compensated for by the input from similar receptors on the unaffected contralateral side. The interruption of spinocerebellar and other fibers passing through the inferior cerebellar peduncle results in signs of cerebellar malfunction on the ipsilateral side of the body, including hypotonia, ataxia, and poorly coordinated voluntary movements (Chap. 18). Irritation of the vestibular nuclei can cause Figure 17.2: Sites of lesions in the lower nystagmus and/or deviation of the eyes to the brainstem as described in the text. In the ipsilateral side. Horner’s syndrome (constricted medulla, the lesions are located (A) in the pupil, ptosis of eyelid, and absence of sweating medial zone and (B) in the posterolateral from half of the face) on the same side can occur tegmentum. In the lower pons, the lesions are if many descending fibers of the autonomic located (C) in the anteromedial tegmentum and nervous system and reticulospinal tracts to the basilar portion. 310 The Human Nervous System

(Schwann) cells of the vestibular nerve. Those nerve (n.VI), facial nerve (n.VII), pyramidal in the vicinity of the internal auditory foramen tract, and medial lemniscus (see Fig. 17.2C). can extend into the cerebellopontine angle The interruption of the fibers of n.VI (lower (CPA), the junction of the cerebellum, pons, motoneurons) and the pyramidal tract (upper and medulla near the emergence of cranial motoneurons) results in an alternating abducent nerves VII and VIII (see Fig. 14.1). In the early hemiplegia. The transection of n.VI on one side stages, symptoms are referable to the eighth produces a medial deviation (adduction) of the cranial nerve; they include (1) tinnitus (ringing affected eye from the unopposed pull of the in the affected ear) followed by progressive medial rectus muscle (eye is cocked in). There deafness on the lesion side and (2) abnormal is also horizontal diplopia (double vision) labyrinthine (vestibular) responses, such as tilt- because the image of an object falls on noncor- ing and rotation of the head with the chin point- responding portions of the two retinas and is ing to the lesion side and, at times, horizontal seen as two objects. Diplopia is maximal when nystagmus. As the tumor enlarges, it exerts the patient attempts to gaze to the lesion side. It pressure on the brainstem and damages the is minimal (or absent) when gaze is directed to inferior and middle cerebellar peduncles, the side opposite the lesion because the unaf- spinothalamic tract, spinal trigeminal tract and fected eye and the affected eye are viewing the facial nerve. The cerebellar signs that result same visual fields. As already stated, damage to from the involvement of the cerebellar pedun- the corticospinal tract causes a contralateral cles include coarse intention tremor, dysmetria, hemiplegia and injury to the medial lemniscus an ataxic gait, dysdiadochokinesis, and hypoto- causes a loss of discriminatory general senses nia on the lesion side (Chap. 18). The loss of (see “Medial Zone of the Medulla”). Interrup- pain and temperature sensation on the ipsilat- tion of n. VII causes an ipsilateral LMN facial eral side of the face, oral and nasal cavities, and paralysis, hyperacusis, and disturbances in on the contralateral side of the body are a con- taste perception, lacrimation, and salivation. sequence of damage to the spinal trigeminal tract and spinothalamic tract, respectively; this combination of ipsilateral and contralateral MEDIAL LONGITUDINAL sensory loss is called alternating hemianesthe- FASCICULUS sia. Injury to the facial nerve results in an ipsilateral LMN paralysis of the muscles of facial Lesions of the medial longitudinal fascicu- expression, loss of the corneal reflex on the lus (MLF) just rostral to the abducent nuclei injured side, and hyperacusis (see Chap. 14, cause internuclear ophthalmoplegia, a distur- “Lesion of the Facial Nerve”). Due to interrup- bance of conjugate horizontal eye movements. tion of the intermediate root of n. VII, there is Usually bilateral, this often is the presenting an ipsilateral loss of taste on the anterior two- syndrome in patients who have multiple scle- thirds of the tongue; lacrimation and salivation rosis; a unilateral form of internuclear oph- also are affected. thalmoplegia results from a vascular accident. Fibers that synchronize the contractions of the lateral rectus of one eye (abductor innervated MEDIAL AND BASAL PORTION by n.VI) and the medial rectus muscle of the OF THE CAUDAL PONS opposite eye (adductor innervated by n.III) become demyelinated. Such a lesion in the The occlusion of paramedian and short cir- MLF results in (1) weakness of adduction of cumferential branches of the basilar artery can the eye when attempting lateral gaze to the result in damage to the following structures opposite side, (2) horizontal nystagmus of within the confines of the lesion: abducent the other eye, which abducts but cannot hold the abducted position, and (3) no impairment Chapter 17 Lesions of the Brainstem 311 with convergence of the two eyes. The obser- formation are associated with coma, which is a vation that the eyes fail to adduct on attempted state of sustained unconsciousness and unre- lateral gaze but do so during convergence sponsiveness. It differs from sleep. which under shows that the lower motoneurons are intact normal circumstances has a circadian rhythm and, therefore, the loss of adduction in this and from which an individual can be com- syndrome is the result of an upper-motoneu- pletely aroused. ron type injury (in this case, internuclear, Bilateral lesions of the basal pons, usually between the abducent and oculomotor nuclei). the result of an occlusion of the basilar artery, Nystagmus in the abducting eye is attributed may completely interrupt the corticobulbar and to interruption of fibers that descend in the corticospinal tracts on both sides. Such lesions MLF from the oculomotor nucleus to the can spare much of the reticular formation and abducent level, where they cross to the oppo- corticobulbar fibers to the oculomotor nuclei, site abducent nucleus. which terminate in the midbrain. These patients can be completely immobile or “locked-in” but not comatose. They are quadriplegic and LATERAL HALF OF THE MIDPONS unable to speak or move the facial muscles or tongue. However, such patients are fully con- The structures within the region of the scious and can communicate by responding lesion (see Fig. 17.3A) include the trigeminal with eye movements because the reticular nerve, spinothalamic tract, lateral lemniscus, medial lemniscus, and the middle cerebellar peduncle. Damage to the trigeminal nerve (n.V) results in (1) the absence of all general senses (anesthesia) on the ipsilateral side of the face, forehead, and nasal and oral cavities (including absence of corneal sensation and the corneal reflex) and (2) a LMN paralysis of the muscles of mastication, with the chin devi- ating to the lesion side when the mouth is opened. Destruction of the medial lemniscus results in a contralateral loss of position, muscle, and joint sense and impaired vibratory sense and tactile discrimination. If the lesion is extensive enough to include the corticospinal tract, the combination of the pyramidal tract and n.V produces an alternating trigeminal hemiplegia. Coma and the “Locked-in” Syndrome The brainstem reticular formation contains the anatomic substrates for the reticular activating system projecting to the diencephalon and cerebral cortex (Chap. 22). The reticular sys- Figure. 17.3: Sites of lesions in the pons tem is of importance in the mechanisms of and midbrain as described in the text. (A) In the arousal, regulation of the sleep–wake cycle, midpons, the lesion is located laterally. In the and the state of alertness. midbrain at the superior colliculus level, the Extensive rapidly occurring bilateral lesions lesions are located (B) in the basilar region and involving the upper pons and midbrain reticular (C) in the tegmentum. 312 The Human Nervous System formation and corticobulbar fibers to the oculo- reflex (stretch reflex). The explanation for motor nuclei are intact. these occasional observations is that the UMN innervation to the LMN supplying these muscles is similar to the corticobulbar–LMN cir- BASAL REGION OF THE MIDBRAIN cuitry to the muscles of facial expression of (WEBER’S SYNDROME) the lower face; that is, the corticobulbar supply to the part of the facial nucleus innervat- Occlusion of paramedian branches and short ing the lower face is effectively only crossed. circumferential branches of the basilar and pos- The result is weakness of the muscles of the terior cerebral arteries can produce Weber’s lower half of the face; the soft palate and syndrome (see Fig. 17.3B), which is a conse- uvula will be drawn to the same side as the quence of damage to the oculomotor nerve lesion, and the tongue will deviate to the (n.III), the corticospinal tract, and a variable opposite side when protruded. number of corticobulbar and corticoreticular Bilateral, diffuse involvement of the corti- fibers. Interruption of all the fibers in the ocu- cobulbar and corticoreticular fibers results in a lomotor nerve results in signs restricted to the pseudobulbar palsy. In this syndrome, there is ipsilateral eye, including drooping of the eyelid a bilateral paralysis or weakness without atro- (ptosis, or inability to raise the eyelid because phy of many muscles innervated by cranial of paralysis of the levator palpebrae muscle); nerves. The muscle groups affected control diplopia (double vision), external strabismus chewing, swallowing, speaking, and breathing. (squint) because of unopposed contraction of Unrestrained crying and laughing occur in the lateral rectus muscle (the eye remains max- many subjects with pseudobulbar palsy. These imally abducted), inability to elevate, depress, emotional outbursts can be related to release or adduct the eye, and a fully dilated pupil from cortical and subcortical influences. (sympathetic tone is unopposed as a result of the loss of parasympathetic fibers in n.III). The consensual light reflex of the contralateral eye UPPER MIDBRAIN TEGMENTUM is normal (Chap. 19). An alternating oculomo- (BENEDIKT’S SYNDROME) tor hemiplegia is a consequence of a LMN paralysis of the extraocular muscles and an Benedikt’s syndrome results from a unilateral UMN paralysis of the contralateral side of the lesion limited to the midbrain tegmentum that body from damage to the corticospinal tract. includes the fibers of the oculomotor nerve, red In general, motor nuclei of the cranial nucleus, superior cerebellar peduncle, medial nerves (except for the neurons of the facial lemniscus, and spinothalamic tract (see Fig. nucleus innervating the lower face) are sup- 17.3C plied by upper motoneurons from both halves ). Damage to the red nucleus and fibers of of the cerebrum (Chap. 11). Hence, unilateral the superior cerebellar peduncle, which pass lesions do not produce an UMN paralysis of through and around it, results in cerebellar signs the muscles innervated by these nerves, except such as coarse intention tremor, dysdiadochoki- for weakness of the contralateral muscles of nesis, cerebellar ataxia, and hypotonia on the facial expression of the lower face. However, contralateral side of the body (Chap. 7). The in some cases, interruption of the upper injury to the third cranial nerve causes a LMN motoneurons to the nucleus ambiguus and paralysis of the ipsilateral extraocular muscles hypoglossal nucleus results in contralateral innervated by the oculomotor nerve and a weakness of the muscles of the jaw, soft dilated pupil (mydriasis) because of loss of palate, and tongue; interruption of UMNs to parasympathetic fibers (see Basal Region of the the motor nucleus of n.V (masticatory Midbrain). The eye cannot be adducted beyond nucleus) can result in an exaggerated jaw jerk the midline, elevated or lowered. Chapter 17 Lesions of the Brainstem 313

Interruption of the crossed spinothalamic tract, trigeminothalamic tract, and medial lem- SELECTED READINGS niscus results in the loss of sense of pain, tem- Collins RC. Neurology. Philadelphia: Saunders; perature, light touch, vibratory sense, pressure 1997. touch, and other discriminatory senses on the Dublin AB, Dublin WB. Atlas of Neuroanatomy opposite side of the body and head. Touch and with Radiologic Correlation and Pathologic other discriminatory senses on the contralateral Illustration. St Louis, MO: WH Green; 1982. side of the forehead can be retained if the Gilman S, Winans S. Manter and Gatz’s Essentials uncrossed posterior trigeminothalamic tract is of Clinical Neuroanatomy and Neurophysiology. intact. 10th ed. Philadelphia: FA Davis; 2003. Patten J. Neurological Diferential Diagnosis. New York: Springer-Verlag; 1977. LESIONS OF BOTH SUPERIOR Rowland LP. Clinical Syndromes of the Spinal Cord COLLICULI (PARINAUD’S and Brain Stem. In: Kandel ER, Schwartz JH, Jessell T, eds. Principles of Neural Science. 3rd SYNDROME) ed. New York: Elsevier; 1991;711–730. Rowland LP, ed. Merritt’s Neurology. 10th ed. Tumors of the pineal gland can compress Philadelphia: Lippincott Williams & Wilkins; both the superior colliculi and pretectum pro- 2000. ducing a paralysis of upward gaze. The pupils Victor M, Ropper AH. Adams and Victor’s Princi- can be dilated with loss of the light reflex, but ples of Neurology. 7th ed. New York: McGraw- they are capable of accommodation. Hill Medical; 2002. 18 Cerebellum

Gross Anatomy Subdivisions of the Cerebellum Salient Features of Function General Cerebellar Circuitry Functional Considerations Cerebellar Dysfunction

The cerebellum is the great coordinator of bose, emboliform, and dentate). The globose muscle action and is important for learning and emboliform nuclei together constitute the motor tasks. It synchronizes contractions of interposed nucleus. muscles within and among groups, smoothing The cerebellar surface is corrugated into out responses by delicately regulating and parallel, long, narrow “gyri” called folia grading muscle tensions. Thus, it plays an (leaves) whose long axes are in the transverse important role in equilibrium and muscle tone. plane; about 15% of the cortex is exposed to Located in the posterior cranial fossa, beneath the outer surface, whereas 85% faces the sulcal the tentorium cerebelli and behind the pons and surfaces between the folia. The cerebellum is medulla, the cerebellum processes sensory connected to the brainstem by three pairs of input related to ongoing motor activity, all on cerebellar peduncles: (1) the inferior cerebellar an unconscious level. It plays no part in con- peduncle is a bridge between the medulla and scious perceptions or in intelligence. the cerebellum and is composed of fibers pro- Sensory input to the cerebellum is derived jecting both to and from the cerebellum; (2) the from the vestibular system, stretch receptors middle cerebellar peduncle is a bridge between (neuromuscular spindles and Golgi tendon the basilar portion of the pons and the cerebel- organs), and other general sensors in the head lum and is composed of fibers projecting to the and body. The auditory and visual systems also cerebellum; (3) the superior cerebellar pedun- send fibers to the cerebellum. This input is cle is a bridge between the midbrain and the functionally integrated into the motor pathways cerebellum and is composed mainly of fibers via outputs mainly to upper motoneurons and projecting from the cerebellum to the brain- cerebellar feedback circuits coming from and stem and the thalamus; it also contains fibers of going to the cerebral cortex, vestibular system, the anterior spinocerebellar tract projecting to and brainstem reticular formation. the cerebellum.

GROSS ANATOMY SUBDIVISIONS OF THE CEREBELLUM

The cerebellum consists of (1) an outer gray Hemispheres, Lobes, and Zones mantle, the cortex, (2) a medullary core of The cerebellar cortex consists of two large white matter composed of nerve fibers project- bilateral hemispheres connected by a narrow ing to and from the cerebellum, and (3) four median portion called the vermis (see Fig. pair of deep cerebellar nuclei (fastigial, glo- 18.1). This transverse organization is further

315 316 The Human Nervous System

Figure 18.1: Major subdivisions and surface landmarks of the unfolded and flattened cerebellum. subdivided into three zones: medial or vermal; logenetically the oldest part of the cerebel- paramedial, paravermal, or intermediate; and lum and the vestibulocerebellum because this lateral or hemispheric. In addition to the cortex, lobe is integrated with the vestibular system. each zone consists of underlying white matter The flocculonodular lobe plays a significant and a deep cerebellar nucleus to which it topo- role in regulation of muscle tone and mainte- graphically projects vermis to fastigial nucleus, nance of equilibrium and posture through paravermal cortex to interposed nuclei, and influences on the trunk (axial) musculature. hemisphere to dentate nucleus (see Fig. 13.11). 2. The anterior lobe, located rostral to the pri- The cortex is characterized by the homoge- mary fissure, is also called the paleocerebel- neous appearance of its many gyri, called folia lum because it is phylogenetically the next (leaves), generally oriented transversely and oldest part. This lobe together with the ver- separated by sulci or fissures. There are five mal and paravermal portions of the posterior deep fissures. Two of these, the primary and lobe constitute the spinocerebellum, which posterolateral fissures best seen in a midsagittal has two somatotopic maps of the entire body section, divide the cerebellum into three lobes surface: one in the anterior and the other in (see Fig. 1.5): the posterior lobe (see Fig. 18.2). The spinocerebellum, which plays a role in the regula- 1. The flocculonodular lobe, behind the pos- tion of muscle tone, receives proprioceptive terolateral fissure, consists of paired and exteroceptive inputs from the body and appendages called flocculi located posteri- limbs via the spinocerebellar pathways, and orly and inferiorly and joined medially by from the head via fibers from the brainstem the nodulus (part of the vermis). It is also (see Fig. 10.7). The anterior lobe homuncu- called the archicerebellum because it is phy- lus also receives auditory and visual inputs. Chapter 18 Cerebellum 317

3. The large posterior lobe is located between parallel to the long axis of the folium. Parallel the primary fissure and the posterolateral fibers form excitatory synapses with dendrites fissure. This phylogenetically newest lobe of Purkinje, stellate, Golgi, and basket cells. (neocerebellum) receives input from the One parallel fiber synapses with the dendrites cerebral cortex via a relay in the basilar of thousands of Purkinje cells and each Purk- pons. It performs a significant role in plan- inje cell receives synapses from thousands of ning and programming of movements parallel fibers. Granule cells, until recently, important for muscular coordination during were considered the only neurons of the cere- phasic activities. bellar cortex whose neurotransmitter (glutamate) is excitatory. Evidence now indicates that Cerebellar Cortex unipolar brush cells also are glutamatergic, but There are three cortical layers: an outer their numbers, about the same as Purkinje cells, molecular layer, a middle or Purkinje cell layer are negligible compared to granule cells. and a granular layer (see Fig. 18.3). The thin Stellate cell and basket cell somata lie Purkinje layer is defined by the cell bodies of wholly within the molecular layer, the former Purkinje cells. All folia have the same neuronal in superficial parts of the layer and the latter in organization. The billions of neurons are deep parts. The axon of both types is oriented divided into five major cell types (granule, at right angles to the long axis of a folium. A Golgi, stellate, basket, Purkinje). A sixth type, single stellate cell axon makes inhibitory called a “unipolar brush cells” first was identi- synaptic connections with the dendrites of sev- fied in 1976 by Altman and Bayer and has been eral Purkinje cells. Each basket cell axon forms extensively studied in recent years. basketlike inhibitory synaptic connections with The estimated 100 billion (1011) granule cell bodies of several Purkinje cells. Note that cells are more numerous than all the neurons in because these terminals are near the initial seg- the cerebral cortex. The small (5–8 μm) cell ment of the axon where the action potential is body and four to six short dendrites are all initiated, the inhibition is very strong (Chap. 3). located within the granular layer; the axon Golgi cells, slightly larger (6–11 μm) than projects into the molecular layer, where it granule cells, are located near the top of the bifurcates as a T into two branches (called par- granular layer and have a cell complement allel fibers) that course in opposite directions equivalent to that of Purkinje cells. The dendritic tree is within the molecular layer, where it receives excitatory input from parallel fibers. The Golgi cell axon terminates within glomeruli of the granular layer by forming inhibitory synapses with dendrites of granule cells, thus forming direct feedback to the latter. A glomerulus (see Fig. 18.3) is a synaptic processing unit, encapsulated by a glial lamella, consisting of (1) an excitatory axon terminal of a mossy fiber, (2) dendritic endings of one or more granule cells, and (3) an inhibitory axon terminal of a Golgi cell synapsing with a dendrite of the granule cell. Dendrioles of a unipolar brush cell, not shown, also are in some glomeruli. Figure 18.2: Somatotopic map of the ante- Unipolar brush cells also are constituents of rior and posterior lobes of the cerebellum illus- the granular layer. Intermediate in size between trating the somatic sensory homunculi. granule and Golgi cells, they occur mainly in 318 The Human Nervous System the vestibulocerebellum and vermis. Although the vestibular nerve and vestibular nuclei, and present in the hemispheres, their density dimin- other loci. Brush cells give rise to branching ishes progressively from the midline. A distinc- axons (intrinsic mossy fibers) that remain tive feature of this neuronal type is a single, within the granular layer and have large termi- short dendrite that gives rise to a spray of nal rosettes within other glomeruli, contacting brushlike dendrioles that extend into a granule cell dendrites as well as dendrioles of glomerulus. A single mossy fiber, in addition to other unipolar brush cells, thus amplifying the terminating on granule cell dendrites, makes effect of the extrinsic mossy fibers and potenti- multiple synaptic contacts with the dendrioles ating vestibular signals. of a unipolar brush cell (a giant glutamatergic Purkinje cells, which form the middle layer, synapse) in the same glomerulus, causing provide the only output from cerebellar cortex strong excitation. This input comes from both and are its final integrating unit. The dendritic

Figure 18.3: Organization and connections of the neurons within a cerebellar folium. A sagittal section through the cerebellum is represented on the right and a transverse section on the left. The long axis of a folium is in the transverse plane. The thin Purkinje cell layer, between the molecular and granular layers, is not labeled. A cerebellar glomerulus, represented in the inset, is encapsulated by a glial sheath. Chapter 18 Cerebellum 319 tree begins at the apical end of the large goblet- on cells of the deep cerebellar nuclei. Every shaped soma (50–80 μm) and arborizes exten- climbing fiber divides within the granular layer sively in the molecular layer in a fanlike into up to 10 branches (also called climbing configuration in the sagittal plane, perpendicu- fibers), each of which enters the molecular lar to the long axis of the folium (see Fig. 18.3). layer and makes up to several hundred synaptic The dendrites are the sites of excitatory axon contacts on proximal dendrites of a single terminals of parallel fibers from granule cells Purkinje cell. Whereas collateral branches can and climbing fibers from the inferior olive and contact several adjacent Purkinje cells, an indi- inhibitory terminations from stellate cells of vidual Purkinje cell receives input from only the molecular layer; this is in addition to the one climbing fiber. powerful inhibitory axo-somatic synapses from Mossy fibers originate from nuclei in the basket cells. Purkinje cell axons pass into the spinal cord, receptors of the vestibular nerve, white matter and form inhibitory synaptic con- and vestibular, trigeminal, pontine, and reticu- nections with neurons of the deep cerebellar lar nuclei of the brainstem. These fibers, which nuclei, releasing GABA as the neurotransmit- branch profusely, exert excitatory influences on ter. The corticonuclear projection has a precise numerous granule cells within glomeruli of the topographic organization: The medial most granular layer. Collaterals of mossy fibers, as vermis projects to the most medial part of the well as of climbing fibers also can, depending fastigial nucleus, the intermediate zone projects on source, form excitatory synapses with the to the interposed nucleus, and the lateral most deep nuclei of the cerebellum. Through their hemisphere projects to the lateral part of the parallel fibers, the packed granule cells make dentate nucleus. Some Purkinje cells from the excitatory synaptic connections with the den- archicerebellum, as well as from the vermis of drites of the Purkinje cells and, in addition, the anterior and posterior lobes, emit axons that with dendrites of stellate cells, basket cells and project out of the cerebellum and form Golgi cells in the molecular layer. After excita- inhibitory synapses with neurons of the lateral tion, the stellate and basket cells, exert inhib- vestibular nucleus. Recurrent axon collaterals itory influences on Purkinje cells. Similarly, of each Purkinje cell make inhibitory connec- the Golgi cells inhibit the granule cells within tions with other Purkinje cells, basket cells, and the glomeruli. Golgi cells. Through these inhibitory influences, The following is an account of how the out- the Purkinje cells modulate the output of the put from the cerebellar cortex is orchestrated. deep cerebellar nuclei and of the lateral vestibu- Purkinje cells, through their axons, are the only lar nucleus. The latter exerts excitatory influ- outlets for processed information from the ences on extensor reflex activity (Chap. 16). cerebellar cortex. Their output, directed to the deep cerebellar nuclei and the lateral vestibular nucleus, is solely inhibitory. Insofar as mossy SALIENT FEATURES OF FUNCTION and climbing fibers supply only excitatory inputs, it is the Purkinje fibers that modulate, Climbing and mossy fibers convey excita- through inhibition, the output from the deep tory input directly from the spinal cord and cerebellar nuclei to targets outside the cerebel- brainstem, through the cerebellar peduncles, to lum (and output from the lateral vestibular the deep cerebellar nuclei and cerebellar cor- nucleus). As mentioned, Purkinje cells are tex. The climbing fibers to each cerebellar excited as well as inhibited by stimuli from hemisphere originate exclusively from the con- other cells. The climbing fibers and granule tralateral inferior olivary nucleus and enter the cells contribute excitatory influences; the stel- cerebellum via the inferior cerebellar peduncle late and basket cells convey inhibitory stimuli. (see Fig. 18.3). They exert powerful excitatory A final element of this mosaic concerns the influences not only on Purkinje cells but also granule cells. Granule cell output is modulated 320 The Human Nervous System by excitatory input from unipolar brush cells tral spinocerebellar tract, reticulocerebellar (mainly in the vestibulocerebellum and vermis) fibers, olivocerebellar fibers, and trigeminocere- and inhibitory influences from Golgi cells. The bellar fibers. The juxtarestiform body (bundle of latter in turn depend on granule cells for their fibers on medial aspect of the inferior cerebellar own activation. This negative feedback circuit peduncle) contains vestibulocerebellar fibers consists of the sequence (1) granule cell, (2) from both the vestibular nuclei and the vestibu- Golgi cell, and (3) Golgi cell axon that extends lar nerve (Chap. 16). The posterior spinocere- back to form inhibitory synapses on granule bellar, cuneocerebellar, and rostral cerebellar cells within glomeruli. tracts convey information from stretch and exte- In summary, the wholly excitatory input to roceptive receptors of the body via the spinal the cerebellum is via mossy and climbing cord to the anterior lobe of the cerebellum fibers. Of the neurons whose cell bodies are (Chap. 10). Reticulocerebellar fibers project located within the cerebellar cortex, the granule from the lateral reticular nucleus of the medulla cells are the only excitatory ones whose axons (input to this nucleus is from the spinal cord, red leaves the layer of origin. Although unipolar nucleus, and fastigial nucleus) and paramedian brush cells also are excitatory, their axons are nuclei of the medulla, largely as uncrossed com- restricted to the granular layer where they ponents, to the anterior lobe and vermis. Olivo- increase the excitation upon granule cells. The cerebellar fibers originate in the contralateral Golgi, Purkinje, stellate, and basket cells are inferior olivary nucleus of the medulla and ter- inhibitory neurons, whose neurotransmitter is minate in all cortical areas of the cerebellum. GABA. They act as modulators. The cerebellar The accessory olivary nuclei project to the ver- nuclei also convey excitatory input to the gran- mis, and the principal olivary nucleus projects to ular layer of cerebellar cortex via nucleocorti- the opposite cerebellar hemisphere. Input to the cal connections, some of which are collaterals inferior olivary nuclei is derived from the cere- of fibers that project out of the cerebellum. bral cortex, brainstem reticular nuclei, dorsal In addition, aminergic cell groups such as column nuclei, red nucleus, and spinal cord, as the locus ceruleus and raphe nuclei of the well as from the cerebellum. The inferior oli- brainstem provide another input to the cere- vary nucleus is the only source of climbing bellum. Their projections terminate in the fibers to the cerebellum. The trigeminocerebel- deep cerebellar nuclei and the cerebellar cor- lar fibers convey influences from stretch and tex, including from the locus ceruleus exteroceptive receptors of the head. Primary directly on Purkinje cell somata. The projec- fibers from the vestibular nerve and secondary tions from the locus ceruleus are noradrener- fibers from vestibular nuclei pass, as vestibulo- gic and those from the raphe nuclei are cerebellar fibers, through the juxtarestiform serotonergic. Input from these sources is body before terminating in the flocculonodular thought to have generalized effects on the lobe and adjacent cortex (referred to as the tone of cerebellar activity. vestibulocerebellum). Secondary but not primary vestibular fibers emit collaterals to the fastigial nuclei as well. GENERAL CEREBELLAR CIRCUITRY The middle cerebellar peduncle (brachium pontis) is composed of crossed pontocerebellar Input to the Cerebellum fibers projecting from the pontine nuclei in the There are approximately three times as basilar pons to the neocerebellum and paleo- many cerebellar afferent fibers as there are cerebellum. This tract conveys influences from cerebellar efferent fibers. the cerebral cortex transmitted via the cortico- The inferior cerebellar peduncle (restiform pontine tract. body) is composed of fibers of the posterior The superior cerebellar peduncle (brachium spinocerebellar tract, cuneocerebellar tract, ros- conjunctivum) contains fibers of the anterior Chapter 18 Cerebellum 321 spinocerebellar tract, which terminate in the lar peduncle to terminate in the brainstem anterior lobe (see Fig. 13.13 and Chap. 10). reticular nuclei (reticulotegmental nucleus) as well as the principal inferior olive. The inter- Output From the Cerebellum posed nuclei project to the caudal (magnocellu- The cerebellum influences motor coordina- lar) part of the red nucleus, which is the source tion almost entirely through indirect pathways of the rubrospinal tract. Descending postdecus- (see Figs. 18.4 and 18.5). There is evidence sup- sational fibers go to brainstem reticular nuclei, porting the presence of a small projection some to the dorsal and medial accessory olives, directly to the spinal cord. The main output from and a few to the upper cervical spinal cord, the cerebellum consists of separate fiber systems where they terminate upon interneurons in the that arise from the three pairs of cerebellar nuclei intermediate gray. (fastigial, interposed, and dentate) and have excitatory influences on their targets. Purkinje cells from the vestibulocerebellum and entire vermis FUNCTIONAL CONSIDERATIONS in part emit axons that leave the cerebellum and directly inhibit the vestibular nuclei. The cerebellum, as indicated, can be divided The outflow through the juxtarestiform body into four anatomic zones: (1) median zone or includes (1) crossed and uncrossed fastigiobul- vermis, (2) paramedian or intermediate zone, bar fibers from the fastigial nuclei to the (3) lateral zone or lateral hemisphere, and (4) vestibular nuclei and reticular nuclei of the pons floccular–nodular lobe or vestibulocerebellum and medulla, (2) a few fibers that synapse (see Fig. 18.1). Three recognized functional monosynaptically on lower motoneurons in the divisions include the (1) spinocerebellum, contralateral upper cervical spinal cord, and (3) which comprises the anterior lobe and the some direct fibers from the cortex of the median and paramedian zones of the posterior vestibulocerebellum (flocculonodular lobe) and lobe, (2) cerebrocerebellum, which comprises throughout the vermis to the vestibular nuclei. the lateral zone, and (3) vestibulocerebellum or Some fibers from the fastigial nuclei pass the flocculonodular lobe. around the rostral aspect of the superior cere- The spinocerebellum is involved in the con- bellar peduncle as the uncinate (hooked) fasci- trol of movements of the body axis (posture) culus before passing through the juxtarestiform and primarily proximal limbs. It receives body (see Figs. 13.11 and 18.5). Each fastigial somatosensory input from the spinal cord, pro- nucleus receives input from the vestibular viding details about the progress of ongoing nuclei and cortex of the archicerebellum. movements, and generates information to cor- The superior cerebellar peduncle consists rect errors. The cerebrocerebellum receives primarily of efferent fibers from the dentate, strong input from the cerebral cortex and is emboliform, and globose nuclei. Those arising involved in the planning of movement and from the large dentate nucleus are called the learning of sequences in complex movements dentatorubral, dentatothalamic, and denta- such as playing a piano. The vestibulocerebel- toreticular tracts. The entire outflow crosses to lum receives input from the vestibular receptors the opposite side in the lower midbrain as the and is involved in the maintenance of balance decussation of the superior cerebellar pedun- and regulation of head and eye movements. It is cle. Most fibers from the dentate nucleus proj- important to realize that these circuits are ect rostrally to the ventral lateral and indicative of the complex anatomic circuitry by intralaminar thalamic nuclei, with some fibers which the cerebellum is integrated into the con- terminating in the rostral (parvocellular) third trol of motor activity of the muscles of the body. of the red nucleus, which gives rise to the These functional divisions of the cerebellar rubroolivary tract. Other fibers turn caudally as cortex have similar patterns in the organization the descending branch of the superior cerebel- of their intrinsic circuitry, as described previ- 322 The Human Nervous System

Figure 18.4: Cerebellar (neocerebellar) connections with the cerebral cortex, thalamus and some brainstem nuclei. ously in this chapter. Each division differs, Each of the circuits outlined below is organ- however, from the others with respect to the ized to become involved in specific aspects of specific sources of afferent input and the spe- the functional control of certain muscle groups. cific neural centers to which it projects. In brief, the vermis is associated with the Chapter 18 Cerebellum 323 control of axial muscles, the intermediate tracts to the cortex of the vermis (see Fig. 18.2 hemisphere is associated with the control of and Chap. 10). In addition, afferent input from limb muscles, the cerebrocerebellum is associ- the head is derived from the spinal trigeminal ated with the planning of movement, and the nucleus and vestibular, auditory, and visual sys- vestibulocerebellum is associated with the tems. The vermal cortex projects to the fastigial maintenance of balance and control of eye nucleus, which, in turn, projects to two differ- movements. Recall that the deep cerebellar ent regions via fibers passing through the nuclei receive excitatory input from the climb- inferior cerebellar peduncle. (1) The largest ing fibers, which originate from the inferior oli- number of fibers terminate in the vestibular vary nucleus. Note that these circuits are nuclei and a substantial group descends in the organized to relay their influences selectively juxtarestiform body and central tegmental tract to either the medial or lateral descending motor of the brainstem to pontine and medullary systems (Chap. 8). reticular nuclei. (2) A few fibers ascend and terminate mainly in the contralateral ventral lat- Circuitry Associated With the Vermis eral (VL) nucleus of the thalamus. Projections (Vermal Zone) from this part of the VL ascend and terminate Somatic sensory information from the body in the regions of the primary motor cortex, and limbs is conveyed somatotopically via the which give rise to the anterior corticospinal dorsal spinocerebellar and cuneocerebellar tract. The pontine and medullary reticular

Figure 18.5: The vestibulocerebellar pathways. Left: input to the cerebellum; right: output from the cerebellum. 324 The Human Nervous System nuclei give rise respectively to the medial and capsule, the crus cerebri of the midbrain, and lateral reticulospinal tracts. All three of these terminate in the ipsilateral pontine nuclei. tracts belong to the medial descending systems These nuclei give rise to pontocerebellar fibers, (Chap. 11), which terminate in the medial col- which decussate and form the middle cerebel- umn of spinal gray matter where lower lar peduncle; they terminate in the contralateral motoneurons innervating axial musculature are cerebellar cortex of the lateral hemisphere. located. Note the linkage between the vermis Axons of Purkinje cells arising from this cortex (vermal zone) and the control of the axial and project to the dentate nucleus. This nucleus girdle musculature. Purkinje cells in the vermis gives rise to fibers that course through the supe- also project to the ipsilateral lateral and inferior rior cerebellar peduncle to two different struc- vestibular nuclei tures. (1) Some fibers contribute to the following circuit: They cross in the decussation Circuitry Associated With Intermediate of the superior cerebellar peduncle and termi- Hemisphere (Paravermal Zone) nate in the contralateral parvocellular division Somatic sensory information is conveyed of the red nucleus, which gives rise to the via the dorsal spinocerebellar and cuneocere- rubroolivary fibers that terminate in the inferior bellar tracts to the cortex of the intermediate olivary complex. A few postdecussational lobe (Chap. 10). This cortex projects to the fibers in the peduncle turn caudally and go interposed nuclei, which give rise to fibers that directly to the inferior olivary complex. This pass through the superior cerebellar peduncle complex is the source of olivocerebellar fibers and cross in the decussation of the superior that decussate and enter the inferior cerebellar cerebellar peduncle. Some fibers terminate in peduncle to terminate as climbing fibers. The the magnocellular portion of the red nucleus. inferior olive is the only source of climbing Others ascend and terminate in the VL. The fibers; they terminate and synapse with neurons ventrolateral nucleus projects to the primary in both the deep cerebellar (fastigial, interposi- motor cortex (area 4) and the supplementary tus and dentate) nuclei and axodendritically on motor cortex (area 6). The lateral descending Purkinje cells of the cerebellar cortex. (2) The system originates from these sources, the largest number of fiber crosses over in the rubrospinal tract originates from the magno- decussation of the superior cerebellar peduncle cellular portion of the nucleus ruber, and the and ascends to the thalamus where they termi- lateral corticospinal tract originates from the nate in VL. This nucleus projects to primary primary motor and supplementary cortices. motor cortex and premotor cortex. The primary These tracts control the activity of the muscu- motor cortex gives rise to the lateral corti- lature of the extremities. Note the linkage cospinal tract of the lateral descending system between the intermediate hemisphere and con- and anterior corticospinal tract of the medial trol of musculature of the extremities. descending system. The premotor cortex gives rise to corticoreticular fibers to the pontine and Circuitry Associated With the medullary reticular nuclei, which give rise to Cerebrocerebellum (Lateral Hemisphere the medial and lateral reticulospinal tracts of or Zone) the medial descending system. Note the linkage The cerebellar hemispheres are reciprocally between the lateral hemispheric zone and the interconnected with the cerebral cortex. The cerebrum for the planning of movement. output originates from many areas of the cerebral cortex, but largely from the motor cortices Circuitry Associated With the (areas 4 and 6) and the somatic sensory cortices Vestibulocerebellum (Flocculonodular Lobe) (areas 1, 2, 3, and 5). These projections com- The input to the vestibulocerebellar cortex is prise the corticopontine fibers that pass succes- derived from the vestibular nuclei and directly sively through the posterior limb of the internal from the vestibular labyrinth via some fibers of Chapter 18 Cerebellum 325 the vestibular nerve, the only primary fibers to mation derived from the periphery to the cere- enter the cerebellum. Purkinje cell axons from bellum. Rather, these tracts are thought to be in this cortex project ipsilaterally to the fastigial an internal feedback circuit to the cerebellum. nucleus and to the medial, inferior, and superior These nuclei can be monitoring neural activity vestibular nuclei. Cortex of the uvula, which can of the descending motor pathways and then in terms of connectivity be considered as part of informing the cerebellum. the vestibulocerebellum, also sends fibers to the lateral vestibular nucleus. The projections to the Postulated Role of Cerebellum in vestibular nuclei (the only projections from the Cognitive and Language Function cerebellar cortex to a noncerebellar site) indicate The presence of reciprocal connections that these nuclei are similar to deep cerebellar between phylogenetically new cerebellar struc- nuclei. The medial vestibular nucleus gives rise tures (ventrolateral parts of the dentate nucleus, to the medial vestibulospinal tract of the medial referred to as neodentate, and some of the lat- descending system. A few fibers from the fasti- eral lobe cortex) and the frontal association gial nucleus ascend and pass through the supe- areas of the cerebral cortex suggest that the rior cerebellar peduncle and terminate in the cerebellum has a role in cognitive function. contralateral VL nucleus. These VL neurons Evidence from imaging studies (magnetic reso- project to those sites of primary motor cortex nance imaging [MRI] and positron-emitting that give rise to the anterior corticospinal tract of tomography [PET]) support the view that the the medial descending system. Note the linkage “computational power of the cerebellum” is between the flocculonodular lobe and the axial used for some nonmotor activities such as puz- musculature (see discussion of the vestibular zle solving and language processing. Deficits system in Chap. 16). in the latter and in error detection have been reported in cases with unilateral cerebellar Thalamic Projections of the Cerebellar Nuclei damage documented by PET. As noted, the dentate, interposed, and fastigial nuclei all project to the ventrolateral nucleus of the thalamus. Fibers originating CEREBELLAR DYSFUNCTION from these nuclei terminate in a relatively acel- lular zone sandwiched between, and separate The cerebellar cortex participates in mecha- from, the projection fields of the somatosen- nisms of motor function via the Purkinje cells, sory pathways and of the basal ganglia in the which modulate the level of excitability of the ventral posterior and ventral anterior nuclei, deep cerebellar nuclei and their output. The respectively. The entirely crossed terminations delicate and subtle interactions of the cerebel- from the dentate and interposed nuclei are sep- lar cortex with the deep nuclei are basic to the arate but interdigitating. The small number of precision, speed, and coordination essential for fibers from the fastigial nucleus is distributed motor activities. These are expressions of bilaterally to a more limited region. This indi- synergy—the cooperative activity of all the cates that the functional differences of the cere- muscles utilized in each motor act. bellar zones are retained at thalamic levels. The Injury to the cerebellum or its afferent/effer- cerebellar nuclei also project to the intralami- ent pathways eliminates cerebellar influences nar group of the thalamic nuclei. on structures important for control of motor activity. This causes so-called release phenom- Internal Feedback Connections ena that are expressions of the loss of negative to the Cerebellum feedback. For instance, a tremor occurs when The anterior spinocerebellar and the rostro- moving the upper extremity to touch an object cerebellar tracts that terminate in the vermis with a finger and the arm oscillates back and (Chap. 10) probably do not relay sensory infor- forth as the tip of finger approaches the object. 326 The Human Nervous System

In the normal cerebellum, negative feedback underlying dentate and interposed nuclei. With activity reduces each overshoot to insignifi- neocerebellar lesions, tendon reflexes are cance, like an automatic pilot in an airplane. diminished (hypotonia); this effect is expressed Thus, the cerebellum acts as a servomechanism as a pendular knee jerk that swings freely back in a negative feedback system, functioning to and forth. Muscles tire easily (asthenia). An prevent oscillations (tremor) during motion and arm extended horizontally gradually drifts thereby maintaining stability in a movement. downward when the eyes are closed because Unilateral cerebellar lesions have ipsilateral proprioceptive sense is used improperly. Asyn- effects. Symptoms are expressed on the same ergia, or loss of muscular coordination, is side of the body because the pathways from the expressed by jerky, puppetlike movements, cerebellum decussate and integrate with path- including the decomposition of movement, dys- way systems that, in turn, cross over to the side metria, past-pointing, and dysdiadochokinesis. of the original cerebellar output to exert their Decomposition of movement is the breaking effects. For example, one side of the cerebellum up of a movement into its component parts; projects via the crossed dentatothalamocortical instead of a smooth, coordinated flow of move- pathway to the contralateral red nucleus and ment in bringing the tip of the finger of the cerebral cortex. In turn, the rubrospinal and cor- extended upper extremity to the nose, each ticospinal tracts are crossed descending path- joint of the shoulder, elbow, wrist, and finger ways. In effect, the cerebellum exerts its might flex independently (puppetlike) in an influences through a double-crossing of (1) the almost mechanical fashion. Dysmetria, or the ascending fibers of the decussating superior inability to gauge or measure distances accu- cerebellar peduncle and (2) the decussating rately, results in the overshooting of an descending rubrospinal and corticospinal tracts. intended goal by consistent pointing toward the Lesions of the cerebellum result in distur- lesion side of the object (past-pointing). Dysdi- bances expressed as a constellation of symp- adochokinesis is the impairment of the ability toms and neurological signs. Cerebellar cortex to execute alternating and repetitive move- possesses a good margin of physiologic safety; ments, such as supination and pronation of the with sufficient time, the neurologic symptoms forearm, in rapid succession with equal excur- attenuate, and the resulting compensation, pre- sions. Tremor is expressed during the execution sumably by other mechanisms in the brain, of a voluntary movement. It is absent or dimin- markedly reduces the severity of the deficits. ished during rest. Such a tremor, which is dis- Small lesions can produce no symptoms or played during movements but not at rest, is only transient ones, whereas large lesions pro- referred to as a cerebellar or intention tremor. duce severe symptoms. Disturbances following An ataxic gait, or the asynergic activity cerebellar lesions are related to the site of elicited during walking, is a staggering move- pathology, which, in many instances, is not ment resembling that of drunkenness. The restricted to one subdivision. Lesions of the ataxia is a result of incoordination of the trunk neocerebellum interfere with pathways chan- and proximal girdle muscles. A tendency to neled toward corticospinal and associated veer or to fall to the side of the lesion is appar- pathways and, thus, selectively affect skilled ent. To counteract the unsteadiness, a patient movements. Lesions of the archicerebellum will stand or walk with legs far apart (broad- whose output goes to medial descending motor based stance). Clinicians usually equate asyn- systems cause disturbances of equilibrium and ergy with ataxia. balance. Lack of check (rebound phenomenon) is demonstrable in neocerebellar lesions. Lack of Neocerebellar Lesions check is the inability of a rapidly moving limb, Neocerebellar in the context of lesions refers to stop quickly and sharply; in the attempt to to both the cortex of the hemisphere and the stop the limb there is an overshoot and then a Chapter 18 Cerebellum 327 rebound (overshoot in the opposite direction). cles without any signs of tremor or hypotonia. For example, the forearm is flexed at the elbow Children with nodular lobe tumors have a ten- against a strong resistance exerted by the dency to fall backward, sway from side to side, examiner; when the examiner suddenly and walk with a wide base and an ataxic gait. removes the resistance, the forearm jerks for- They might be unable to maintain an upright ward and the subject is unable to check the balance. motion before the hand strikes the chest. A scanning speech,ordysarthria, occurs Neurodegenerative Diseases Affecting because of an incoordination of the muscles the Cerebellum used in speaking. The speech is hesitating, Cerebellar ataxia together with dementia is slurred, and explosive in quality, with a tele- distinguished by a spongiform degeneration of graph-staccato pace (pauses in the wrong cortical neurons in the cerebellum and cere- places). Although the mechanisms of speech brum. Degeneration coupled with marked glial are impaired, there is no aphasia (Chap. 25). proliferation cytoplasmic vacuoles is referred However, there do appear to be disturbances in to as spongiform. The main clinical signs are verbalization and some aspects of reasoning. cerebellar ataxia and progressive dementia. Diseases expressing these manifestations Lesions of the Archicerebellum and Vermis include Kuru, documented in New Guinea of the Anterior and Posterior Lobes where human brains were eaten while prepar- The archicerebellum consists of the floccu- ing bodies for burial, Creutzfeldt–Jacob dis- lonodular lobe of which the nodulus is part of ease, shown to be transmittable, scrapie, a the vermis. The remainder of the vermis of the disease found in sheep, and mad cow disease. anterior and posterior lobes is closely related to All of these related diseases appear to be the flocculonodular lobe in that Purkinje cells caused by modifications of the conformation of project to the fastigial nuclei as well as directly proteins called “prions” (Prusiner, 1998). to the lateral and other vestibular nuclei; the entire vermis receives input from the vestibular complex. SUGGESTED READINGS Lesions of the archicerebellum and other parts of the vermis produce disturbances in Altman J, Bayer SA. Time of origin and distribution stance and gait. The patient stands and walks of a new cell type in the rat cerebellar cortex. with feet several inches apart (broad-based Exp. Brain Res. 1977;29:265–274. gait) and has difficulty in placing the heel of Dino MR, Schuerger RJ, Liu Y, Slater NT, Mugnaini one foot in front of the other in a sequential E. Unipolar brush cell: a potential feedforward excitatory interneuron of the cerebellum. Neuro- order (impairment of tandem gait). Titubation, science 2000;98:625–636. a rapid rhythmic tremor of the head or body, Gebhart AL, Petersen SE, Thach WT. Role of the can occur, sometimes accompanied by nystag- posterolateral cerebellum in language. Ann. NY mus (rhythmic oscillation of the eyes). Acad. Sci. 2002;978:318–333. Cortical degeneration affecting the vermis Gerrits NM, Ruigrok TJH, de Zeeuw CI, eds. Cere- of the anterior and posterior lobes is seen in bellar Modules: Molecules, Morphology, and some alcoholic patients. Disturbances involve Function. New York: Elsevier; 2000. the lower limbs and gait, which is ataxic and Glickstein M. The cerebellum and motor learning. wide based. Asynergia of the lower limbs can Curr. Opin. Neurobiol. 1992;2:802–806. be demonstrated by the heel–shin test in which Hua SE, Houk JC. Cerebellar guidance of premotor the heel of one foot is made to slide down the network development and sensorimotor learning. Learn. Mem. 1997;4:63–76. shin of the opposite leg. Ito M. The Cerebellum and Neural Control. New Lesions involving the flocculonodular lobe York: Raven; 1984. and uvula can result in ataxia of the trunk mus- 328 The Human Nervous System

Ito M. Synaptic Plasticity in the cerebellar cortex Prusiner SB. Prions. Proc. Natl. Acad. Sci. USA and its role in motor learning. Can. J. Neurol. 1998;95:13363–13383. Sci. 1993;20(Suppl. 3):S70–S74. Raymond JL, Lisberger SG, Mauk MD. The cere- Kelly RM, Strick PL. Cerebellar loops with motor bellum: a neuronal learning machine? Science. cortex and prefrontal cortex of a nonhuman pri- 1996;272:1126–1131. mate. J Neurosci. 2003;23:8432–8444. Robinson FR. Role of the cerebellum in movement Leiner HC, Leiner AL, Dow RS. Cognitive and lan- control and adaptation. Curr. Opin. Neurobiol. guage functions of the human cerebellum. Trends 1995;5:755–762. Neurosci. 1993;16:444–447. Thach WT. A role for the cerebellum in learning Llinás RR, Sotelo C, eds. The Cerebellum Revisited. movement coordination. Neurobiol. Learn. Mem. New York: Springer-Verlag; 1992. 1998;70:177–188. Manto M-U, Pandolfo M. The Cerebellum and its Thach WT, Bastian AJ. Role of the cerebellum in the Disorders. Cambridge: Cambridge University control and adaptation of gait in health and dis- Press; 2002. ease. Prog. Brain Res. 2004;143:353–366. Middleton FA, Strick PL. Basal ganglia and cerebel- Thompson RF, Kim JJ. Memory systems in the brain lar loops: motor and cognitive circuits. Brain Res and localization of a memory. Proc. Natl. Acad. Brain Res. Rev. 2000;31:236–250. Sci. USA 1996;93:13438–13444. Miller LE, Holdefer RN, Houk JC. The role of the Voogd J. The human cerebellum. J. Chem. Neu- cerebellum in modulating voluntary limb move- roanat. 2003;26:243–252. ment commands. Arch. Ital. Biol. 2002;140: Voogd J, Glickstein M. The anatomy of the cerebel- 175–183. lum. Trends Neurosci. 1998;21:370–375. Nunzi MG, Birnstiel S, Bhattacharyya BJ, Slater Zagon IS, McLaughlin PJ, Smith S. Neural popula- NT, Mugnaini E. Unipolar brush cells form a glu- tions in the human cerebellum: estimations from tamatergic projection system within the mouse isolated cell nuclei. Brain Res. 1977;127: 279–282. cerebellar cortex. J. Comp. Neurol. 2001;434: Zeeuw Cide, Strata P,Voogd J. The Cerebellum: From 329–341. Structure to Control. New York: Elsevier; 1997. 19 The Visual System

Anatomy of the Eye Retina Topographic (Retinotopic) Representation of the Visual Fields Retinogeniculostriate Pathway Visual Cortex The M (Magnocellular) and P (Parvocelllar) Pathways Reflex Pathways Control of Eye Movements Lesions of the Visual Pathways

We live largely in a visual world and yet our lens, located behind the iris diaphragm, is sus- eyes can detect only a small part of the broad pended by fine “guy ropes” called zonula fibers spectrum of electromagnetic radiation engulf- that encircle it and are anchored in the folds of ing us. The eyes are sensitive only in the wave- the ciliary body. lengths of the visual spectrum ranging from The cornea is a nonadjustable lens of the 400 to 700 nm, i.e., from blue to red. Signals eye, whereas the lens proper is adjustable. The from the eyes are transmitted centrally via sev- ciliary body contains involuntary muscles that eral pathways or channels reflecting different vary the tension exerted on the lens by the functional aspects of vision. The visual system zonula fibers. Their contraction alters the shape analyses such features as color, brightness, and, thus, refractive power of the lens called form or detail, three-dimensionality, location accommodation. The inner part of the ciliary and motion of an object. body, called the ciliary processes, secretes the aqueous humor, which circulates through and fills the anterior and posterior chambers of the ANATOMY OF THE EYE eye. The aqueous humor is returned to the venous circulation by diffusing through a tra- The eye is a globe composed of three layers becular network located deep to the irido- (see Fig. 19.1). The posterior five-sixths of the corneal angle of the anterior chamber (see Fig. outer layer consists of the tough fibrous sclera; 19.1). the transparent cornea covers the anterior part. The iris diaphragm surrounds the pupil. The middle layer consists of the vascularized The contractile state of the smooth muscles of choroid, the ciliary body and iris. The retina the iris results in the enlargement or reduction forms the inner layer. The neural portion of the in the diameter of the pupil and thereby regu- retina at the back of the eye contains the sen- lates the amount of light passing into the sory receptors (rods and cones). The non-neu- depths of the eye. Contraction of the radial ral portion consists of the unpigmented muscles of the iris results in dilation of the epithelium of the ciliary body and the pig- pupil. Contraction of the circular (sphincter) mented epithelium at the back of the iris. The muscles causes pupillary constriction.

329 330 The Human Nervous System

Figure 19.1: Horizontal equatorial section through the human right eye. The visual axis (VA) is the line joining the fixation or “nodal” point (center of object in focus) within the lens with the fovea. The optical axis (OA) is the line passing through the optical centers of the principal refract- ing surfaces, the cornea, and lens.

can detach from the retina. Collapse of the vit- RETINA reous humor leads to release of fibrous densities called floaters or muscae volitantes (flying Light passes through the cornea, lens, and flies)—compressed strands of gel and other two fluids—the aqueous humor in the anterior debris that can interfere with vision and be chamber between the cornea and the lens and bothersome. the vitreous humor between the lens and the retina—to reach the retinal photoreceptors (see The neural retina is part of the central nerv- Fig. 19.1). The aqueous humor is a clear ous system (CNS). Its five cell types include watery fluid that supplies nutrients to the avas- photoreceptor (rods and cones), bipolar, hori- cular cornea and lens. The vitreous humor is a zontal, amacrine, and ganglion cells (see Fig. moderately turgid gelatinous substance that is 19.2). Anatomically, the photoreceptor, bipolar, actually a form of connective tissue (98% and ganglion cells are vertically oriented water, 2% collagen and hyaluronic acid) com- sequentially within the retina. This forms a posed of a network of collagen fibrils. It con- direct functional pathway for “vertical infor- stitutes 80% of the volume of the eyeball and mation flow” to the brain. In contrast, the hori- maintains its shape. The vitreous becomes zontal and amacrine cells are horizontally more fluid with age; the mass decreases and oriented for “lateral information flow” within Chapter 19 The Visual System 331 the retina. The macula is a yellowish spot Rods and Cones (3 mm in diameter) in the middle of the retina Transduction in the photon-absorbing pho- with relatively few blood vessels, in the middle topigment triggers activation of a G-protein of which is the 0.4-mm fovea centralis contain- (transducin) and, in turn, a second-messenger ing only cone receptors (see Fig. 19.1). Cones biochemical cascade that regulates the opening diminish toward the peripheral part of the and closing of the c-GMP (guanosine mono- retina, where there are only rods. phosphate) ion channels of the membrane of The panorama seen by both eyes, fixed on the outer segment of the rods and cones (see one point at a single moment, is called the Fig. 19.3). All rods contain the photopigment visual field. Quanta of light called photons rhodopsin, which is sensitive to a broad range enter the eyes to stimulate the photopigments in of the visual spectrum with maximal absorp- the disks of the outer segments of the rods and tion at 495 nm. Rhodopsin mediates vision in cones (see Fig. 19.3). dim light. There are three types of cone, each

Figure 19.2: Laminar and cellular organization of the retina. 332 The Human Nervous System

Figure 19.3: A rod and a cone. Each rod (or cone) consists of an outer segment and an inner segment connected by a cilium. The outer segment of the rod is rod shaped and that of the cone is cone shaped. In both, the receptor disks are specialized structures of the plasma membrane that contain the photopigments (integral proteins). The new disks of a rod are continuously formed by repeated infolding of the plasma membrane at the base of the outer segment. The disks of the cones are not continuously replaced. The inner segment contains biosynthetic organelles and synaptic terminals. Chapter 19 The Visual System 333 with a photopigment sensitive to different phenomenon is explained by changes in the wavelengths of light, named short- (blue), degree of pupillary constriction and the response medium- (green), and long- (red) wavelength of the photoreceptors. This response is the cones. result of closure of the ion channels of the pho- The rods and cones generate separate paral- toreceptors, leading to a decrease in triggering lel processing pathway systems that transmit the second-messenger photoinduction cascade, information related to (1) light intensity and (2) thus reducing sensitivity of the receptors to spatial resolution (i.e., acuity or the ability of light. the eye to distinguish detail). The retinal gan- To summarize functional differences, the glion cells of these systems have a special role rods and cones allow the visual system to concerned with processing luminance contrast resolve the contested demands of sensitivity to (see later). light and visual acuity. The rod system is spe- The rod system has a low capacity for spa- cialized for sensitivity to light at the expense of tial resolution but is most sensitive to light resolution for visual acuity. The cone system is intensity. The cone system, in contrast, has a specialized for visual acuity at the expense of very high capacity for spatial resolution but is sensitivity to light. The rods and cones both relatively insensitive to light; thus, it is special- contribute to light adaptation. ized for visual acuity. The cone system also is The light receptors in each eye number important for color vision. about 91 million rods and 4.5 million cones. Within the retina, there is substantial conver- Dark and Light Adaptation gence from the rods to the approximately 1 The firing frequency of a receptor and its million ganglion neurons and slight to no con- neuronal connections declines under conditions vergence by cone systems. Within the fovea of constant stimulation called adaptation. Dark centralis, where visual acuity is sharpest and adaptation to light is the adjustment to the dark color vision is optimal, there is a “private-line that occurs during the shift from all-cone day- system” of 1:1 connectivity between a cone, to light vision to all-rod night vision. Rods are a bipolar cell, to a ganglion cell, to a neuron in insensitive to longer wavelengths at the red end the lateral geniculate nucleus of the thalamus of the visual spectrum. Thus, a pilot flying at (see Fig. 19.2). night, or a radiologist, can attain and retain dark-adapted vision by wearing red goggles in Center-Surround Receptive Fields and bright light, relying on long-wavelength red Center-Surround Retinal Ganglion Cells cones for visual functioning during this period. Each of the 1 million ganglion cells in the Dark adaptation is explained by a combina- retina receives stimulation from a spot in the tion of responses involving dilation of the pupils environment. The cell’s view of the environ- and adjustments in both the active circuitry ment is called its center-surround receptive within the retina and in the recycling of field. It consists of a small circle composed of rhodopsin in the rods. The latter is critically either an on excitatory center (like a hole in a important in the modulation of the cycle of doughnut) coupled with an antagonistic off adjustments to either increased or reduced inhibitory surround (the doughnut), or an off sensitivity of the photoreceptors and the main- center and an on surround (see Fig. 19.4). Two tenance of the photoreceptive pigments. Adap- classes of retinal ganglion cells are designated tation allows the visual system to respond as either on-center or off-center ganglion cells: effectively to the enormous range and varying Each is characterized by a receptive field com- degrees of luminal intensity from extremes of prised of a center and an antagonistic surround. brightness to darkness. On-center and off-center ganglion cells are Light adaptation is associated with the retina present in roughly equal numbers, with each becoming less sensitive to bright light. The pair of ganglion cells receiving inputs from a 334 The Human Nervous System

Figure 19.4: Diagram showing the functional organization of the visual system. (A) (a) Lateral view of visual pathway. The fibers projecting from the lateral geniculate body (LGB) to primary visual cortex (area 17, visual area 1, V1) comprise the optic radiations (geniculocalcarine pathway). (b) Medial view of the occipital lobe illustrating the primary visual cortex. (c) Ganglion cells of retina with center-surround (C-S) receptive field. (d) LGB: the magnocellular neurons (laminae I and II) are functionally color blind and have fast response, high-contrast sensitivity, and low resolution; parvicellular neurons (laminae III through VI) are functionally color selective and have slow response, low-contrast sensitivity, and high resolution. All neurons have center-surround receptive fields. (e) Cell of lamina IV (area 17) with center-surround receptive field. (f) Section through primary visual cortex and its laminae (see text for explanation). (g) Simple cell and complex cell, each with a receptive field comprised of an on-slit flanked by off-slits. (B) (h) Lateral view of the cerebral hemisphere showing some of Brodmann’s areas and extrastriate visual areas. (i) Representa- tion of portion of area 17 [refer to part (f)]. (j) Surface view of functional segregation of area 18 (visual area 2). B, blob; C-S, center-surround receptive field (on-center off-surround illustrated); IB, interblob; ITC, inferotemporal cortex; LGB, lateral geniculate body and its layers 1 through 6 (layers 1, 2, solid circles; layers 3–6, open circles); MT, middle temporal area (movement and stereopsis); STS, superior temporal sulcus; V4, visual area 4 (color). (Adapted from Livingstone and Hubel, 1988.) Chapter 19 The Visual System 335

Figure 19.4 (continued) single photoreceptor–bipolar cell sequence. In zation between the center and the surround is turn, each ganglion cell transmits via its axon known as center-surround opponency. This dif- all-or-none action potentials to a center-sur- ference is an expression of luminance contrast. round neuron in the lateral geniculate nucleus Actually, luminance contrast is a form of lateral (LGN). The retinal circuitry of the bipolar inhibition (or surround inhibition, Chap. 3), cells, horizontal cells, and amacrine cells com- which is a physiologic information processing municate via graded potentials. In contrast, the mechanism common to all sensory systems. ganglion cells communicate via action poten- The essential element in this contrast process is tials to the LGN. Signals from cones within the the inhibitory dopaminergic center-surround surround of a bipolar cell’s receptive field are amacrine cell that, by its inhibitory effect, mediated by horizontal cells and the intrinsic enhances the intensity of the luminance con- retinal circuitry before going to the ganglion trast (Dopamine, Chap. 15). cells. Because of the antagonistic surround, a gan- A ganglion cell is especially sensitive to glion cell responds more vigorously to all spots luminance contrast but relatively insensitive to of light confined to its retinal field center than the overall general level of illumination; that is, to uniform illumination of the visual field. Bor- the ganglion cell is responsive to the differ- ders and edges between light and dark (center ences between the intensity level that falls on and surround) are subjectively intensified by its receptive field center as contrasted to the luminance contrast. Artists commonly take antagonistic surround. The antagonistic organi- advantage of this phenomenon by darkening 336 The Human Nervous System the dark side of a border and whitening the are sculpted and refined by the influences of light side. amacrine cells. Each cone in the center of a receptive center surround field synapses (1) directly with two Types of Retinal Ganglion Cells types of bipolar cell and a horizontal cell and There are a few functionally distinct cate- (2) indirectly via local retinal circuitry with gories of ganglion cell distributed throughout amacrine cells. Each cone synapses with both the retina. Those important for perception are on-center and off-center bipolar cells. Cones referred to as M (<10% of the total) and P gan- release the neurotransmitter glutamate, which glion cells (80–90%), which are linked to rods inhibits (hyperpolarizes) on-center bipolar cells and cones. They give rise to separate parallel and excites (depolarizes) off-center bipolar pathways that go to the cerebral cortex. Approx- cells. The bipolar cells directly synapse with imately 2% of retinal ganglion cells contain an retinal ganglion cells and largely determine intrinsic photopigment melanopsin and are spe- their responses. The on-center bipolar cells, cialized to respond directly to luminance. They which become depolarized by the illumination project via the optic nerve to the suprachias- of the receptive field center, depolarize (excite) matic nucleus of the hypothalamus (retinohypo- an on-center ganglion cell. An off-center bipo- thalamic tract) an integral component of the lar cell evokes the opposite response. Signals circadian cycle discussed in Chapter 21. Other from the cones in the surround of a bipolar ganglion cells, which in part also can be linked receptive field are conveyed by horizontal cells to melanopsin, project to subcortical centers and the lateral retinal circuitry. The intrinsic cir- involved in reflexes. Among these are the pre- cuitry of bipolar, horizontal, and amacrine cells tectum, part of the pupillary light reflex pathway leading to the retinal ganglion cells is linked by for adjusting the size of the pupil, and the supe- graded potentials. In turn, the ganglion cell out- rior colliculus for coordinating head and eye put is transmitted centrally via action potentials. movements (see “Control of Eye Movements”). Retinal cells designated according to size, as The Roles of the Retinal Cells that Link the magnocellular (M) ganglion cells and parvo- Photoreceptors to the Ganglion Cells cellular (P) ganglion cells are of prime signifi- The bipolar cells provide a direct link cance. This correlates with the fact that the between the photoreceptor terminals and the former project to the two magnocellular layers dendrites of both on-center and off-center gan- and the latter to the four parvocellular layers of glion cells via rod and cone pathways. The hor- the lateral geniculate nucleus (see Fig. 19.4). izontal cells modulate the lateral interactions Both of these cell types increases in size rela- between photoreceptor terminals and the den- tive to distance from the fovea, where there are drites of bipolar cells and, in addition, transfer only P cells. The P ganglion cells, specialized information from distant cones to bipolar cells for visual acuity, are much smaller and have and ganglion cells. The amacrine cells mediate more restricted dendritic fields. The M cells, (1) lateral interactions between bipolar cell ter- with wider dendritic fields, detect low lumi- minals and the dendrites of ganglion cells and nance and movement. (2) antagonistic inputs from bipolar cells in the Retinal ganglion cells are the recipients of ganglion cell surround. There are over 20 dif- highly processed information generated by the ferent morphological types of amacrine cell intrinsic circuitry of photoreceptors, bipolar that release at least 8 different transmitters. cells, horizontal cells, and amacrine cells. The Some types have action potentials. Processing on-center and off-center ganglion cells, present by the amacrine cells contributes to ganglion in roughly equal numbers, transmit action cells having different functional features. The potentials via axons of the optic nerves that par- physiological responses of the ganglion cells tially decussate in the optic chiasm and form the are largely determined by the bipolar cells and optic tracts, which terminate in the LGN. Chapter 19 The Visual System 337

mation for visual perception (e.g., center sur- TOPOGRAPHIC (RETINOTOPIC) rounds) from the retina (see Fig. 19.4). The gan- REPRESENTATION OF THE glion cell axons coalesce at the optic disk (blind VISUAL FIELDS spot) and emerge from the eyes as the optic nerves, which are surrounded by meninges. The The retina of each eye is divided into a tem- nerves pass through the optic chiasma, where poral (lateral) half or hemiretina and a nasal fibers from the nasal hemiretina decussate and (medial) half by a vertical line passing through join the fibers from the temporal hemiretina of the fovea at the posterior pole of the eye. the opposite eye, which remain uncrossed, Hemiretinas, in turn, are subdivided into upper forming the optic tract. The temporal and lower quadrants by a horizontal line hemiretina of one eye and the nasal hemiretina through the fovea. The retina also is subdivided of the other eye view the same visual field so into three concentric circles: a small macular that the tract conveys information from the area, a pericentral (paramacular) area, and a opposite hemifield of both eyes; that is, the peripheral (monocular) area. optic tract on one side carries information Light rays that reach the eye from points in related to the contralateral visual fields. Most the visual fields are refracted by the cornea and fibers in the optic tract terminate in the LGN. the lens to form an inverted (upside down) and reversed (temporal–nasal) retinal image. In this Lateral Geniculate Nucleus sense, the eye resembles a camera—the retina The lateral geniculate in humans and other corresponding to the film. Hence, (1) the tempo- primates consists of six distinct cellular layers, ral visual field is projected to the nasal numbered in a ventral–dorsal sequence, and hemiretina and the nasal visual field is projected separated by thin fibrous bands. Layers one and to the temporal hemiretina and (2) the upper two contain larger neurons than the other four visual field is projected to the lower retina and the lower visual field is projected to the upper layers, dividing the LGN into magnocellular retina (see Fig. 19.5). Most of the visual field is and parvocellular parts. Axons of ganglion shared by the two eyes (binocular field), but the cells project to layers 2, 3, and 5 of the ipsilat- monocular area (monocular crescent) in the eral LGN and to layers 1, 4, and 6 of the con- extreme temporal field is seen only by the ipsi- tralateral LGN (see Figs. 19.4 and 19.6). There lateral eye when the eyes are fixed. Images of is no crosstalk between the layers. Fibers from points in the visual field are topographically the lower retina terminate laterally in the lateral formed on the retina, called a retinotopic or geniculate body (LGB), whereas fibers from visuotopic representation. The retinotopic the upper retina are distributed medially; organization is present at all levels of the visual macular inputs are located centrally. LGN neu- pathway. Similar to other sensory systems, the rons have properties that are similar to those representation of different parts of the visual expressed by the M and P ganglion cells, which field is disproportionate in size throughout the are their source of ascending input. The LGN, pathway, reflecting the fact that the fovea has the like other thalamic nuclei, gets a larger descend- greatest density of receptors and the peripheral ing input from the cerebral cortex, as described retina the least, Approximately half the fibers in in Chapter 23, and also receives afferents from the optic nerve are connected with the macula. the brainstem reticular formation.

RETINOGENICULOSTRIATE VISUAL CORTEX PATHWAY Primary Visual (Area 17, Striate) Cortex The retinogeniculostriate pathway to pri- Primary visual cortex is located in Brod- mary visual cortex conveys elemental Infor- mann’s area 17 largely buried within the 338 The Human Nervous System

Figure 19.5: The pathway of light from visual fields to the retina to lateral geniculate bodies and to primary visual cortex. The macular field projects to the posterior aspect of primary visual cortex (solid black). The area just rostral to this receives the rest of the binocular field, and still more rostral is the area for the monocular visual field. The upper half of the visual field projects to cortex below the calcarine sulcus (lingual gyrus). The lower half of the visual field projects to cortex above the sulcus (cuneate gyrus). Chapter 19 The Visual System 339 calcarine fissure on the medial surface of the The striate cortex is structurally laminated occipital lobe (see Figs. 1.5, 1.7, and 25.3). This horizontally into six layers and functionally cortex also is designated as the striate cortex organized vertically into columns called ocu- because of a prominent band of grossly visible lar dominance columns that are about 500 μm myelinated fibers in layer IV and as the visual wide and 2 mm deep (see Fig. 19.6). The ocu- area 1 (V1) to differentiate it from the numerous lar dominance columns are divided into orien- association areas numbered sequentially V2–V8. tation preference columns, which vary from Layer IV, known as the inner granular layer 30 to 100 μm in width. The cells in each lam- because of a large concentration of small stellate ina of a column respond and share to some cells, is highly developed and divided into degree the preferences exhibited by neurons in IVA–IVC, which are even further subdivided. all laminae.

Figure 19.6: Schematic of ocular dominance columns in area 17 showing some of their connectivity. Orientation columns (not illustrated) are also present in area 17. The nasal half of the retina projects to laminae 1, 4, and 6 of the contralateral lateral geniculate body (LGB) and the temporal half of the retina to laminae 2, 3, and 5 on the ipsilateral side. The magnocellular laminae 1 and 2 are represented by solid circles and the parvocellular laminae 3–6 are represented by open circles. N, nasal half of retina; T, temporal half of retina. (Adapted from Hubel and Wiesel, 1977.) 340 The Human Nervous System

Ocular Dominance Columns (ODC). Each angles, and corners and have special movement cell of the lateral geniculate is strictly monocular, and orientation properties. These properties are receiving input from one or the other eye, but not explained, in part, by the convergence of inputs both. In turn, each LGN neuron stimulates cells from simple cells. The simple and complex in lamina IV in a column of primary visual cor- cells are detectors of the receptive fields of tex, which also contains only monocular cells. straight-line segments, whereas hypercomplex The adjacent column receives geniculocortical cells are detectors of curved-line segments. terminations conveying signals from the other Area 17 has simple cells and complex cells, eye. The P and M pathways remain separated— whereas areas 18 (V2) and 19 (V3), which also fibers from the magnocellular LGN terminate in are in the occipital lobe, contain complex and Area 17, layer IVα and those from the parvocel- hypercomplex cells. This is a step in the process lular layers terminate in Area 17, layer IVβ. Cells that is a basis for the discrimination of form. within lamina IV interconnect with cells in more superficial and in deeper layers within the col- Blobs (Puffs) and Interblobs (Interpuffs). A umn where right and left eye columns are linked. regular array of zones called blobs and Although neurons in these other layers of the interblobs characterize laminae II and III of the ODC are binocular, they are dominated by the primary visual cortex (see Fig. 19.4). The zones laterality of input to the lamina IV cells. Bilateral are defined histochemically based on whether input from the two eyes through ocular domi- they stain darkly and are rich in the mitochon- nance columns is important for depth perception drial enzyme cytochrome oxidase (the blobs) or of a near object and is based on the fact that the stain lightly (the interblobs) (Wong-Riley et al., retinal images have a slightly different perspec- 1978). The blobs are color sensitive, orienta- tive. The functionally characterized columns are tion-nonspecific, and exhibit high spontaneous selectively responsive modules. activity. The interblob zones are relatively color insensitive, are orientation-specific, and exhibit Orientation Preference Columns. Cortical low spontaneous activity. Neurons in lamina I cells that are responsive to visual stimuli mainly project to the other columns of the striate cor- are classified on the basis of their receptive tex. Neurons in laminae II–IV project to extras- fields as center-surround simple, complex,or triate visual areas; those in lamina V project to hypercomplex. Neurons in lamina IVC of the the superior colliculus and LGB, and those in striate cortex are relatively unresponsive to lamina VI project back to the LGN. spots of light, in contrast to the center-surround In summary, the two principle roles of stri- cells that characterize ganglion cells and neu- ate cortex are as follows: (1) To fuse the inputs rons of the LGB. Simple cells and complex cells from both eyes into one image. Most cortical are responsive to short line segments with a par- cells of the ODCs have binocular receptive ticular orientation (vertical, horizontal, or fields and have the same size, shape, and orien- oblique at 1 o’clock, 2 o’clock, etc.). A bar tation and roughly the same position in the (line) of light activates a linear array of on- or visual field of each eye. They can have a role in off-center retinal ganglion cells and LGN neu- the perception of depth. (2) To analyze the rons. The geniculocortical fibers converge on a visual world with respect to the orientation of simple cell, which is maximally excited by a the stimuli in the visual fields. Each image in line with a particular orientation. Neighboring the visual field can be decomposed into short columns have slightly different orientation pref- segments of different orientation as an early erences. An orderly shift in the axis of orienta- step necessary for the discrimination of form. tion responsiveness occurs successively in adjacent columns, which complete a 360° cycle Visual Association Areas (Extrastriate Cortex) about every 0.75 mm. Complex and hypercom- The multiple visual association areas are plex cells respond optimally to edges, bars, cytoarchitecturally different from primary Chapter 19 The Visual System 341 visual cortex. Lacking the prominent band of The anatomic and electrophysiologic dispar- myelinated fibers in layer IV that characterizes ities between M and P ganglion cells described area 17, they collectively are referred to as the earlier reflect the fact that the pathways arising extrastriate cortex. The extrastriate cortex is from the two cell types are important for dif- largely dependent on the striate cortex for func- ferent aspects of visual perception. The M cells tional activation. Both area 18 (V2) immedi- have larger cell bodies, wider dendritic fields, ately surrounding area 17 and area 19 (V3) are and larger axon diameters. Thus, M cells have in the occipital lobe (see Figs. 25.5 and 25.6). larger receptive fields and faster conduction Within the extrastriate cortex, which extends velocities than do P cells. Magnocellular genic- into the parietal and temporal lobes, there are ulate cells respond to moving stimuli and are over 30 areas that are predominately or exclu- concerned with high-sensitivity vision of form sively functionally specialized visual subareas and contour, but are somewhat color-blind and (see Fig. 19.4B). Like V1, many have complete lacking in resolution or fine detail. The P cells retinotopic maps. have slower conduction velocities and are less sensitive to light, but they can resolve color and fine detail. Functionally, the M cells have a THE M (MAGNOCELLULAR) AND more sustained response. Information about P (PARVOCELLLAR) PATHWAYS color vision is transmitted by P cells, but not by M cells. This relates to the observations that P The processing pathways from the retina lead cells are sensitive to differences in the wave- to the coordination of the visual field inputs from lengths of light and stimulate the receptive both eyes and their fusion into a single image in fields of complex cells of blobs within the stri- the striate cortex, The independent features of ate cortex. Monkeys with lesions in the magno- form, depth motion, and color (e.g., center-sur- cellular layers of the LGN do not show changes round line segments) are initially demonstrated in visual acuity or perception of color, but do in the striate cortex. The concurrent circuitry of exhibit a reduced ability to perceive moving the M and P pathways to the striate cortex con- stimuli. In contrast, lesions of the parvocellular tinue as parallel pathway streams to the extrastri- layers of the LGN have no effect on detection ate cortex (areas 18, 19, V2–V6, and others) for of movement, but profoundly impair visual processing into congruent visual images. acuity and color perception. The M pathway is The M cells and P cells (retinal ganglion especially involved with information concern- cells and LGN cells) are linked together by ing movements of objects through space. The P common center-surround receptive fields, pathway is primarily concerned with high- which are major components of the combined resolution vision such as the detailed apprecia- M pathway and P pathway. These two pathways tion of the shape, size, and color of objects. The project to and through primary visual cortex to multitude of features viewed at each moment is the extrastriate cortex as distributed processing processed in parallel by the M and P pathways streams involved in visual perception. Within and distributed to the numerous extrastriate each cerebral hemisphere, (1) the dorsal or pari- cortical areas. etal stream, comprised primarily of fibers of the The dorsal or parietal M stream is concerned M stream with some contribution from the P with contrast, movements of objects in space, stream, extends from the striate cortex to area spatial localization, and stereopsis, including 18 and through the middle temporal area (MT, where an object is. The ventral, or temporal, V5) to the posterior parietal lobe cortex and (2) combination of P and M stream pathways is the ventral or temporal stream of combined M important for high-resolution vision, including and P pathways extends from striate cortex to the detailed analysis of shape, size, and color. and through V2, V3, and V4 to the inferior tem- The dorsal stream for spatial localization is poral cortex (see Fig. 19.4). channeled to the MT area and posterior parietal 342 The Human Nervous System lobe cortex. The ventral stream for object to be of importance in interconnecting the recognition is channeled to inferotemporal cor- visual association areas (Chap. 23). tex. Area MT contains neurons that respond selectively to the direction of a moving edge without regard to color. Ablation of the MT in REFLEX PATHWAYS monkeys leads to impairment in the ability to perceive the direction of motion of a simulated Pupillary Light Reflex Pathway pattern while other aspects of visual perception to the Pretectum (see Fig. 19.7) remain intact. In contrast, area V4 responds When a bright light is directed into an eye, selectively to color without regard to direction the pupils of both eyes constrict as a result of of movement. The P stream is important for contraction of the constrictor muscles of the high-resolution vision—the detailed analyses iris. The response in the stimulated eye is called of the shape size and color of objects. The ven- the direct light reflex and that in the unstimu- tral stream depends on both M and P systems lated eye is called the consensual light reflex. from V1 to V4 and is divided further into two The sequence and course of neurons in this arc streams: one involving the striate cortex blobs are as follows: Axons of the ganglion cells of for color, form, and movement and the other each eye pass via the optic nerve, chiasma involving the interblobs for contrast. These dif- (where some of the fibers decussate), tract, and ferences are justification for calling the streams brachium of the superior colliculus before ter- two parallel pathways. However, it should be minating bilaterally in the pretectum of the noted that there is crosstalk between the two midbrain. The paired pretectal nuclei are inter- streams at the cortical level. connected by fibers passing through the poste- Details remain to be elucidated concerning rior commissure. The pretectal nucleus on each the steps taken connecting the complex visual side projects bilaterally to pupillomotor cells in images from the patterns of dark and light that the accessory oculomotor nuclei of Edinger– fall on the retina followed by the processing in Westphal. The Edinger–Westphal nucleus gives the neuronal pathways culminating in the more rise to preganglionic parasympathetic fibers abstract processing in the dorsal parietal stream that enter the oculomotor nerve and terminate and ventral inferior temporal stream of the M in the ciliary ganglion within the orbit. Post- and P pathways to the numerous cortical visual ganglionic fibers from the ciliary ganglion areas. The pulvinar, which is the largest thala- elicit contraction of the constrictor smooth mic nucleus, can play a substantial role in inte- muscle of the iris, which decreases the diame- grating the separate pieces of information ter of the ipsilateral pupil. received by different regions of the extrastriate The consensual light reflex occurs because cortex. It receives its first major afferent input the pretectum receives input from both eyes from the extrastriate cortex, with which it is and, in turn, projects bilaterally to the Edinger– reciprocally interconnected, and is considered Westphal nucleus. These reflexes are carried

Figure 19.7: The pupillary light reflex and the accommodation reflex pathways and the pathway for pupillary dilatation. The light reflex pathway is mediated by axons from photopigment- containing ganglion cells that terminate bilaterally in the midbrain pretectum, located immediately in front of the superior colliculus. The pretectal nuclei are a relay to the Edinger–Westphal (E-W) nucleus on both sides. The latter gives rise to parasympathetic preganglionic fibers in the oculomotor nerve that terminate in the ciliary ganglion whose postganglionics elicit pupillary constriction. Although not classified as part of the light reflex, the diameter of the pupil is controlled by interaction between the parasympathetic and sympathetic nervous systems. The E-W nucleus also Chapter 19 The Visual System 343

gives rise to fibers that descend through the brainstem to the sympathetic outflow in the upper thoracic spinal cord. Preganglionics ascend to the superior cervical ganglion whose postganglionics elicit pupillary dilatation. Accommodation is mediated via (1) the ascending visual pathway, (2) descending corticocollicular fibers from the occipital (area 19), and frontal (area 8) lobes, (3) a relay in the superior colliculus to the E-W nucleus, (4) the preganglionic parasympathetic outflow through the oculomotor nerve to the ciliary ganglionic, which gives rise to (5) postganglionic fibers that activate the ciliary muscles. 344 The Human Nervous System out unconsciously without any cortical involve- syndrome, the pupil is small in dim light and ment. This reflex is preserved even after lesions does not constrict further when the eye is involving the lateral geniculate bodies, optic exposed to bright light. However, the same radiations or visual cortex. Individuals afflicted pupil will constrict further during the accom- with cortical blindness resulting from complete modation–convergence reaction. This syn- destruction of both striate cortices retain the drome is presumed to be caused by lesions in light reflexes. the pretectum.

Accommodation Reflex Circuit (see Fig. 19.7) Pupillary Dilatation Circuit (see Fig 19.7) The adjustments of the lens by the action of Descending sympathetic pathways pass the ciliary body to bring an object into focus are through the brainstem and anterior half of the known as accommodation. The ciliary body is spinal cord before terminating on pregan- the ring of tissue that encircles the lens and con- glionic neurons of the intermediolateral cell tains the circular and radial smooth muscle column at C8 and T1 spinal levels. The pregan- fibers that adjust the refractive power of the lens glionic fibers ascend through the sympathetic and also has a vascular component (the ciliary chain and synapse in the superior cervical processes) that secretes the aqueous humor that ganglion. Postganglionic sympathetic axons fills the posterior and anterior chambers of the course along branches of the internal carotid eye (see Fig. 19.1). Unlike the light reflexes, cir- artery to reach the radial smooth muscle fibers cuitry of the accommodation reflex includes the in the iris, whose contraction dilates the pupil. visual cortex; an individual does exert some con- Interruption of the preganglionic or postgan- trol in selecting an object brought into focus. glionic fibers results in an ipsilateral Horner’s Impulses from the eye are relayed via the visual syndrome (Chap. 12); the syndrome can occur pathways to the visual cortex. Neurons in the following lesions in the brainstem. visual areas have axons, which descend through the optic radiation to the superior colliculus. In turn, collicular neurons project to the preganglionic parasympathetic neurons of the acces- CONTROL OF EYE MOVEMENTS sory oculomotor nucleus of Edinger–Westphal, which, after passing through the oculomotor The Retino–Superior–Colliculus nerve, synapse with postganglionic parasympa- (Retino-Tectal) Pathways for thetic neurons in the ciliary ganglion. These neu- Coordinating Eye and Head Movements rons innervate the smooth muscles in the ciliary The superior colliculus has a major role in body, which regulate the tension on the lens. coordinating eye and neck movements to detect, capture, track, and maintain the visual Accommodation–Convergence image on the fovea called foveation. The super- Reaction Circuit ficial layers of the superior colliculus receive Shifting focus from a distant object to a near direct visual input from the retina and indirect one involves a triad of actions. Contraction of input from the visual cortex. Visual information the ciliary muscles causes the lens to thicken in is coordinated with auditory and vestibular order to bring the object into focus by accom- inputs, which are distributed to the intermedi- modation. The eyes converge as the medial ate layers. The superior colliculus controls the recti muscles contract and the pupils constrict proper tracking of the eyes to a vast repertoire to enhance the definition of the image. of environmental stimuli. Superior colliculus cells are especially responsive to motion within Argyll–Robertson Pupil the receptive field. Descending projections The Argyll–Robertson pupil can occur in from the visual cortex and the frontal eye fields syphilis of the central nervous system. In this (Brodmann’s area 8) project to the superior col- Chapter 19 The Visual System 345 liculus and to the paramedian pontine and mid- fixation of the eyes on an object while the brain gaze centers for control or horizontal and head is in motion. It requires coordinated vertical eye movement (EOM), respectively contraction of the extraocular muscles, (Chap. 16). The gaze centers provides the basis which is mediated by ascending pathways of for integrated EOMs in response to sensory the vestibular system for control of EOMs, information that helps to locate moving objects and by descending vestibular pathways to in space. The deeper layers of the superior col- the neck musculature to maintain head posi- liculus project to the gaze centers and are the tion. This “keep eyes on target” activity is source of the tectospinal tract for coordination expressed as the head turns in one direction of head and eye positions and tectopontine and the eyes move in the opposite direction fibers for relay to the cerebellum. As with other so that the gaze remains fixed on the object. muscle groups, the coordination of eye muscles 4. Vergence eye movements. Influences from is influenced by the cerebellum and basal gan- cortical areas 19 and 22 direct convergence glia (Chaps. 18 and 24). so that both eyes remain fixed upon a near object. Under normal circumstances, diver- Types of Eye Movements gence beyond the parallel position usually Eye movements are categorized as conjugate does not occur. (i.e., both eyes move in parallel) or disconjugate (i.e., eyes move in opposite directions as occurs A duck hunter sitting in a gently rocking during ocular convergence to focus on a near boat in a tidal marsh illustrates the action of object). Conjugate EOMs are mediated through these four systems. The hunter scans the sky for the superior colliculus and the paramedian pon- a duck using saccadic eye movements from tine and midbrain reticular formation point to point (a visual image is not recogniza- (Chap.16). Four basic types of EOMs are rec- ble during saccades because the motion during ognized; each is activated by an independent the saccade is too fast). Smooth pursuit move- control system involving different regions of ments follow the duck, once it is spotted. If the the brain. duck flies close by, the vergence (convergence) eye movements combine with the pursuit 1. Fast saccadic eye movement, movement on movements as the hunter’s vision shifts from command, searching movement. This move- far to near vision. During the entire sequence, ment is the saccade (e.g., fast component in the hunter employs VOR movements to com- nystagmus), in which the eyes are searching pensate for movements of the head caused by for an object upon which to fixate. Activa- the rocking of the boat. tion of the frontal eye fields (area 8) by a “command,” or stimulation of the superior colliculus, evokes this quick voluntary LESIONS OF THE VISUAL PATHWAYS movement of the eyes. The visual image is suppressed during a saccade. Electrical By convention, injury to the visual path- stimulation of area 8, or of the superior col- ways causes defects described in terms of liculus, causes the eyes to deviate to the gaps in the visual field of each eye, as shown opposite side. in Fig. 19.8. Defects limited to the same 2. Slow pursuit or tracking an ongoing motion. visual field of each eye are called homony- This action occurs while following a moving mous, whereas those located in different fields object (following a bird in flight). Activation are heteronymous. Partial lesions produce par- of cortical areas 18 and 19 evokes this tial defects in the fields of vision. Damage to movement. a small area of the retina results in a blind spot 3. Vestibuloocular reflex (VOR) eye move- (scotoma) referred to the visual field of the ments. The VOR EOMs serve to maintain affected eye. The optic disk, where the optic 346 The Human Nervous System

Figure 19.8: Lesions at different sites within the visual pathways. The corresponding visual field defects are represented on the right side of the drawing. nerve fibers converge to leave the retina, is a normal eye because the afferent limb of the natural blind spot because it contains no reflex from the blind eye is interrupted. receptors. The optic disk is 3 mm (15() medial A midline lesion of the optic chiasma to the fovea. Thus, because of reversal of the (following compression from a tumor of the image, the blind spot is 15° lateral (i.e., in the pituitary gland or from a craniopharyngioma temporal field). Complete interruption of the located immediately behind the chiasma) can optic nerve results in permanent blindness in interrupt the decussating fibers from both eyes one eye (see Fig. 19.8A). The direct light (see Fig. 19.8B). This results in blindness in the reflex in that eye is eliminated. However, a nasal half of the retina (the temporal half of the blind eye can still accommodate and exhibit visual field of each eye); it is called bitemporal the consensual light reflex because the normal heteronymous hemianopsia (hemianopia) or eye activates the intact efferent part of the tunnel vision. Damage to the nondecussating reflex arc to the blind eye. On the other hand, fibers on one (right) side of the optic chiasma the consensual light reflex is eliminated in the results in a right nasal hemianopsia (see Fig. Chapter 19 The Visual System 347

19.8C) (i.e., blindness in the temporal half of the Dacey DM, Packer OS. Colour coding in the pri- retina [nasal half of the visual field of one eye]). mate retina: diverse cell types and cone-specific The complete interruption of the optic tract, lat- circuitry. Curr. Opin. Neurobiol. 2003;13: eral geniculate body, optic radiations, or the 421–427. entire primary visual cortex on one side (e.g., Dacey DM, Peterson BB, Robinson FR, Gamlin PD. right) results in a contralateral homonymous Fireworks in the primate retina: in vitro photody- hemianopsia, or blindness in the field of vision namics reveals diverse LGN-projecting ganglion cell types. Neuron 2003;37:15–27. on the side opposite (left) the lesion (see Fig. Desimone R. Neural mechanisms for visual memory 19.8D). Macular sparing (preservation of the and their role in attention. Proc. Natl. Acad. Sci. visual field of the maculae) sometimes occurs USA 1996;93:13494–13499. following strokes involving the visual cortex. Deyoe EA, Trusk TC, Wong-Riley MT. Activity cor- This phenomenon is attributable to a dual vascu- relates of cytochrome oxidase-defined compart- lar supply to this region from branches of both ments in granular and supragranular layers of the middle and posterior cerebral arteries as well primary visual cortex of the macaque monkey. as to the extensive cortical representation of the Vis. Neurosci. 1995;12:629–639. central visual field. A lesion of the entire cuneate Dowling JE. The Retina: An Approachable Part of gyrus (includes entire primary visual cortex the Brain. Cambridge, MA: Belknap Press of above the calcarine sulcus) on one side results in Harvard University Press; 1987. contralateral homonymous lower quadrantic Grill-Specton K, Levan AC. The human visual cor- anopsia (see Fig. 19.9E) because pathways from tex. Ann. Rev. Neurosci. 2004;27:649–677. the upper temporal quadrant of the ipsilateral Hattar S, Liao HW, Takao M, Berson DM, Yau KW. retina and upper nasal quadrant of the contralat- Melanopsin-containing retinal ganglion cells: eral retina are interrupted. Conversely, a lesion architecture, projections, and intrinsic photosen- Science of the lingual gyrus (below the calcarine sulcus) sitivity. 2002;295:1065–1070. Hattar S, Lucas RJ, Mrosovsky N, et al. Melanopsin or interruption of the optic radiations on one side and rod-cone photoreceptive systems account for as they pass through the temporal lobe (loop of all major accessory visual functions in mice. Archambault–Meyer) results in contralateral Nature 2003;424:75–81. homonymous upper quadrantic anopsia (see Hubel DH. Eye, Brain, and Vision. New York: Sci- Fig. 19.8F) because pathways from the lower entific American Library; 1987. temporal quadrant of the ipsilateral retina and Hubel DH, Wiesel TN. Functional architecture of lower nasal quadrant of the contralateral retina macaque monkey visual cortex. Proc. R. Soc. are interrupted. Lond. B: Biol. Sci. 1977;198:1–59. A lesion in cortical area 8 in one hemisphere Kleinschmidt A, Buchel C, Zeki S, Frackowiak RS. results in the deviation of the eyes to the same Human brain activity during spontaneously side. reversing perception of ambiguous figures. Proc. R. Soc. Lond. B: Biol. Sci. 1998;265:2427–2433. Livingstone M, Hubel D. Segregation of form, color, SUGGESTED READINGS movement, and depth: anatomy, physiology, and perception. Science 1988;240:740–749. Adams DL, Zeki S. Functional organization of Marcus DS, Van Essen DC. Scene segmentation and macaque V3 for stereoscopic depth. J. Neuro- attention in primate cortical areas V1 and V2. J. physiol. 2001;86:2195–2203. Neurophysiol. 2002;88:2648–2658. Adams MM, Hof PR, Gattass R, Webster MJ, Oyster CW. The Human Eye: Structure and Func- Ungerleider LG. Visual cortical projections and tion. Sunderland MA: Sinauer Associates; 1999. chemoarchitecture of macaque monkey pulvinar. Purves D and Lotto RB. Why We See What We Do: J. Comp. Neurol. 2000;419:377–393. An Empirical Theory of Vision. Sunderland, MA: Dacey DM. Parallel pathways for spectral coding in Sinauer Associates; 2003. primate retina. Annu. Rev. Neurosci. 2000;23: Rodieck RW. The First Steps in Seeing. Sunderland 743–775. MA: Sinauer Associates; 1998. 348 The Human Nervous System

Shipp S, Zeki S. The functional organization of area Wong-Riley M, Antuono P, Ho KC, et al. V2, II: the impact of stripes on visual topogra- Cytochrome oxidase in Alzheimer’s disease: bio- phy. Vis. Neurosci. 2002;19:211–231. chemical, histochemical, and immunohistochem- Van Essen DC, Lewis JW, Drury HA, et al. ical analyses of the visual and other systems. Vis. Mapping visual cortex in monkeys and humans Res.1997;37:3593–3608. using surface-based atlases. Vis. Res. 2001;41: Zeki S. A Vision of the Brain. Oxford: Blackwell 1359–1378. Scientific; 1993. Wong-Riley MT, Hevner RF, Cutlan R, et al. Zeki S. Improbable areas in the visual brain. Trends Cytochrome oxidase in the human visual cortex: Neurosci. 2003;26:23–26. distribution in the developing and the adult brain. Vis. Neurosci. 1993;10:41–58. 20 Autonomic Nervous System

The Somatic Motor and Autonomic Nervous Systems Compared General Organization of the Autonomic Nervous System Sympathetic (Thoracolumbar) Division Parasympathetic (Craniosacral) Division Enteric (Gut) Division (“Gut-Brain,” “Minibrain”) Sensory and Humoral Systems Central Autonomic Control Circuits Denervation Sensitivity and Sympathectomy Neural Control of the Urinary Bladder Megacolon (Hirschsprung) Disease

The contraction (or relaxation) of muscles autonomic nervous system (ANS) is to influ- and the secretion of glands is an overt expres- ence those visceral activities that are directed sion of the functional activity of the nervous toward maintaining a relatively stable internal system. These actions are mediated through the environment. For example, functional expres- somatic motor system and the autonomic (vis- sions of the activity of the ANS are the mainte- ceral) nervous system. The somatic motor sys- nance of (1) blood pressure commensurate with tem innervates the voluntary (skeletal, striated) the demands of the organism and (2) a constant muscles, whereas the autonomic nervous sys- body temperature. These two systems are not tem influences the activities of involuntary independent; they interact. With a drop in body (smooth) muscles, cardiac (heart) muscle, and temperature, the somatic motor system responds glands. The autonomic nervous system is often by generating heat through contraction of vol- called the general visceral efferent system or untary muscles, and the ANS simultaneously vegetative motor system because the effectors stimulates the constriction of cutaneous blood are associated with the visceral systems over vessels to reduce radiational heat loss. In which only minimal, if any, direct conscious general, the somatic system reacts rapidly to control can be exerted. stimulation, whereas the autonomic system responds with a greater lag time. The two systems differ significantly with THE SOMATIC MOTOR AND reference to the anatomic organization of the AUTONOMIC NERVOUS final neuronal linkage between the central SYSTEMS COMPARED nervous system (CNS) and the peripherally located effectors. The somatic motor system The role of the somatic motor system is to has a one-neuron linkage to alpha and/or regulate and perform the coordinated muscular gamma motoneurons. From a cell body in the activities associated with the maintenance of brainstem or spinal cord, each somatic LMN posture and with phasic movements; these gives rise to an axon that passes through a cra- expressions are related to adjustments to the nial or spinal nerve to make synaptic connec- external environment. The general role of the tions with voluntary muscle fibers (Chap. 11).

349 350 The Human Nervous System

In contrast, the autonomic system has a two- nial or peripheral nerve and synapses, either neuron linkage to peripheral effectors (see Fig. directly or via an interneuron, with a second 20.1). The first neuron, called a preganglionic neuron (or neurons) located in an autonomic neuron, originates in the brainstem or spinal ganglion outside the CNS, This second neuron, cord and has an axon that passes through a cra- called a postganglionic neuron, or autonomic

Figure 20.1: Motor innervation of the peripheral effectors. (A) The parasympathetic outflow from the medulla innervates cardiac muscle, smooth muscle, and glands. The lower motoneuron innervates striated muscle. (B) Sympathetic outflow from the spinal cord innervates cardiac muscle, smooth muscle, and glands. Sympathetic ganglia have interneurons called small intensely fluorescent (SIF) cells, which contain catecholamine fluorescent dopamine and norepinephrine. Chapter 20 Autonomic Nervous System 351 motoneuron, has an axon that terminates in (1) its preganglionic fibers emerge with cranial endings associated with smooth muscles, car- nerves III, VII, IX, X and at spinal cord levels diac muscle, or glands and, as recently recog- S2–S4 and (2) the neurosecretory transmitter nized, cell constituents associated with released by the postganglionic fibers is acetyl- immune organs. The preganglionics are myeli- choline. nated B fibers and the postganglionics are The enteric division (ENS), also called the unmyelinated C fibers. When denervated, gut brain or minibrain, is an intrinsic network smooth muscles and glands generally continue of neurons and connections that extends along to show significant levels of activity. the entire length of the digestive system (Gr. Although the ANS frequently is considered enteron) from the esophagus to the rectum, only in terms of its preganglionic and postgan- otherwise known as the enteron gut or gas- glionic motor components, there are extensive trointestinal (GI) tract. Two interconnected ascending and descending visceral pathways, ganglionic plexuses form the ENS. Sensory just as in the somatic system. neurons communicate via interneurons with the two plexuses: Auerbach’s myenteric plexus and Meissner’s submucosal plexus (see Fig. 20.4). GENERAL ORGANIZATION OF THE (1) The motor Auerbach’s myenteric plexus, AUTONOMIC NERVOUS SYSTEM consisting of radially oriented axons, is located between the circular and longitudinal smooth The ANS is composed of three divisions or muscle laminae of the external muscularis systems: (1) sympathetic (see Fig. 20.2), (2) layer. It controls gut motility. The enteric sen- parasympathetic (see Fig. 20.3), and (3) enteric sory neurons are integrated into enteric feed- (see Fig. 20.4). back circuits projecting centripetally to the The sympathetic division stimulates those abdominal prevertebral, celiac, and superior activities that are mobilized by the organism and inferior mesenteric ganglia adjacent to the during emergency and stress situations, the so- posterior abdominal wall; these ganglia project called “fight, fright, and flight” responses. back to the gut. (2) Meissner’s plexus, located These include acceleration of the rate and force in the submucosa of the gut, is concerned with of the heartbeat, increase in the concentration of chemical monitoring of gut contents and con- blood sugar, and increase in blood pressure. In trolling glandular secretion. A key feature of contrast, the parasympathetic system stimulates the ENS is its anatomical and physiological activities associated with conservation and independence. With this system intact, the gut restoration of body resources. These include a can function autonomously even when com- decrease in heart rate and a rise in gastrointesti- pletely deprived of sympathetic and parasym- nal activities associated with increased diges- pathetic innervation. Functionally, the tion and absorption of food. The enteric nervous submucosal plexus controls the secretory func- system (ENS) is involved in gut functioning and tions of the gut and the myenteric plexus con- can operate without CNS control. trols gut motility. The sympathetic division is also called the thoracolumbar or adrenergic system because (1) its preganglionic fibers emerge from all tho- SYMPATHETIC racic and the upper two lumbar levels (T1 (THORACOLUMBAR) DIVISION through L2) and (2) the neurosecretory transmitter released by the postganglionic fibers in The organization of the sympathetic system most loci is norepinephrine, also known as is illustrated in Fig. 20.2. The peripheral and noradrenalin. central control of each target organ comes from The parasympathetic division is also called preganglionic neurons in a continuum of spinal the craniosacral or cholinergic system because cord segments with functionally differentiated 352 The Human Nervous System

Figure 20.2: The sympathetic (thoracolumbar) division of the autonomic nervous system. Chapter 20 Autonomic Nervous System 353 columns of neurons. Preganglionic fibers of the nerves that target cranial viscera, including in sympathetic system originate from cell bodies the eye and pineal gland. Vasoconstrictor, pilo- located in the intermediolateral nuclei of lam- motor, sudomotor, and secretomotor neurons ina VII, which extends from spinal levels T1 are included. Stellate ganglia at the rostral end through L2. Visceral afferents to the sympa- of the sympathetic chain emit postganglionic thetic preganglionic neurons are conveyed via fibers to the heart, lungs, neck, and upper fibers of the dorsal roots to the spinal cord and extremities. The paravertebral ganglia do not by cranial nerves via relays in the solitary project to the extremities along the major blood nucleus, as noted in Chapters 7 and 14. The vessels. Splanchnic nerve projections to the preganglionic sympathetic fibers pass succes- viscera mainly innervate blood vessels. The sively through the ventral roots (referred to as prevertebral ganglia, which regulate motility the thoracolumbar outflow), spinal nerves, and secretions, receive input from midthoracic white rami communicantes (branches of the and upper lumbar spinal cord segments. Post- spinal nerves) and the sympathetic trunk (see ganglionic fibers arising from the prevertebral Fig. 7.2). The fibers terminate in either (1) par- ganglia form perivascular plexuses innervating avertebral ganglia of the sympathetic chain the abdominal and pelvic viscera. (trunk) or (2) they pass through the chain and Diffuse and extensive branching patterns are enter visceral nerves, which go to prevertebral characteristic of postganglionic noradrenergic (collateral) ganglia (see Fig. 20.2). The par- nerves of the sympathetic nervous system. A avertebral ganglia, which are located along the single neuron can have many terminal branches bodies of the vertebral column from upper over 14 cm long with several thousand vari- cervical through coccygeal levels, receive their cosities containing the transmitter (norepineph- input exclusively from the thoracolumbar rine) and modulators (Neuropeptides, Chap. 15). sympathetic outflow. The paired sympathetic These varicosities make numerous en passage chains meet in the midline in a terminal gan- “synaptic junctions” with muscle and glandu- glion on the coccyx, called the ganglion impar lar cells (see Fig. 15.4). The visceral effector is or coccygeal ganglion. The prevertebral gan- a muscle bundle rather than a single cell; indi- glia are located in the abdomen adjacent to the vidual muscle cells are linked and coupled by abdominal aorta and its main branches: the gap junctions, which cause electrotonic spread celiac, aorticorenal, and superior mesenteric of activity between them. and inferior mesenteric ganglia (derived from In general, the sympathetic outflow is dis- T6 through L2 spinal levels). The sympathetic tributed as follows: T1–T5 to the head and ganglia contain small intensely fluorescent neck, T1–T2 to the eye, T2–T6 to the heart and (SIF) inhibitory interneurons (see Fig. 20.1) lungs, T6–L2 to the abdominal viscera, and that mainly are dopaminergic. L1–L2 to the urinary, genital, and lower diges- Paravertebral ganglia project to the viscera tive systems. of all somatic dermatomes (see Fig. 20.2). The neurotransmitter released by the pre- Postganglionic fibers from cells in the paraver- ganglionic nerve terminals is acetylcholine, tebral ganglia pass via the gray rami communi- which is deactivated rapidly by cholinesterase cantes (1) and spinal nerves before terminating or recycled; that released by the postgan- in the sweat glands and smooth muscles of glionic nerve terminals is norepinephrine blood vessels and hair (erector pili muscles) of (noradrenalin, levarterenol) and is either the body wall and extremities and (2) small deactivated slowly by monoamine oxidase nerves and perivascular plexuses to the visceral (MAO) and catechol-O-methyl transferase structures of the head and thorax (e.g., pupil- (COMT) or retrieved by reuptake for reuse by lary dilator muscle, heart, and bronchioles). the nerve terminals (Chap.15). The MAO is Axons from the superior cervical ganglia fol- located intracellularly, whereas COMT is low the internal carotid artery before joining extracellular. 354 The Human Nervous System

Adrenal Gland pelvic viscera. The body wall and the extremi- The cells of the medulla of the adrenal gland ties do not have a parasympathetic innervation. are actually specialized postganglionic neu- Following is a list of the four cranial nerve rons. Preganglionic cholinergic fibers from T6 brainstem preganglionic parasympathetic to T9 stimulate the adrenal chromaffin cells to nuclei, their connections, and the organs inner- release both epinephrine and norepinephrine vated (see Fig. 20.3). (1) Preganglionic fibers into the circulatory system, which distributes from the accessory oculomotor nucleus of these neurosecretions through the body. Within Edinger–Westphal in the midbrain pass via the the medulla, there are about eight cells that oculomotor nerve and terminate in the ciliary release epinephrine to one cell that releases ganglion. Postganglionic neurons innervate the norepinephrine. The adrenal medulla-released sphincter (constrictor) muscles of the pupil and transmitters act in conjunction with the norepi- the ciliary muscles involved with accommoda- nephrine released by sympathetic postgan- tion (focusing the lens of eye). (2) Preganglionic glionic fibers. In humans and other mammals, fibers from the superior salivatory nucleus pass where the adrenal cortex and medulla are juxta- via cranial nerve VII and terminate in the ptery- posed, epinephrine is the main catecholamine. gopalatine and submandibular ganglia. Post- The adrenal cortex envelops the medulla and ganglionic neurons innervate numerous glands synthesizes glucocorticoids, which are essen- in the head, including lacrimal, submandibular, tial for the conversion of norepinephrine to epi- and sublingual glands and glands of the nasal, nephrine. oral, and pharyngeal cavities. (3) Preganglionic fibers from the inferior salivatory nucleus pass Systemic Effects of Sympathetic Innervation via the glossopharyngeal nerve and terminate The sympathetic system is structurally and in the otic ganglion on postganglionic neurons functionally organized to exert its influences that innervate the parotid gland. (4) Pregan- over widespread body regions or even the glionic fibers from the dorsal motor nucleus of entire body for sustained periods of time. Every the vagus pass via cranial nerve X and synapse preganglionic neuron has a relatively short in terminal ganglia (located adjacent to or axon, which synapses with many postgan- within visceral organs). Postganglionic neurons glionic neurons, each of which has a long innervate the viscera of the thorax and branching axon forming numerous neuroeffec- abdomen (e.g., heart, lungs, and GI tract) as far tor junctions over a wide area. The widespread as the splenic flexure (junction of transverse and sustained sympathetic effects are the result and descending colon on left side). The vagus of the slow deactivation of norepinephrine and nerve is prototypical of the parasympathetic of the systemic distribution of norepinephrine system. Its long preganglionic axons synapse in and epinephrine released by the adrenal terminal ganglia located in or near the targets medulla. of the very short postganglionic axons with little divergence. Hence, the effects are localized rather than widespread. It is interesting to note PARASYMPATHETIC that of the 5000 neurons of the vagus nerve (CRANIOSACRAL) DIVISION innervating the gut, about 90% are afferent neurons and only 10% are preganglionic The cranial portion of the parasympathetic parasympathetic neurons. system is associated with four cranial nerves The pelvic hypogastric plexuses comprise (III, VII, IX, and X) that supply innervation to the ganglia controlling the genitourinary organ the head, thorax, and most of the abdominal systems. The sacral portion of the parasympa- viscera (see Fig. 20.3). The sacral portion takes thetic system originates from cell bodies origin from spinal cord levels S2–S4 and sup- mainly in the gray matter of levels S2–S4; the plies innervation to the lower abdominal and preganglionic neurons pass via the pelvic Chapter 20 Autonomic Nervous System 355

Figure 20.3: The parasympathetic (craniosacral) division of the ANS. 356 The Human Nervous System splanchnic nerves to synapse in terminal gan- different cell types have been described releas- glia whose postganglionic neurons innervate ing more than 20 different transmitters and the lower abdominal and pelvic viscera com- modulators. Enteric ganglia form an intrinsic prising the colon distal to the left colic flexure nervous system, processing peripheral and cen- and the urogenital viscera. The sacral parasym- trally integrated information and coordinating pathetic outflow is involved with the “mecha- the activity of all component parts of the gut. nisms of emptying” by urination and defecation They regulate digestive processes by exerting and with erection. local reflex control over parasympathetic out- With regard to the urinary bladder, the nor- flows to the gut. The ENS controls the func- epinephrinergic sympathetic innervation con- tions of the GI tract, pancreas, and gallbladder. tributes to the relaxation of the detrusor muscle The ENS has a complex neural organization. It (muscle of the bladder) and increased tone of promotes homeostasis by regulating gut blood the internal sphincter. The cholinergic vessel tone, motility, fluid transport, nutrient parasympathetic innervation stimulates con- absorption, and enterochromaffin cell glandular traction of the detrusor muscle and relaxation activity (see “The Peristaltic Reflex”). The net- of the internal sphincter. work is comprised of sympathetic and With regard to the pelvic GI tract, the sympa- parasympathetic preganglionic neurons and thetic innervation contributes to decreased parasympathetic postganglionic neurons, in motility of the sigmoid colon and rectum addition to local sensory neurons and interneu- and contractions of the internal sphincter. rons (see Fig. 20.4). It is responsive to alter- The parasympathetic innervation stimulates ations in the tension of the gut wall and to increased motility of the sigmoid colon and rec- changes in the chemical environment within tum and decreased tone of the internal sphincter. the gut. The enteric motor neurons control the Except for the voluntary striated muscles of smooth muscle of the gut and local blood ves- the external sphincter innervated by somatic sels, as well as secretions of the glandular cells motor nerves, the musculature of the pelvic vis- of the mucosa. cera consists of smooth involuntary muscula- In essence, neurons of the ENS are organ- ture innervated by the ANS. ized as a mini nervous system that consists of The pararsympathetic system is primarily two major plexuses of neurons that extend as organized to respond transiently to a specific continuums along the entire length of the GI stimulus in localized and discrete regions. Each tract. These are (1) the myenteric plexus (Auer- long preganglionic axon synapses with a few bach’s plexus) located between the inner circu- postganglionic neurons with short axons, exert- lar and outer longitudinal smooth muscle layers ing influences over a small area. The rapid of the muscularis externa and (2) the submu- deactivation of acetylcholine by cholinesterase cosal plexus (Meissner’s plexus) located in the restricts the time course over which a specific submucosa, with branches extending into the quantity of released acetylcholine is effective. mucosa. In general, Auerbach’s plexus controls motility of the gut (peristalsis) and Meissner’s plexus is involved with the secretory aspects of ENTERIC DIVISION gut function. (“GUT-BRAIN,” “MINIBRAIN”) The parasympathetic postganglionic neurons receive neural influences from (1) intrinsic sen- The organization of the enteric system is sory neurons and interneurons within the gut and illustrated in Fig. 20.4. The enteric system, (2) the extrinsic preganglionic parasympathetic conceptualized as the “brain of the gut”, carries neurons and postganglionic sympathetic fibers. out automatic functions. It contains approxi- The intrinsic sensory neurons with cell bodies mately 100 million neurons, about the same located in the submucosa and external muscular number as in the entire spinal cord. About 10 layer of the gut have dendritic processes that Chapter 20 Autonomic Nervous System 357 extend into the mucosal layer. Dendritic neurons respond to mediators released from the processes of the mechanosensory and chemo- several types of enteroendocrine cell of the sensory cells respond to tension (stretch) within mucosal epithelium (see “The Enteroendocrine the gut proper, tonicity, and the chemical envi- System”). They have been likened to enteric ronment within the gut lumen. Sensory afferent taste buds, which transduce signals generated by

Figure 20.4: The enteric division of the ANS. Schema of the sympathetic and parasympathetic innervation of the gastrointestinal (GI) tract. The general visceral efferent (GVE) innervation of the smooth muscles and glands of the small intestine by the sympathetic (dark black line) and parasympathetic (light double lines) nervous systems. From their location between the two peritoneal layers of the dorsal mesentery the nerve fibers of these systems enter and are distributed as the components of (1) the myenteric (Auerbach’s) plexus within the stroma between the longitudinal and circular muscle laminae of the muscularis layer and (2) the submucosal (Meissner’s) plexus of the submucosa of the GI tract. Postganglionic sympathetic nerve fibers from the celiac and superior mesenteric ganglia, located near the aorta, join these plexuses. Preganglionic parasympathetic fibers from the dorsal motor nucleus of the vagus also join these plexuses and terminate within scattered groups of parasympathetic postganglionic neurons whose axons are distributed within the plexuses. General visceral afferent (GVA) nerve fibers within these plexuses are not illustrated; they are the substrate for the autonomous control of gut reflexes exerted by the enteric nervous system in the absence of input from the CNS. 358 The Human Nervous System the GI lumen and project by their axon branches input and project output that influences the in the lamina propria of the mucosa. These sen- activity of cardiac muscle. The mechanism in sory neurons can interact with interneurons of the heart is similar to those of the ENS and the Meissner’s plexus and of Auerbach’s plexus. immune system that manifest memory (Rosen The axons arising from Meissner’s plexus and Ploknikov, 2002). extend both orally and caudally. The neurons of the plexus act as chemical monitors of the envi- The Enteroendocrine System ronment of the gut lumen and the secretory The ENS has roles in the motility of the gut, aspects of gut function. Submucosal sensory the absorption of nutrients, the rate of prolifer- cells that project to the mucosa, and collaterals ation of epithelial cells lining the GI tract, and to blood vessels, coordinate functional and vaso- the release of hormones and neuropeptides by motor responses to mucosal signals. The axons enterochromaffin cells of the enteroendocrine of Auerbach’s plexus are oriented radially. Some system. The substances released by the latter neurons of these gut plexuses are integrated into system include such agents as gastric inhibitory feedback circuits, with their axons projecting peptide (GIP), the neuropeptide motilin, centripetally to the prevertebral sympathetic secretin (elicits pancreatic secretion), and ganglia (celiac and superior and inferior gan- cholecystokinen (elicits contraction of the gall- glia located near the aorta), and these ganglia bladder). Gastrin stimulates the release of send fibers back to the gut. hydrochloric acid by the parietal cells of the The complex neural organization has a stomach and first part of the duodenum. Other major role in homeostasis by the coordinated cells secrete serotonin that also influences gut modulation of gut motility and peristalsis, gut motility in the stomach and small intestine. blood vessel tone, fluid transport, and Somatostatin is released by lining cells of the enteroendocrine cell secretion. Meissner’s sub- gut. Cells in the intestine secrete GIP, which mucosal plexus combines fewer neurons and inhibits gastric secretion. Motilin and sub- glia with inner interganglionic connections. stance P are neuropeptides associated with the Cross talk between the two ganglionic plexuses regulation of intestinal motility. Vasoactive is subserved by microcircuits comprised of intestinal peptide (VIP) is involved with water interneurons that remain poorly understood. and ion secretion as well as intestinal motility. The ENS synthesizes and is stimulated by virtually all messenger molecules involved in cen- Enteric Glial Elements Are Supportive and tral and peripheral autonomic, endocrine and Act in Consort With the ENS as Pacemakers immune regulation. Enteric neural elements are supported by astrocyte-type enteric glia that have the mor- Intrinsic Cardiac Nervous System phological characteristics of CNS astrocytes. Recent evidence suggests the existence of a Interstitial cells located between nerve termi- cardiac nervous system comparable to the nals and smooth muscle cells are electrotoni- ENS. For example, the presence of interneu- cally coupled by gap junctions between smooth rons in parasympathetic cardiac ganglia in or muscles of the gut. These cells subserve pace- near the heart suggests a potential for involve- maker slow-wave functions manifested by the ment in reflex reactions that can occur inde- intestinal musculature. Based on adult trans- pendent of CNS activity (see Fig. 20.3). This is genic mouse models, enteric glial cells are similar to the role of the parasympathetic gan- essential in maintaining the integrity of the glia of the ENS. Interneurons within these gan- small intestine. glia can exhibit pacemaker activity that is not generated synaptically, but might contribute to The Peristaltic Reflex the ongoing activity of other ganglionic neu- The peristaltic reflex was first recognized as rons. A subset of these interneurons can process a pressure-evoked descending progressive wave Chapter 20 Autonomic Nervous System 359 and attributed to a “local nervous mechanism of The overall control and regulation of con- the bowel” consisting of oral contraction/anal tractile activity of the gut is not focused at the relaxation. Sensory neurons have long been pacemaker sites, but, rather, is directed to the known to elicit peristaltic reflex responses to smooth muscle fibers throughout the gut. The alterations in the tension in the wall of the gut control system effecting this regulation and in the chemical environment. The expres- involves (1) the enteric circuitry, (2) the feed- sion of the intrinsic neural circuitry within the back circuits of afferent fibers from the gut to gut is generally initiated by moderate distention. the prevertebral ganglia (located near the aorta) The reflex persists in vitro in isolation of the and efferent fibers back to the gut, and (3) dorsal roots, cranial nerve ganglia, and the CNS, influences from the sympathetic and parasym- indicating that the wall of the bowel contains all pathetic systems. A major role of this system is of the essential neural elements (i.e., primary to act as the coordinator of Starling’s “law of sensory neurons, interneurons, and motor neu- the intestine” (e.g., a bolus of food within the rons to perform normal gut functions). intestine initiates a band of constriction proxi- A peristaltic wave is evoked by an increase mally and relaxation distally, resulting in a in the intraluminal pressure on the luminal sur- peristaltic wave) by modulating through inhibi- face of the bowel that activates the mechanore- tion the spontaneous rhythmic contractile ceptors of the surface of the enterochromaffin activity of the gut. cells in the epithelial lining of the mucosa. The The ENS influences other organ systems, peristaltic wave, which can occur in the including the prevertebral sympathetic ganglia, absence of vagal stimulation, is initiated as a and, thus, can coordinate the activity of the GI response to the following neural sequence. (1) tract with that of the gallbladder, pancreas, and Pressure-evoked stimulation of the receptors of other organ systems. enterochromaffin cells activates them to release serotonin. (2) Serotonin stimulates the intrinsic Autonomic Innervation of the ENS primary sensory neurons and interneurons that Relative to the large numbers of enteric neu- project to the myenteric plexus. (3) This input rons, autonomic inputs are sparse, although contributes to stimulating and sustaining potentially powerful in view of their extensive rhythms of the peristaltic waves. Two other fea- branching patterns. There are impressive sym- tures are also involved in the intrinsic reflex pathetic/parasympathetic innervations of the activity of the gut. (1) Smooth muscle cells, upper and lower ends of the GI tract and related either individually or in groups, exhibit sponta- vasculature. The ENS is involved in tonic and neous waves of electrical depolarization linked phasic regulation of sympathetic postgan- to rhythmic contractions. The contractions glionic norepinephrinergic motor neurons that spread from one muscle cell to another because innervate myenteric and submucosal neurons they are electrotonically coupled by low-resist- and those involved in regulating mucosal blood ance gap junctions (Chap. 3). Each wave can flow (see Fig. 20.5). occur depending, in part, on the magnitude of depolarization. (2) The fundus of the stomach and first part of the duodenum are two sites in the gut that have roles as pacemakers (equiva- SENSORY AND HUMORAL SYSTEMS lent to the pacemakers in the heart). In humans, the basic depolarization rhythm of the pace- Visceral Sensory Systems maker (a) in the fundus governs the 3 per minute Sensory systems differentially regulate auto- waves of contraction prevalent in the stomach nomic discharges. The vagus and the splanch- and (b) in the duodenum governs the 11 per nics (greater, lesser, least), and lumbar and minute waves of contraction prevalent in the pelvic afferent nerves convey information from small intestine. visceral sensory receptors. Vagal afferents 360 The Human Nervous System terminate in the solitary nucleus of the medulla, sory afferents directly or indirectly modulate whereas those in the peripheral nerves travers- the activities of the sympathetic and parasym- ing the dorsal roots terminate in the dorsal horn pathetic motor systems. Most vagal and sacral and central gray of the spinal cord. Viscerosen- afferents respond to distension and contraction

Figure 20.5: Adrenergic nuclei and pathways of the ANS. The adrenergic pathways are activated by homeostatic challenges that mediate compensatory autonomic, endocrine, and behavioral responses. From visceral receptors in the neck (e.g., carotid sinus and carotid body), thorax, and abdomen, the glossopharyngeal and vagus nerves convey inputs to the epinephrinergic solitary nucleus. The adrenergic nuclei of the medulla include the solitary nucleus (C3 and C1) rostral ventrolateral reticular nucleus (nRVL), the norepinephrinergic C1 and C3 groups within the tegmentum, and interneurons of the lateral tegmental field. These medullary nuclei are functionally interconnected with other neuronal centers of the brainstem and cerebrum by two longitudinally oriented pathways: the periventricular tract within the central gray and the (trans)tegmental tract within the reticular formation. These tracts are bidirectional pathways that transmit stress-related information. Generalized arousal states preparatory to sympathetic/defense reactions involve C1 and C3 projections to the norepinephrinergic A5 nucleus, parabrachial nucleus, locus ceruleus, periaqueductal gray, and cerebral centers, including the amygdala, the hypothalamus, the visceral periventricular thalamus of the limbic system, and the dorsomedial thalamic nucleus associated with the mesolimbic network. The nRVL sends fibers to the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus and sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord. The precise roles of the epinephrinergic transmitter network in cardiovascular regulation are uncertain although electrophysiological studies disclose activity patterns that are respiratorily modulated and coupled to the cardiovascular cycle. Chapter 20 Autonomic Nervous System 361 of visceral organs, encoding intraluminal activ- ferent physiological conditions. The dual ity or volume. Vagal sensory afferents encode hypothesis of antagonism in the ANS is no baroreceptors, arterial, gastrointestinal, and longer tenable” (Bannister and Mathias, 1999). hepatic chemoreceptors and osmoreceptors, (2) Organs, as effectors, react predominantly to and volume changes in the cardiac atria, lungs, either sympathetic or parasympathetic activa- gut, and urinary bladder. Pelvic afferents signal tion. (3) Excitatory reactions are the general genitourinary pain and inflammation, as well as rule, whereas inhibitory reactions such as distension and contraction. Abdominal and relaxation are rare. The iris, heart, and urinary pelvic afferents are involved in cardiac–cardiac bladder are organs reacting to centrally and reflexes, renal–renal reflexes, other organ spe- peripherally integrated inputs from both sys- cific reflexes, and nociceptive reflex circuit tems. Visceral afferents with cell bodies in functions. dorsal root ganglia and vagal and glossopha- As an example of visceral afferent reflex ryngeal sensory ganglia and characterized by activity, the cardiovascular system, is regulated unmyelinated or thinly myelinated axons are by precise visceral sensory reflexes, ensuring not associated with a specific system, but exert that an adequate supply of oxygenated blood is influences over both systems. provided to the different body tissues, The The response of an individual receptor to a afferent monitoring of this homeostatic process specific neurotransmitter is not solely deter- is initiated by the receipt (1) of information mined by the neurotransmitter; the nature of from chemoreceptors about the level of oxygen the receptive sites of the receptor is also a sig- and carbon dioxide in the blood and (2) of nificant factor. The response of an effector is blood pressure information in the arterial sys- determined by the neurotransmitter–receptor tem from mechanoreceptors (baroreceptors) in linkages. For, example, norepinephrine stimu- the elastic walls of the carotid sinus, heart, and lates the contraction of smooth muscles of an major arteries. The chemoreceptors in the arteriole (vessel constricts) and the relaxation nerve endings in the highly specialized carotid (dilation) of smooth muscles of the bronchial body and the aorta respond directly to the par- tubes in the lungs. The different responses to tial pressure of oxygen and carbon dioxide in the same neurosecretions are explained by dif- the blood. The nerve endings in the barorecep- ferences in the nature of the receptor sites of tors respond to deformational changes of the smooth muscles. Different neurotransmitters elastic walls of the carotid sinus and blood ves- can stimulate different effectors to respond in a sels resulting from the forces exerted by similar way. For example, the radial muscle of changes in blood pressure. The afferent projec- the iris contracts when stimulated by norepi- tions from the carotid sinus and carotid body nephrine, whereas the sphincter muscles of the convey information via the glossopharyngeal iris contract when stimulated by acetylcholine; nerve to the solitary nucleus of the medulla (see both are smooth muscles. Table 20.1 lists the Fig. 20.5). response of various organs to sympathetic and parasympathetic stimulation. The diversity of Effector Organ Responses autonomic responses and functions is achieved The reactions of peripheral tissues and primarily by different types of receptors for the organs to sympathetic and parasympathetic two classes of postganglionic transmitters: (1) activity patterns are defined by the responses of norepinephrine for the sympathetic system and receptors to nerve stimulation. Several general (2) acetylcholine for the parasympathetic principles apply to autonomic effector organ system. responses to the evoked release of endogenous A dual innervation of the body by both the neurotransmitters. (1) Sympathetics and parasympathetics and parasympathetics is usual, sympathetics are not antagonistic; rather, they but not universal. (1) The heart has a true recip- act synergistically and differentially under dif- rocal innervation (dual) innervation, with the 362 The Human Nervous System

Table 20.1: Some Comparisons Between the Sympathetic and Parasympathetic Nervous Systems General Sympathetic nervous system Parasympathetic nervous system Outflow from CNS Thoracolumbar levels Craniosacral levels Location of ganglia Paravertebral and prevertebral Terminal ganglia near effectors ganglia further from effectors Ratio of preganglionic to Each preganglionic neuron Each preganglionic neuron postganglionic neurons synapses with many synapses with a few postganglionic neurons postganglionic neurons Distribution in body Throughout the body Limited primarily to viscera of head, thorax, abdomen, and pelvis Specific Structures Structure Sympathetic function Parasympathetic function Eye Radial muscle of iris Dilates pupil (mydriasis) Sphincter muscle of iris Contraction of pupil (miosis) Ciliary muscle (accommodation) Relaxation for far vision Contraction for near vision Glands of head Lacrimal gland Stimulates secretion Salivary glands Scanty thick, viscous secretion Profuse, watery secretion Heart Rate Increase Decreases Force of ventricular contraction Increase Blood vessels Generally constrictsa Slight effect Lungs Bronchial tubes Dilates lumen Constricts lumen Bronchial glands Stimulates secretion Gastrointestinal tract Motility and tone Inhibits Stimulates Sphincters Stimulates Inhibits (relaxes) Secretion May inhibit Stimulates Gallbladder and ducts Inhibits Stimulates Liver Glycogenolysis increase (blood sugar) Adrenal medulla Secretion of epinephrine and norepinephrinea Sex organs Vasoconstriction, constriction of Vasodilation and erection vas deferens, seminal vesicle, and prostatic musculature (ejaculation) Skin Sweat glands Stimulateda Blood vessels Constricted Slight effect Neurotransmitter at neuroeffector Usually norepinephrinea Acetylcholine junction Inactivation of transmitter Slow and reuptake Rapid a Exceptions: Some postganglionic neurons of the sympathetic nervous system are cholinergic neurons. Sympathetic neuroeffector transmission mediated by acetylcholine includes (1) some blood vessels in skeletal muscles and (2) most sweat glands. The postganglionic sympathetic neurons that innervate the sweat glands are, before innervating the sweat glands, adrenergic neurons. Following the innervation of the sweat glands they become cholinergic neurons (see section concerning neural specificity and plasticity, Chap. 6). The sweat glands of the palm are innervated by adrenergic neurons. The cells of the adrenal medulla are actually postganglionic cells: they are innervated by preganglionic cholinergic sympathetic neurons, Chapter 20 Autonomic Nervous System 363 sympathetics acting to increase the rate of the increasing salivary secretion and the latter act- heart beat and the parasympathetics acting to ing as a modulator. Another example is the decrease it. (2) The salivary glands are inner- presence of neuropeptide Y (NPY) in sympa- vated synergistically, with sympathetic activity thetic vasoconstrictor axons, which potentiates producing a thick, viscous secretion and the action of norepinephrine on the contractile parasympathetic producing a profuse, aqueous apparatus of smooth muscle. Vagal-induced secretion. (3) The constriction and dilatation of slowing of the heart is inhibited by NPY, which the pupil exemplifies an activity resulting from is released by increased sympathetic activity. the stimulation of different muscle groups. The Constituents of the prevertebral sympathetic pupil of the eye dilates when the radial (dilator) ganglia include small intensely fluorescent muscles innervated only by sympathetic fibers (SIF) cells, containing monoamines and neu- are stimulated and it constricts when the ropeptides. The cotransmission of specific sphincter (constrictor) muscles innervated only combinations of transmitters and modulators by parasympathetic fibers are stimulated. (4) has been suggested as a form of chemical cod- Some structures are only innervated by one ing, especially in the enteric system. system: Hair muscles (erector pili muscles that The purinergic transmitters responsible for produce goose pimples), sweat glands, and most NANC inhibition are ATP or related most arterial blood vessels are stimulated only purine compounds such as adenosine (Chap. by sympathetic fibers (see Fig. 20.2). 15). The nitrergic transmitter responsible for An autonomic neuron can exhibit a func- some NANC inhibition is the free-radical nitric tional form of plasticity by modifying or alter- oxide (NO) (Chap. 15). ing its transmitter or receptor sensitivity during development and aging (Chap. 6). For example, the postganglionic sympathetic fibers innervat- CENTRAL AUTONOMIC ing the sweat glands in the human are func- CONTROL CIRCUITS tionally adrenergic before birth and become cholinergic postnatally. Central autonomic control circuits coordinate autonomic functions and the ongoing Cotransmission of Nonadrenergic and behavioral needs of the organism through the Noncholinergic Transmitters in the ANS activities of the somatomotor, endocrine, and Over 10 putative transmitters and modula- autonomic systems. These systems are repre- tors have been identified and added to the clas- sented in overlapping regions of the brain. The sical autonomic transmitters, norepinephrine, behavioral strategies and reflex mechanisms and acetylcholine. These neuroactive nonadren- within these circuits act in the defense of the ergic and noncholinergic (NANC) agents are organism and in homeostasis, which are coor- active in neurotransmission at synapses of sym- dinated by interconnected groups of nuclei in pathetic, parasympathetic, and enteric neurons. the brainstem and higher forebrain centers. Most autonomic neurons contain two to several Three of the key components of the central agents, including acetylcholine, amino acids, autonomic control circuits are the solitary biogenic amines, neuropeptides, and others nucleus, which receives visceral sensory infor- (Chap. 15). The current thesis is that many, if mation, the hypothalamus, which is the most not all, neurons of the ANS store and release important neural center in the overall control of more than one agent. Note the large vesicles visceral and endocrine functions, and the ros- containing a neuropeptide and small vesicles tral ventrolateral reticular nucleus (n RVL), a containing norepinephrine in the varicosities in major relay motor nucleus regulating the auto- Fig. 15.4. For example, acetylcholine and VIP nomic nervous system (see Fig. 20.5). The soli- are cotransmitters of the parasympathetic fibers tary nucleus is the major recipient of visceral innervating the salivary glands, with the former afferent inputs including taste. Afferent infor- 364 The Human Nervous System mation is, in turn, utilized to modulate several sional complex circuitry. In the first, informa- autonomic functions such as cardiovascular tion is directed locally into lower brainstem reflexes, which are discussed later in the chap- visceral circuits such as the cardiovascular and ter. The hypothalamus is the master visceral respiratory centers. In the second, information control center in the regulation of many auto- is directed to the more extensive and complex nomic and endocrine responses and in home- circuitry of the upper brainstem and forebrain ostasis generally (Chaps. 21 and 22). The components of the central autonomic control adrenergic nRVL regulates autonomic responses network (see Fig. 20.6). The latter is integrated (1) via projections both to the preganglionic into behavioral responses associated, for exam- neurons of the dorsal motor nucleus of the ple, with the limbic system (Chap. 22). vagus of the parasympathetic system and to the The central autonomic control nuclei and preganglionic neurons of the intermediolateral centers are interconnected by the tegmental nuclei of the sympathetic system and (2) via tract and periventricular tract to and from the rostral projections to higher centers of the brain parabrachial nucleus, periaqueductal gray, and through the periventricular and the tegmental such forebrain structures as the hypothalamus, tracts of the brainstem (see Fig. 20.5). amygdala, visceral sensory centers, and areas The nuclei forming the extensive central of the thalamus and neocortex (see Fig. 20.5). autonomic control network within the brain- In addition, neural interconnections between stem and forebrain are linked together and inte- these structures result in interactions directed grated by two bidirectional pathways: the to the hypothalamus. The following are exam- (trans)tegmental tract within the reticular for- ples of some functional correlates associated mation and the periventricular tract within the with these centers. central gray matter (see Fig. 20.5). The core Visceral sensory information derived from nuclei of this network comprise the the solitary nucleus is relayed to the para- parabrachial nucleus and the periaqueductal brachial nucleus, which acts as a key brainstem gray of the brainstem, the hypothalamus, the processor projecting to and receiving commu- amygdala of the limbic system, the visceral nications from the periaqueductal gray and sensory thalamic nuclei (Chap. 23), and vis- forebrain centers. The parabrachial nucleus has ceral areas of the cerebral cortex (Chap. 25). a functional role in behavioral responses to var- Critical modulating influences on the central ious visceral sensations including taste as is autonomic network are made by brainstem indicated by the prevention of previously con- noradrenergic cell groups (e.g., A1), adrenergic ditioned behavioral responses to gustatory cues cell groups (e.g., C1 and C3), serotonergic in rodents following its destruction. raphe nuclei, and interneurons within the The periaqueductal gray is a processor. (1) nRVL. These central autonomic control circuits Its projections to the lateral tegmental recep- are functionally endogenous. The basic per- tive field (LTF) of the medulla modulate actions formance of their roles can be performed in the associated with changes in blood pressure and absence of hypothalamic control. heart rate through cardiovascular reflexes. The The general organization of the central auto- resulting “fight or flight” response results in nomic network is illustrated in Fig. 20.5. The reducing the amount of blood flow directed to solitary nucleus receives afferent fibers from the viscera and increasing blood flow to the visceral receptors located in the taste buds, lower extremities to enhance sustained running carotid body, carotid sinus, and many other behaviors. (2) Its projections to the substantia locations associated within the array of visceral nigra and the extrapyramidal system result in organs. The solitary nucleus and its relay nRVL the agonizing facial contortions of a marathon send outputs to autonomic circuits via two gen- runner during the last miles of a race. eral routes: One is a focused relatively simple The amygdala of the limbic system is reflex circuitry and the second is a multidimen- involved in many autonomic responses with Chapter 20 Autonomic Nervous System 365 specific behaviors (Chap. 22). For example, a mus and the lateral tegmental field (LTF) in rat is conditioned to link an auditory cue with the medulla. an unpleasant electric shock, which causes an elevated heart rate. In a short time, just the Functional Neuroanatomy of Autonomic auditory cue suffices to evoke this response, Control Centers in the Medulla (see Fig. 20.6). but a lesion of the central nucleus of the Autonomic regulatory mechanisms of the amygdala blocks it (LeDoux, 2002). This medulla are of critical importance for the reflex amygdaloid nucleus projects to the hypothala- control of the cardiovascular system. The struc-

Figure 20.6: Visceral reflex circuits of the medulla. The circuits within the medulla are essential for the maintenance of visceral (servo-control) reflexes that regulate, among others, the cardiovascular system. Visceral afferent stimuli transmit by the vagus and glossopharyngeal nerves to the solitary nucleus which synapses in the lateral tegmental field (LTF) of the reticular formation (upper left arrow). Other afferent and central inputs converge on the LTF from (1) trigeminal, vestibular, and spinal dorsal horn relay nuclei and (2) from higher centers of the brainstem and cerebrum via the periventricular tract and the tegmental tract (upper right arrow). Following the ongoing central integration of the convergent sensory information, the LTF interacts with circuits modulating cardiovascular reflexes. These comprise the network of reticular formation interneurons, including the medial “vasodepressor” region (MDR) and the “vasopressor” (sympathetic premotor) region of the nRVL. In addition, information is derived from suspected chemoreceptor sensors on the dorsal and ventral medullary surfaces. Myriad transmitter modulators of the visceral nuclei include glutamate and GABA. Note the projection (arrow) from the nRVL to the solitary nucleus indicative of servo-control systems exerting feedback controls by the nRVL ultimately over the sympathetic and parasympathetic outflows. The relay nRVL acts as the final common pathway projecting centrally integrated information (1) via short circuits to the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus and ambiguus nucleus and (2) via the descending reticulospinal tracts to preganglionic neurons of the sympathetic system (center arrow). 366 The Human Nervous System tural and functional integrity of the medullary The sensory convergent LTF receives infor- circuitry is essential in sustaining life by its mation directly from the periphery via the soli- tonic and phasic regulation of the cardiovascu- tary nucleus and its terminal field and lar system involving both sympathetic and indirectly from higher centers in the brainstem parasympathetic activity patterns. Visceral and forebrain (see Fig. 20.6). In turn, the LTF reflexes involve servo-control corrections via acts as a control center exerting regulatory feedback signals such as between the motor influences over autonomic discharge patterns and sensory components. (Note in Fig. 20.6 the generated in activity centers within the medial feedback arrow between the relay motor nRVL vasodepressor region (MDR) and the vasopres- and the sensory solitary nucleus.) Visceral and sor (sympathetic premotor) region near the somatic afferents transmit input over spinal and nRVL in the reticular formation. These visceral cranial nerves to the dorsal horn and solitary and semiautonomic reflexes are mediated by nucleus. Substantial visceral and somatic affer- relays to the nRVL, which serves as the final ent inputs from the solitary nucleus, dorsal common pathway (gateway) by which centrally horn, and trigeminal and vestibular relay nuclei integrated information is used to regulate the are directed to the LTF, which is a sensory con- outflow of the ANS with regard to the demands vergent field within the lateral tegmentum of of all stressors. the medulla (see Fig. 20.6). Much of the visceral sensory outflow from Autonomic Regulation of the solitary nucleus is directed rostrally via the Cardiovascular Functions tracts of the bidirectional periventricular and This account of the fundamentals of central tegmental pathways to the upper brainstem and autonomic control focuses on brainstem regu- forebrain centers of the central autonomic con- lation of the cardiovascular system (CVS). The trol network involved in mediating behavioral brainstem and forebrain centers participate in responses. Of these, the hypothalamus has a the modulation of the dynamics of this CVS broad reach, in that it modulates both visceral system, and its long term stability is dependent responses and endocrine activity. In general, on its integrated neural and humoral mecha- the higher centers communicate via descending nisms. Much of the control of cardiodynamics tracts within the bidirectional periventricular is reflexive. The heart beat is initiated not by and tegmental pathways with the parabrachial the central nervous system but by the heart’s nucleus and the convergent sensory fields in the sinoauricular pacemaker. The heart, unlike the LTF. Joining these convergent fields are inputs blood vasculature vessels, receives dual sympa- from probable chemoreceptive vascular regions thetic and parasympathic (vagal) innervation. on both the dorsal and ventral medullary sur- Cardiovascular reflex arcs powerfully modu- faces of the medulla (see Fig. 20.6). late heart rate and actively depress heart rate in Brainstem and forebrain centers participate the resting state. in the modulation of the dynamics of the car- The medulla oblongata (Fig. 20.5). The diovascular system. For example, the visceral integrity of medulla oblongata is essential in sensory (anterior insula) cortex interacts with sustaining life. Consciousness, awareness of anterior cingulate visceral motor areas (limbic perceptions, and the drives to adapt are system). Electrical stimulation of the latter can dependent on the functional integrity of pon- produce several visceral responses, including tomedullary reticular formation exerting tonic changes in blood pressure. A likely cause of and phasic influences over sympathetic and these pressure changes results from communi- parasympathetic nerve activity patterns. Car- cation via the central control circuitry that acti- diorespiratory circuits coordinate rhythmic vates the sensory convergent field of the breathing and heart rate, maintaining blood medulla followed by the responses of the car- pressure volume, normal oxygenation, and diovascular reflex. acid–base balance. Behavioral regulation of Chapter 20 Autonomic Nervous System 367 breathing has its expression in speech in as well as a final common pathway (gateway) for cen- as in nonverbal and emotional expressions. trally integrated peripheral information to act Coordinated activity of a diffuse network of upon the sympathetic nervous system, while neurons in the visceral emotional brain exerts a exerting feedback influence over craniosacral major influence over the autonomic control cir- parasympathetic tone. The LTF, a sensory con- cuit of the medulla. Sensory systems and cen- vergence zone, may be in a pivotal position to trally generated signals converge on the lateral exert influence over n. RVL sympathetic pre- reticular core, shaping (driving) basal sympa- motor neurons. This key intrareticular circuit is thetic nervous system discharge to the cardio- implicated in maintaining resting discharges of vascular system, adrenal gland, and other sympathetic nerves and resting arterial blood viscera. pressure and heart rate. The n. RVL synthesizes Somatic and visceral autonomic control epinephrine on physiological demand, and is (Figs. 20.4 and 20.5). Somatic and visceral excited by emotional visceral distress, triggering afferents transmit over spinal and cranial global emotional visceral defense reactions. nerves to the spinal dorsal horn and the nucleus The n. RVL differentially and simultaneously of the solitary tract. The spinal dorsal horn coordinates sympathetic and parasympathetic projects to somatic and autonomic neurons in stress response. ventral and lateral horns of the spinal cord, respectively, forming local reflex circuits. Gen- eral viscerosensory cranial and spinal somato- DENERVATION SENSITIVITY visceral nerves transmit to the solitary nucleus, AND SYMPATHECTOMY which projects locally to autonomic control regions of lateral and medial reticular forma- Somatic effectors are dependent on their tion and pontine parabrachial complex forming innervation to maintain structural and func- a reciprocally organized “rapid response” net- tional integrity. When denervated, they eventu- work. Somatic and visceral sensory relay sys- ally atrophy. This is the fate of denervated tems target arrays of reticular interneurons in voluntary muscles as noted in a lower motor the multi-sensory receptive region of the lateral neuron paralysis (Chap. 12). Autonomic effec- tegmental field (LTF). Higher centers in the tors are not wholly dependent on their innerva- brainstem and forebrain converge on LTF (Fig. tion. Denervated involuntary muscles, cardiac 20.6). In turn, the LTF acts as a control center, muscle, and glands continue to function. For exerting regulatory influences over autonomic example, the transplanted heart may function discharge patterns generated in activity centers reasonably well. However, when deprived of within the “medial vasodepressor region” autonomic nervous system influences, these (MDR) and the “vasopressor” (sympathetic effectors are abnormal in that they do not premotor) region near the rostral ventrolateral respond as effectively as they should to satisfy nucleus (n. RVL) in the reticular formation. the changing demands of the organism. Counter-regulatory influences are exerted over When an effector is deprived of its innerva- autonomic nerve discharges to internal organ tion, it may become extremely sensitive to systems. chemical mediators (neurotransmitters). For The LTF and its sympathetic premotor cen- example, the rate of beat of the totally dener- ter. Visceral and somatoautonomic reflexes are vated heart will increase if the heart is exposed mediated by the LTF and cardiorespiratory to just 1 part of epinephrine in 1400 million. neurons in the n. RVL. Evidence suggests that This denervation hypersensitivity is lost follow- the LTF, by integrating peripheral and central ing regeneration of the fibers and reinnervation information, exerts major influence over the n. of the heart. Denervation hypersensitivity is RVL, which directly projects to all sympathetic noticeable in clinical situations following sym- preganglionic cell columns. The n. RVL serves pathectomy. In Horner’s syndrome, the pupil of 368 The Human Nervous System one eye is constricted and does not normally lance during micturition. PMS projections to dilate because it is deprived of sympathetic the “behavioral inhibitory region” of the peri- stimulation. However, when a patient with aqueductal gray may facilitate the state of calm Horner’s syndrome is extremely excited, the during elimination. epinephrine and norepinephrine released by the adrenal medulla can stimulate the hypersensitive denervated dilator muscle of the iris to MEGACOLON respond so that the pupil dilates; this is known (HIRSCHSPRUNG’S DISEASE) as the paradoxical pupillary response. In this condition in young children, a portion of the large bowel is constricted, while the NEURAL CONTROL OF THE colon proximal to the obstructed segment is URINARY BLADDER enormously dilated. The constricted segment contains the flaw responsible for the disease— The urinary bladder is predominately under intrinsic neurons of the intramural plexuses are parasympathetic control. The motor limb of the missing, rendering this aganglionic segment voiding reflexes comprises the parasympathetic unable to relax. However, the region has an contraction of the detrusor muscle (collective autonomic innervation consisting of both term for the bundles of smooth muscle forming cholinergic and adrenergic axons, thus illustrat- the muscular wall of the bladder) stimulated by ing the significance of the intrinsic neurons in cholinergic and purinergic transmitters. This is peristalsis. coordinated with the parasympathetic relaxation of the musculature of the proximal urethra modulated by nitrergic messengers (Chap. 15). SUGGESTED READINGS In addition, there is adrenergic sympathetic control over the proximal urethral musculature Agassandian K, Fazan VP, Adanina V, Talman WT. that results in its constriction during emission Direct projections from the cardiovascular nucleus and ejaculation. This prevents retrograde ejacu- tractus solitarii to pontine preganglionic parasym- lation into the bladder. Thus, the sympathetic pathetic neurons: a link to cerebrovascular regula- and parasympathetic nervous systems function tion. J. Comp. Neurol. 2002;452:242–254. both antagonistically and synergistically to Appenzeller O. Clinical Autonomic Failure: Practi- complement their physiological activities. In cal Concepts. 5th ed. New York: Elsevier.;1986. addition, the somatosensory and motor path- Appenzeller O, Oribe E. The Autonomic Nervous System: An Introduction to Basic and Clinical ways are involved in the volitional control of Concepts. 5th ed. New York: Elsevier.; 1997. storage of urine in the bladder during urination. Bannister R. Treatment of autonomic failure. Curr The CNS integrates behaviors and pelvic organ Opin. Neurol. Neurosurg. 1992;5:487–491. functions via the pontine micturition center Bannister R, Mathias CJ, eds. Autonomic Failure: A (PMC) or Barrington’s nucleus, which is Textbook of Clinical Disorders of the Autonomic located anteromedial to the locus ceruleus and Nervous System. New York: Oxford University lateral to the laterodorsal tegmental nucleus Press; 1999. (Fig. 20.5). The connections of the PMC with Benarroch EE. Central Autonomic Network: Func- the central regulators lead to the integrated tional Organization and Clinical Correlations. process resulting in parasympathetic sphincteric Armonk, NY: Futura; 1997. control of many pelvic visceral structures Blessing W. The Lower Brainstem and Bodily (e.g., distal colon and, of most importance, Homeostasis. New York: Oxford University control of the detrusor muscle). PMC axons Press; 1997. branch to innervate the locus ceruleus, a major Bloom FE. Neuropeptides. Sci. Am. 1981;245: arousal/attentional center, which promotes vigi- 148–168. Chapter 20 Autonomic Nervous System 369

Bolis L, Licinio J, Govoni S. Handbook of the Auto- Hess WR. Diencephalon: Autonomic and Extra- nomic Nervous System in Health and Disease. pyramidal Functions. New York: Grune & Strat- New York: Marcel Dekker; 2003. ton; 1954. Brading A. 1999. The Autonomic Nervous System and Hoyle CHV, Lincoln J, Burnstock G. Neural control its Effectors. Malden, MA: Blackwell Science. of pelvic organs. In: Rushton DN, ed. Handbook Brown M, Tache Y. Hypothalamic peptides: central of Neuro-urology. New York: Marcel Dekker; nervous system control of visceral functions. 1994:1–54. Fed. Proc. 1981;40:2565–2569. LeDoux JE. Synaptic Self: How Our Brains Become Burnstock G, Hoyle CHV. Autonomic Neuroeffector Who We Are. New York: Viking, 2002. Mechanisms. Philadelphia, PA: Harwood Acade- Levenson RW. Blood, Sweat, and Fears: The Auto- mic; 1992. nomic Architecture of Emotion. Ann. NY Acad. Burnstock G, Sillito AM. 2000. Nervous Control of Sci. 2003;1000:348–366. the Eye. Amsterdam: Harwood Academic. Loewy AD, Spyer KM. Central Regulation of Auto- Cannon W. The Wisdom of the Body. New York, WW nomic Functions. New York: Oxford University Norton; 1932. Press; 1990. Cortelli P, Pierangeli G. Chronic pain–autonomic Miller NE. Biofeedback and visceral learning. interactions. Neurol. Sci. 2003;24(Suppl. 2): Annu. Rev. Psychol. 1978;29:373–404. S68–S70. Milner P and Burnstock G. Neurotransmitters in the Elfvin LG, Lindh B, Hokfelt T. The chemical neu- autonomic nervous system. In: Korczyn, ed. roanatomy of sympathetic ganglia. Annu. Rev. Handbook of Autonomic Nervous System Dys- Neurosci. 1993;16:471–507. function. New York: Marcel Dekker; 1995. Fisher LA, Brown MR. Neuropeptides and the auto- Robertson D, Baggioni I, Burnstock G, Low P, eds. nomic nervous system. Psychother. Psychosom. Primer on the Autonomic Nervous System. 2nd 1993;60:39–45. ed. San Diego: Elsevier, Academic, 2004; pp. Furness JB. Intestinofugal neurons and sympathetic 1–457. reflexes that bypass the central nervous system. J Rosen M, Plotnikov A. The pharmacology of car- Comp. Neurol. 2003;455:281–284. diac memory. Pharmacol Ther. 2002;94:63–75. Furness JB, Clerc N, Kunze WA. Memory in the Ruggiero DA, Underwood MD, Mann JJ, Anwar M, enteric nervous system. Gut 2000;47(Suppl. 4): Arango V. The human nucleus of the solitary iv60–iv62. tract: visceral pathways revealed with an “in Gershon MD. The Second Brain: The Scientific Basis vitro” postmortem tracing method. J. Auton. of Gut Instinct and a Groundbreaking New Under- Nerv. Syst. 2000;79:181–190. standing of Nervous Disorders of the Stomach and Saper CB. The central autonomic nervous system: Intestine. New York: HarperCollins; 1998. conscious visceral perception and autonomic pat- Goldstein DS. The Autonomic Nervous System in tern generation. Annu. Rev. Neurosci. 2002;25: Health and Disease. New York: Marcel Dekker; 433–469. 2001. Sved AF, Ito S, Sved JC. Brainstem mechanisms of Grazzi L, Bussone G. Effect of biofeedback treat- hypertension: role of the rostral ventrolateral ment on sympathetic function in common medulla. Curr. Hypertens. Rep. 2003;5:262–268. migraine and tension-type headache. Cephalal- Webster JI, Tonelli L, Sternberg EM. Neuroen- gia 1993;13:197–200. docrine regulation of immunity. Annu. Rev. Guillemin R. Control of adenohypophysial func- Immunol. 2002;20:125–163. tions by peptides of the central nervous system. Welch M, Keune J, Welch-Horan T, Anwar N, Harvey Lect. 1978;71:71–131. Anwar M, Ruggiero D. Secretin activates vis- Harris-Warrick RM. Dynamic Biological Networks: ceral brain regions in the rat including areas The Stomatogastric Nervous System. Cambridge, abnormal in autism. Cell. Mol. Neurobiol. MA: MIT Press; 1992. 2003;23:817–837. 21 Hypothalamus

General Functional Considerations Basic Circuits of the Hypothalamus Neurohumoral Reflexes Influences on the Autonomic Nervous System Temperature Regulation Regulation of Water Balance Food Intake and Energy Balance Expressions of Emotion and Behavior Circadian Rhythms The Circumventricular Organs

The hypothalamus functions primarily in telencephalic structure, whereas the rest of the homeostasis (the maintenance of a relatively hypothalamus is diencephalic. The preoptic constant internal body environment). Its effects area is so closely associated with the hypothal- are exerted through the autonomic nervous amus, however, that it is considered a part of system, the endocrine system, and the somatic the hypothalamus. motor system. Its influence is widespread and The hypophysis (pituitary gland) comprises is even involved with emotions and behavior. two major subdivisions: the adenohypophysis The 4-g hypothalamus is located in the basal (an epithelial structure) and the neurohypoph- region of the diencephalon adjacent to the third ysis (a neural structure). The adenohypophysis ventricle. In its rostrocaudal extent from the develops as an outpocketing from the embry- lamina terminalis to the midbrain, the hypo- onic pharynx, whereas the neurohypophysis thalamus is divided into nuclei and four major originates as an outgrowth from the region of areas (see Figs. 21.1 and 21.2): (1) a rostral or neural tube giving rise to the hypothalamus. preoptic area, (2) a supraoptic area located The adenohypophysis consists of the pars above the optic chiasma, (3) a tuberal area (the distalis (anterior lobe), pars tuberalis, and pars region of tuber cinereum extends from optic intermedia (see Fig. 21.1). The neurohypophy- chiasma to the mammillary body), and (4) a sis comprises the median eminence of the tuber caudal or mammillary area that grades into the cinereum, infundibular stem, and infundibular midbrain central gray. The hypophysis (pitu- process (pars nervosa, neural lobe). The median itary gland) extends ventrally from the tuberal eminence, which extends from the optic chi- area. Some important hypothalamic nuclei asma to the infundibular stem, differs from the include the suprachiasmatic nucleus of the pre- rest of the hypothalamus. The median emi- optic area, the paraventricular nucleus and nence and the infundibular stem are known as supraoptic nucleus of the supraoptic area, the the hypophysiotropic area, where the neurally lateral and ventral nuclei of the tuberal area, derived hypothalamic- releasing hormones are and the mammillary nuclei of the mammillary released and transferred to the hypophyseal area. Developmentally, the preoptic area is a portal system (see Fig. 21.2).

371 372 The Human Nervous System

Figure 21.1: Some hypothalamic nuclei and the hypophysis. The hypothalamus is composed of four nuclear areas: (1) the rostral or preoptic area, including the suprachiasmatic nucleus; (2) the supraoptic area, including the supraoptic, anterior, and paraventricular nuclei; (3) the tuberal area, including the infundibular, ventromedial, and dorsomedial nuclei; and (4) the caudal or mammillary area, including the posterior nucleus and mammillary body.

endocrine outflow with the behavioral status GENERAL FUNCTIONAL of the organism. The hypothalamus coordi- CONSIDERATIONS nates the behavioral and emotional responses generated in the forebrain. The processed The hypothalamus acts (1) to integrate information is sent via neural pathways to somatic, visceral, and behavioral information control centers in the brainstem that mediate from the internal and external environment ongoing metabolic activities needed to pro- and use it (2) to coordinate the autonomic and duce coordinated autonomic control and Chapter 21 Hypothalmus 373 behavior. These pathways include (1) the lat- 1. Regulation of body temperature via activi- erally located medial forebrain bundle and (2) ties ranging from the control of metabolic the medially located periventricular circuits thermogenesis to behaviors such as wearing with the periaqueductal gray of the midbrain garments appropriate for given weather con- (see Figs. 21.3 and 21.4). An additional route ditions involves the vascular portal system coordinat- 2. Regulation of blood pressure and electrolyte ing the hypothalamus with the pituitary gland. composition—via mechanisms ranging In essence, the hypothalamus functions to from control of fluid intake and salt appetite integrate autonomic and endocrine responses to blood osmolality and vasomotor tone. with behaviors, especially those concerned 3. Regulation of energy metabolism via control with the homeostatic requirements of every- of food intake, digestion, and the metabolic day life. rate. The hypothalamus integrates and controls 4. Regulation of reproduction via control of the following essential functions: hormones, pregnancy, and lactation.

Figure 21.2: Some hypothalamic nuclei and the hypophysis. The supraopticohypophyseal tract extends from the supraoptic and paraventricular nuclei to the capillary bed of the neurohypophysis. The hypophyseal–portal system is a vascular network extending from the base of the hypothalamus and upper neurohypophysis to the anterior lobe of the hypophysis. 374 The Human Nervous System

Figure 21.3: The major tracts conveying input to the hypothalamus.

Figure 21.4: The major tracts conveying output from the hypothalamus. Chapter 21 Hypothalmus 375

5. Regulation of emergency responses (e.g., the median eminence, pars tuberalis and physical and immunological) to stress via infundibular stem; this capillary plexus col- control of blood flow to muscle and other lects into the hypophyseal portal system of tissues and the release of adrenal stress hor- blood vessels (hypothalamic portal system mones such as cortisol. and hypophyseal portal vein). This portal system is a vascular network commencing as a Intrinsic Hypothalamic Receptors capillary bed in the median eminence and col- Some neurons within the hypothalamus act lecting into several main channels before as intrinsic receptors involved in several vital arborizing into a capillary (sinusoidal) bed in functional activities: thermal receptors for tem- the adenohypophysis. perature regulation and osmoreceptors for The hypophyseal portal system is the vascu- water metabolism. For example, hypothalamic lar pathway through which the neural language receptors monitor the temperature of the blood from the hypophysiotropic area, in the form of flowing through the hypothalamic capillaries, releasing hormones (RH), is transferred and enabling the organ to perform its role as the conveyed to the pars anterior to trigger the integrator of body temperature. The efferent endocrine language of the hypophysis. More limb of the reflex includes (1) descending auto- specifically, the hypothalamic nerve fibers lib- nomic pathways to the sweat glands and erate the releasing hormones from these nerve peripheral blood vessels and (2) descending endings into the capillary plexuses of the somatic pathways to the trunk musculature for median eminence and infundibular stem; these panting and shivering. hormones are conveyed through the hypophyseal portal vessels to the adenohypophysis, Neurohumoral Reflexes where they stimulate or inhibit the release of The neurohumoral reflex arc utilizes both a number of the hypophyseal hormones (see the nervous system (neuro) and the blood vas- “Releasing Hormones”). cular system (humoral). To perform its role in water metabolism, for example, the hypothalamus utilizes an intrinsic hypothalamic receptor BASIC CIRCUITS OF THE to monitor the osmolality of the blood flowing HYPOTHALAMUS through the brain. The neuronal receptors are stimulated to release a neurosecretion, antidi- The hypothalamus is strategically located uretic hormone (ADH), which is conveyed via between the cerebrum and the brainstem. The nerve fibers (supraopticohypophyseal tract) to complex neural circuits associated with the the infundibular process of the hypophysis (see hypothalamus have reciprocal and widespread Fig. 21.2), where it is stored and released into connections with these regions. The hypothala- the systemic blood system and conveyed to its mus derives its major input from the nonspe- target structures in the kidney. Such reflexes cific reticular pathways and little, if any, from are discussed more fully below. the specific lemniscal pathways. The structures projecting to, and receiving input from, the Hypophyseal Portal System and hypothalamus include the brainstem reticular Hypothalamic-Releasing Hormones formation, limbic lobe (including hippocampus The hypophysis receives its blood supply and amygdala), thalamus, and olfactory path- from several arteries (see Fig. 21.2). A pair of ways. The major pathway of the hypothalamus inferior hypophyseal arteries from the internal is the medial forebrain bundle. This is an intri- carotid arteries furnishes blood to the infun- cate complex of short, multisynaptic, multineu- dibular process and infundibular stem. Several ronal chains extending from the limbic system superior hypophyseal arteries from the inter- to the lateral hypothalamus and the paramedian nal carotid arteries form a capillary plexus in tegmentum of the midbrain. 376 The Human Nervous System

Input (see Fig. 21.3) e. the dorsomedial and midline nuclei of the The input to the hypothalamus is conveyed thalamus, which project to the hypothala- via (1) ascending pathways from the spinal cord, mus and amygdala. brainstem tegmentum, and periaqueductal gray 3. The blood vascular system conveys influ- matter (see Fig. 20.5), (2) descending fibers ences to which the hypothalamus might from the forebrain, and (3) the blood vascular respond. These include hormones, tempera- system. The neurons of the hypothalamus ture of the blood and osmolality of the respond to a variety of messengers. They contain blood, plasma. receptor sites for (1) such neurotransmitters as acetylcholine, norepinephrine, dopamine, sero- Output (see Fig. 21.4) tonin, and numerous neuropeptides and (2) such The output from the hypothalamus is con- agents as sex steroid hormones, thyroxin, and veyed via (1) ascending fibers to the forebrain, hormones released by the adenohypophysis. (2) descending fibers to the brainstem and spinal cord, and (3) fibers and blood vessels to 1. The ascending pathways from (a) the spinal the hypophysis (endocrine effector projections). cord are spinohypothalamic pain fibers and from (b) the brainstem mainly are fibers of 1. The ascending fibers from the hypothalamus the mammillary peduncle from the dorsal to the forebrain include those projecting to and ventral tegmental nuclei (see Fig. the anterior and dorsomedial thalamic nuclei, 13.14), fibers of the dorsal longitudinal fas- septal nuclei, and septal (subcallosal) area. ciculus from the periaqueductal gray matter, 2. The descending fibers to the midbrain and fibers of the medial forebrain bundle from pons project to the dorsal and ventral the midbrain tegmentum, and catecholamine tegmental nuclei, superior central nucleus (a pathways from several brainstem nuclei, raphe nucleus), and the periaqueductal gray including some noradrenergic fibers from matter. The dorsal vagal nucleus and adja- the locus ceruleus that partially ascend with cent nuclei in the medulla also receive pro- the central tegmental tract (Chap. 22). jections from the hypothalamus. The 2. The descending fibers from the forebrain descending tracts from the hypothalamus include the following (see Fig. 21.3): include the dorsal longitudinal fasciculus, a. Fibers of the fornix originating in the hip- medial forebrain bundle, and mammil- pocampus and the septal nuclei of the lotegmental fasciculus. limbic system. The hippocampus is a sig- 3. The influences from the hypothalamus to the nificant channel for afferent and neocorti- hypophysis are conveyed via the hypophy- cal input to the hypothalamus. seal portal system to the adenohypophysis b. Fibers originating in the cortex of the and via the supraopticohypophyseal tract to uncus and amygdala. These project via the neural lobe (see below). the stria terminalis and ventral amygdalofugal pathway to the hypothalamus. These projections to and from the hypothal- The primary olfactory cortex projects via amus are involved with the functional activities fibers of the medial forebrain bundle of the autonomic nervous system (Chap. 20), (Chap. 22). Thus. the olfactory system limbic system (Chap. 22), and endocrine sys- has a direct route to the hypothalamus. tem via the neurohumoral reflexes. c. Fibers arising from melanopsin-containing retinal ganglion cells terminate in the suprachiasmatic nucleus. NEUROHUMORAL REFLEXES d. The orbitofrontal cortex and septal nuclei, the source of fibers of the medial fore- The hypothalamus is integrated into distinct brain bundle. neurohumoral reflexes in which two separate Chapter 21 Hypothalmus 377 fiber pathways extend from the hypothalamus 4. Growth hormone-releasing hormone (GRH to the hypophysis. The neurons of these path- or GHRH) that regulates the release of ways are involved with both neurally and growth hormone (somatotropin) from the humorally conveyed stimuli. hypophysis. 5. Prolactin-releasing factor (PRF) is the Tuberohypophyseal Tract putative releasing hormone that regulates The tuberohypophyseal tract projects from the release of prolactin (lactogenic hor- the hypothalamic nuclei located in the hypo- mone, mammotropic hormone) from the physiotropic area in the medial basal hypothal- hypophysis. amus (includes the tuber cinereum) and 6. Melanocyte-stimulating hormone-releasing terminates in the infundibular stem (see Fig. factor (MRF) is the putative releasing hor- 21.2). The neurons of this tract elaborate and mone that stimulates the release of melano- convey hypophysiotropins (hypothalamic- cyte stimulating hormone and β-endorphin releasing hormones) to the capillary loops of from the hypophysis. In man, melanocyte- the hypophyseal portal system and, via this stimulating hormone (MSH) stimulates the vascular system, to the adenohypophysis of the formation of melanin pigment and its dis- pituitary gland. These hypophysiotropins are persion in melanocytes. peptides that exert their influences upon the release (or nonrelease) of various hypophyseal Inhibiting Hormones hormones into the systemic circulation. The neurons of the tuberohypophyseal tract consti- 1. Growth hormone release-inhibiting hormone tute the parvocellular neurosecretory system, (GIH, GHRIH) also called somatostatin so called because its neurons have axons with (SS) or somatotropin release-inhibiting hor- small diameters. In a sense, the portal system mone (SRIH) acts to inhibit the release of into which the hypophysiotropins are released growth hormone and thyrotropin from the is actually a huge synaptic cleft; the portal hypophysis. system bridges the gap between the presynap- 2. Prolactin release-inhibiting hormone (PIH) tic tuberohypophyseal tract and the postsynap- or dopamine (DA) acts to inhibit the release tic cells of the anterior lobes. In another of prolactin from the hypophysis. context, the portal veins are a “final common 3. Melanocyte-stimulating hormone release- pathway.” inhibiting factor (MIF) acts to inhibit the release of melanocyte-stimulating hormone. Releasing Hormones 1. Gonadotropin-releasing hormone (GnRH) A complex series of feedback systems to the that regulates the release of follicle stimulat- hypothalamus and to the hypophysis have a ing hormone (FSH, follitropin) and luteiniz- significant role in regulating and controlling ing hormone (LH, lutropin) from the the secretory activity of these hormones. They hypophysis. comprise (1) a long feedback loop, in which the 2. Thyrotropic hormone-releasing hormone hypothalamus monitors hormones synthesized (TRH) that regulates the release of thyrotro- by the peripheral target organs (e.g., thyroxine pin (thyroid-stimulating hormone, TSH) and released by the thyroid gland is fed back via the prolactin from the hypophysis. bloodstream to be monitored by the hypothala- 3. Corticotropin-releasing hormone (CRH) that mus), (2) a short feedback loop, in which each regulates the release of adrenocorticotropin tropic hormone of the pituitary gland is fed (adrenocorticotropic hormone, ACTH), cor- back to, and monitored by, the hypothalamus, tisol, and β-lipotropin from the hypophysis. (3) an even shorter feedback loop, in which the (β-lipotropin hormone is a precursor of releasing hormones feed back to and are moni- endorphins and ACTH.) tored by the hypothalamus, and (4) a feedback 378 The Human Nervous System loop in which each tropic hormone within the (prohormones) of the hormones that are con- tissues is fed back to the hypophysis to influ- veyed by axoplasmic flow to the neural lobe. ence and regulate the release of the same tropic Oxytocin and ADH are synthesized in the cell hormone (e.g., growth hormone). bodies in different neurons. Both types of neu- All of the hypophysiotropic peptides origi- rons are located in both the supraoptic nucleus nally found in the hypothalamus are now and paraventricular nucleus. With the appropri- known to be ubiquitous in the brain, although ate stimulus, an action potential is conveyed located in certain neurons. They are also found down the axon. This triggers the inflow of cal- in the tissues of the gastrointestinal tract. The cium followed by the release of the ADH or vasoactive intestinal peptide (VIP), which was oxytocin at this neurovascular synapse with the originally identified in the gut, is also found in fenestrated capillary wall into the systematic the central nervous system (CNS). The role of circulation. hypophysiotropic peptides in these organs has not, as yet, been resolved. In addition, receptors for these substances have been found in many INFLUENCES ON THE AUTONOMIC peripheral organs, but it is not clear what role NERVOUS SYSTEM these peptides play. The peptides, once released into the synap- The hypothalamus is the chief subcortical tic space, are not recovered by a neuronal center regulating all kinds of visceral activities uptake mechanism similar to that for norepi- and some somatic functions; it acts primarily as nephrine. Apparently, all of the peptides avail- a modulator of autonomic centers in the brain- able to presynaptic release sites are totally stem and spinal cord (Chap. 20). dependent on ribosomal synthesis in the cell The anterior hypothalamus (preoptic and body and are transported by axoplasmic flow to supraoptic regions) has an excitatory parasym- the synaptic terminals. The neuropeptides pathetic (or inhibitory to sympathetic activity) within neurons of the CNS coexist with the role. The stimulation of this region can produce classical neurotransmitters. When released in a decrease in the rate of the heartbeat, a the synaptic cleft, they act to alter the excitabil- decrease in blood pressure, dilatation of the ity of the postsynaptic membrane. cutaneous blood vessels, an increase in motility, peristalsis, and secretion in the gastrointestinal Supraopticohypophyseal Tract tract, constriction of the pupil, and increased The supraopticohypophyseal tract (see Fig. sweating. Activity in this region produces a 21.2), made up of about 100,000 unmyelinated parasympathetic (vagal) tone and such somatic fibers, extends from the supraoptic and par- responses as panting. Lesions in this area can aventricular nuclei to the capillary bed of the result in the production of sympathetic effects. neurohypophysis (posterior lobe). The fibers The posterior hypothalamus has an excita- convey, via axoplasmic transport, antidiuretic tory sympathetic role. Activation of this region hormone (ADH, vasopressin), which is can produce an increase in the rate of the heart- involved with the homeostatic role of conserv- beat, an increase in blood pressure, constriction ing water regulating the tonicity of body fluids, of cutaneous blood vessels, a decrease in motil- and oxytocin, which has a role in stimulating ity, peristalsis, and secretion in the gastroin- the contraction of smooth muscles of the uterus testinal tract, dilatation of the pupil, and and promoting the ejecting of milk from the erection of hair. Activity in this region pro- lactating mammary glands by stimulating con- duces a sympathetic tone and such somatic tractions of its myoepithelial cells. responses as shivering, running, and struggling. The neurons of this tract constitute the mag- The descending projections from the hypo- nocellular neurosecretory system with its large- thalamus are involved with regulating a variety diameter axons. They synthesize the precursors of bodily functions through its influences on the Chapter 21 Hypothalmus 379 autonomic nervous system (Chap. 20). Some of receptor neurons, which monitor the tempera- its influences are involved with certain somatic ture of the blood. This “thermostat” regulates the functions. The latter include a role in (1) shiver- heat-producing and heat-conserving control sys- ing produced by the activity of voluntary mus- tems. In effect, the continuous fine adjustments cles and (2) the activities of the voluntary necessary for maintaining a constant normal palatal and pharyngeal muscles associated with body temperature depend on the hypothalamus. the ingestion of food (the latter are innervated The anterior hypothalamus acts to prevent a by the nucleus ambiguus, a brainstem nucleus). rise in body temperature. It activates those The descending fibers influencing the auto- processes that favor heat loss, including vasodi- nomic nervous system include the (1) dorsal latation of cutaneous blood vessels, sweating longitudinal fasciculus (DLF) in the medial (evaporation of water for cooling), and panting. brainstem tegmentum and (2) fibers in the dor- Destruction of this “heat-dissipating region” solateral tegmentum. The DLF extends caudally can produce a highly elevated body tempera- in the medulla and innervates the superior and ture (hyperthermia). inferior salivatory nuclei and the dorsal motor The posterior hypothalamus contains a nucleus of the vagus nerve; all are the source of region that triggers those activities concerned parasympathetic outflow (Chap. 20). Some with heat production and heat conservation. fibers terminate in the nucleus solitarius, a vis- These include the metabolic heat-producing ceral sensory nucleus (Chap. 14). These fibers systems (thermogenesis by the oxidation of glu- can constitute a reflected feedback pathway cose), vasoconstriction (especially of cutaneous modulating visceral sensory input. The fibers in blood vessels), erection of hair (goose pimples), the dorsolateral tegmentum extend throughout and shivering. The malfunctioning of this the length of the spinal cord. Some of their region can produce a cold-blooded mammal fibers can terminate in the parasympathetic that cannot sustain a uniform body temperature. nuclei of the brainstem and they also terminate Pyrogenic substances, produced in some (1) in the lateral intermediate zone of T1 to L2, diseases, affect the hypothalamus, causing a the location of the outflow of the sympathetic fever known as neurogenic hyperthermia. system, and (2) S2 to S4, the location of the outflow of the parasympathetic system. A lesion in the dorsolateral tegmentum of REGULATION OF WATER BALANCE the medulla can interrupt the descending sympathetic fibers and result in Horner’s syndrome The hypothalamus has significant roles in (Chap. 12). This can be the consequence of an fluid balance by regulating both the intake (by obstruction of the posterior inferior cerebellar drinking) and output (through kidneys and artery (PICA) (Chap. 4). The symptoms sweat glands) of water. Evidence indicates that include miosis of the pupil, ptosis of the eyelid, a “drinking” or “thirst” center is located in the decreased sweating, and increased warmth and lateral hypothalamus and a “thirst satiety” cen- redness on the side of the face; all occur on the ter in the medial hypothalamus. The osmore- ipsilateral side, indicating that these fibers ceptor neurons in these hypothalamic centers descend without crossing. respond to the osmolality (electrolyte composition) of the blood passing through these nuclei. They set off events that stimulate or TEMPERATURE REGULATION inhibit water intake. Other factors such as dryness of the oral mucosa from decreased sali- The hypothalamus has an essential role in vary flow also influence intake of water. A salt body temperature; it regulates the balance appetite is generated by the effect of the elec- between heat production and heat loss. More trolyte composition of the blood on the gusta- specifically, the hypothalamus has thermal tory system. 380 The Human Nervous System

The hypothalamus has a crucial role in the eat. Destruction of the pair of nuclei produces conservation and loss of body water through an animal exhibiting decreased physical activ- the regulation of urine flow in the kidneys by ity and a voracious appetite (not true hunger) ADH, which is produced by the neurons of the with a twofold to threefold increase in food supraoptic and paraventricular nuclei of the intake. The animal becomes obese. Stimulation hypothalamus. ADH (vasopressin) is synthe- of the lateral hypothalamic nucleus induces the sized by the neurons in these nuclei and carried animal to eat, whereas its destruction produces by axoplasmic transport in the supraopticohy- an animal that refuses to eat until severe ema- pophyseal tract to the neurohypophysis, where ciation from starvation ensues. it is stored or released into the systemic blood Two theories have been proposed to explain circulation. The ADH acts upon the kidney how these centers are influenced. According to (distal convoluted and collecting tubules) to the glucostat hypothesis, hypothalamic neurons increase the reabsorption of water from the respond to blood glucose levels. According to dilute glomerular filtrate in the tubules back the thermostat hypothesis, blood temperature is into the bloodstream, thus concentrating the the causative factor, with an increase resulting urine. Water is thereby conserved and is not from the specific dynamic action of ingested excreted in the urine. Increases in osmolality in blood and with a decrease resulting from dissi- blood flowing through the hypothalamus stim- pation of heat through the skin. ulate the release of ADH; this results in antidi- uresis and conservation of water. Decreases in osmolality inhibit the release of ADH; this EXPRESSIONS OF EMOTION results in diuresis and excretion of water in AND BEHAVIOR urine. Other factors can have a role; vascular receptors monitoring blood volume or flow in The behavioral patterns associated with the body project input to the hypothalamus, in emotional experiences are of two general types: this way influencing the release of ADH. (1) subjective “feelings” and (2) objective A deficiency in the formation and release of physical expressions. The subjective aspects of ADH can result in diabetes insipidus (increased emotion, from depression to euphoria, are more excretion of water without increase in sugar), intimately bound up with the cerebral cortex. in which as much as 10–12 L of urine may be Many of the objective physical expressions are excreted per day. largely mediated through the hypothalamus Following an injury of the infundibular stem and are recognizable as the enhanced activity and the axons of its neurons, diabetes insipidus of the autonomic nervous system. They include may result. This may be temporary, because the alterations in heartbeat (palpitations) and blood axons regenerate and a new functional neuro- pressure, blushing and pallor of the face, dry- hypophysis is established. ness of the mouth, clammy hands, dilatation of the pupil (glassy eye), cold sweat, tears of happiness or sadness, and changes in the concen- FOOD INTAKE AND tration of blood sugar. Stimulation of the ENERGY BALANCE hypothalamus in man is said to evoke changes in blood pressure and rate of heartbeat without The hypothalamic region involved with any psychic manifestations. feeding responses has been called the “appes- tat,” with the ventral medial hypothalamic Sexual Expressions nucleus called the “satiety center” and the lat- The sympathetic and parasympathetic sys- eral hypothalamic nucleus called the “hunger” tems are integrated in sexual and reproductive or “feeding” center. Stimulation of the ventral activities. Commencing with sexual arousal median nucleus inhibits the animal’s urge to elicited from either psychologic or genital stim- Chapter 21 Hypothalmus 381 ulation, the subsequent phases are essentially locus ceruleus with their widespread distribu- similar in both male and female. In the next tion (Chap. 15), (2) the release of pain-blunting phase, the engorgement of the erectile tissue endorphins and enkephalins by the hypothala- resulting in the erection of the clitoris and penis mus and other neural complexes (Chap. 9), and is a response to parasympathetic stimulation (3) the release of the stress-response hormones (nervus erigentes of S3 and S4). Loss of by the hypothalamus and pituitary gland, parasympathetic activity, as in diabetic neuropa- namely corticotropin-releasing hormone thy, results in impotency in the male (failure of (CRH), adrenocorticotropic hormone (ACTH), erection and ejaculation). In the female, the and cortisol by the adrenal gland. Cortisol is an parasympathetic fibers stimulate the secretions adrenal stress hormone that mobilizes energy from the cervical glands to further moisten the and inhibits the immune system. vagina and engorge the labia minora. Stimula- tion by sympathetic fibers produces peristaltic waves that propel semen along the ductus defer- CIRCADIAN RHYTHMS ens and contractions that discharge emission secretions from the seminal vesicles and prostate Cues of environmental time such as the gland to form the substance of the ejaculate. The daily light/dark cycle entrain (synchronize) phase of ejaculation through and out of the ure- physiological and behavioral activities to a thra involves the coordinated activity of the 24–hour day/night cycle—the circadian rhythm parasympathetic fibers and somatic motoneu- (circa, about + diem, day). An endogenous rons (pudendal nerves S2–S4). During the oscillator called the internal circadian clock orgasm, the motoneurons evoke the spasmodic (pacemaker) located in the suprachiasmatic contraction of the bulbocavernous, ischiocav- nucleus generates and controls the circadian ernous, and pelvic floor voluntary muscles that rhythm. This clock allows organisms to antici- eject the ejaculate from the penis. Weakness of pate rhythmic changes in the environment and erection or premature ejaculation can occur as alter their physiological state, thus providing the consequence of overactivity of the sympa- them with an adaptive advantage. Although the thetic system. Often, this has an emotional basis. cycle persists in the absence of environmental Depression of sympathetic activity, following cues, its duration is altered by external signals treatment with certain drugs, could result in called zeitgebers (time givers). Zeitgebers reset impaired ability to ejaculate. the clock so that internal time matches local time (entrainment). For example, light is a “Pleasure Centers” and “Punishing Centers” powerful timing cue, which is linked to the The hypothalamus is very closely linked to active phase of the circadian cycle in some ani- the limbic system and, not uncommonly, is mals (diurnal) and to the inactive phase in oth- considered part of it. Stimulation of some parts ers (nocturnal). Most adult humans and diurnal of the hypothalamus elicits expressions of animals sleep at night when it is dark, whereas pleasure or of punishment (see Chap. 22). nocturnal animals sleep mostly during the day when it is light. Circadian rhythms also are Responses to Intense Stress and Trauma manifested by fluctuations in body tempera- The response of the brain to profound crises ture, metabolic rate, urine production, and hor- involving intense stress and trauma is to mobi- mone secretions. The ubiquitous seasonal lize the resources that act to protect the organ- rhythms of mammals, including the annual ism. This includes activating the neural circuits migrations of caribou, the winter hibernation of involved with the “fight, fright and flight” marmots and bears, and the reproductive cycles activities (Chap. 20). Among these are (1) the of rutting elk in the autumn, resulting in fauns release of catecholamines for the initial prepa- being born in the spring, might also be regu- ration for the emergency by the neurons of the lated by circadian clocks. 382 The Human Nervous System

The Suprachiasmatic Nucleus dated by direct observation, electrical record- In vertebrates, the circadian clock is located ings of brain waves (electroencephalogram or in the suprachiasmatic nucleus (SCN). The EEG), recordings of muscle activity (elec- SCN, located in the anterior hypothalamus just tromyogam), and recordings of eye movement above the optic chiasma (see Fig. 21.1) is the (electro-oculogram). Stage 1 is a transitional internal master clock of the circadian timing light sleep that lasts for but a few minutes dur- system, a system of neural circuits with the pri- ing which muscles relax as one drifts in and out mary role of adapting to the environmental of wakefulness. The body temperature is lowered, the eyes make slow rolling movements, solar rhythms of light/dark, called the sleep– and the subject sees fragmentary images. The wake cycle. The rhythm that is generated by the frequency of the EEG diminishes and the SCN is called the endogenous “free-running” amplitude slightly increases. This is the lightest rhythm. It is approximately but not exactly 24 level of sleep from which one can be easily hours and varies for different species. The aroused. Stage 2 sleep is slightly deeper and endogenous rhythm is entrained to environ- lasts for about 5–15 minutes. During this stage, mental light–dark cycles. the heart and respiratory rates decrease and eye An endogenous biological clock oscillates movements almost cease. The frequency of in the fetus. Apparently, this clock is entrained the EEG diminishes further and the amplitude by circadian signals from the mother and pre- increases. The pattern is interspersed with high- pares the developing fetus to adapt more read- frequency spikes referred to as sleep spindles. ily to adjust to life following birth. It should be Stage 3 sleep is regarded as moderately deep. noted that circadian rhythms tend to be dis- Body movements are absent and the EEG is rupted in people who are blind. characterized by low-frequency, higher-ampli- Light that stimulates the retina activates a tude waves and a reduction in spindle activity. recently discovered subset of light-detecting Stage 4 is the deepest level during which it is retinal ganglion neurons whose dendrites con- most difficult to awaken a sleeping subject. The tain the photopigment melanopsin. These muscles are greatly relaxed and blood pressure, widely dispersed neurons, constituting about heart rate, and breathing are at their lowest. The 2% of retinal ganglion cells, have tortuous pupils are constricted (miosis). The EEG is broad overlapping dendritic fields optimally characterized by low-frequency high-amplitude arranged to detect low levels of light. Follow- waves and its conformation conveys the desig- ing stimulation, this population fires continu- nation slow-wave sleep. This phase lasts about ously without adaptation for at least 20 20–40 minutes. Following stage 4, the EEG minutes, in contrast to ganglion cells that pattern reverts to a pattern resembling the receive input from rods and cones. Activation waking-state, high-frequency, low-amplitude. of the melanopsin-containing ganglion cells, However, this phase is characterized by rapid which project directly to the SCN via the eye movements (REM) and this aspect is strik- retinohypothalamic tract, entrains mammalian ingly different from the other stages collec- circadian rhythms to environmental time. As tively called non-REM sleep. The period indicated in Chapter 19, these cells also have following REM sleep is accompanied by a been implicated in circuitry to the pretectum complete inhibition of tone in other skeletal mediating the pupillary light reflex and to the muscles. The sequence of non-REM and REM superior colliculus controlling eye movements. phases normally has four to six cycles per night. During REM sleep, electrical activity of the Sleep–Wake Cycle brain is unusually high, somewhat resembling A normal day is divided into waking and that of wakefulness. This REM stage is called sleeping phases. Sleep typically occurs in paradoxical sleep, during which most dreams repetitive cycles of different stages as eluci- replete with visual imagery occur and can be Chapter 21 Hypothalmus 383 readily retrieved. Heart rate and blood pressure ing effects mediated by melatonin. Some recent rises along with EEG activity. Homeostatic observations do indicate that it can facilitate mechanisms are attenuated. Respiration is rel- sleep onset in elderly humans who are deficient atively unresponsive to changes in CO2 and in melatonin. It might be of value in overcom- responses to heat and cold are greatly reduced. ing jet lag. In REM sleep, the rate and depth of breathing Both sleep and wakefulness are activities increases, but the muscles are greatly relaxed, generated by the interplay of neuronal popula- more so than during the deepest levels of non- tions involving circuitry within the basal fore- REM sleep. Most dreaming, night terrors, and brain and brainstem reticular formation (Chap sleep walking occurs during stage 4 and REM 22). The neurons of these sleep-control circuits sleep. REM sleep normally follows immedi- are linked and coordinated by many neuro- ately after each stage 4 non-REM period, but transmitters and the suprachiasmatic nucleus. can occur occasionally after any one of the The following are some components of these four stages. There is a general reduction of the circuits that are included because of their asso- non-REM periods as the night progresses, ciation with certain features of the EEG and especially in stages 3 and 4, and an increase in behavioral expressions. the REM periods toward the end of a normal Neurons within the basal nucleus of Meynert sleep. About half of the night’s sleep occurs (see Fig. 22.2) located in the basal forebrain during the third and longest REM cycles, have a modulatory role during arousal and selec- which can last 40–50 minutes. Occasionally, tive attention. Neurons, called waking-up neu- each REM cycle can be followed by at least 30 rons located mainly in the brainstem reticular minutes of non-REM sleep before a new cycle formation, actively fire both during the wakeful begins. The start of the non-REM phase to the state and in REM sleep. The firing of neurons in end of the REM phase averages about 90–110 the pontine reticular nuclei during REM sleep minutes. concurrently activates a circuit that elicits REMs and another circuit that inhibits lower motoneu- Melatonin. The neurohormone melatonin, rons of the spinal cord, which prevents move- synthesized in the pineal gland from trypto- ments of the limbs (running during a dream). phan, has been implicated as a modulator of the The latter occurs because the upper motoneu- sleep–wake cycle and is promoted as a safe nat- rons stimulate spinal interneurons that release ural sleeping pill. The pineal, one of the cir- the inhibitory transmitter glycine at their cumventricular organs described in the next synapses with lower motoneurons. section, is a highly vascular neuroendocrine gland located in the caudal epithalamus (see Figs. 13.3 and 21.5). Its pinealocytes THE CIRCUMVENTRICULAR ORGANS (parenchymal cells) have processes that extend to perivascular spaces that surround fenestrated Adjacent to the median ventricular cavities capillaries. The suprachiasmatic nucleus, (third ventricle, cerebral aqueduct, and fourth which receives retinal input, regulates the ventricle) are specialized areas called circum- release of melatonin into the pineal capillaries ventricular organs. These include (1) the and the vascular circulation. In turn, melatonin median eminence of the tuber cinereum, the modulates brainstem circuits associated with neurohypophysis, and the pineal body, which the sleep–wake cycle. are sites of neuroendocrine activity, and (2) the When given to rats during the daytime, organum vasculosum of the lamina terminalis, melatonin stimulates wakefulness. On the other subfornical organ, subcommissural organ, and hand, it has a substantial sleep-inducing (hyp- the area postrema (see Fig. 21.5), which are notic) effect in birds. As yet, human studies chemoreceptive areas whose functional roles have not demonstrated consistent sleep-induc- are not fully understood. The common vascu- 384 The Human Nervous System

Figure 21.5: Midsagittal view of the brain illustrating the location of the circumventricular organs.

lar, ependymal, and neural organization of Median Eminence of the Tuber Cinereum these structures differs from that found in typi- The median eminence of the tuber cinereum cal brain tissue. They are referred to as “being is that portion of the floor of the hypothalamus in the brain but not of it” and as leaky areas, where the releasing and inhibiting hormones are primarily because they lack a blood–brain bar- released from the axon terminal into the capil- rier. All circumventricular organs are unpaired lary loops of the hypophyseal portal system. In and located along the ventricular surface near essence, it is the site of the neurovascular link the midline except for the paired area postrema between the CNS and the adenohypophysis. of the medulla. These leaky areas are isolated from the brain by a lining of specialized ependymal cells, called tanacytes, that separate Neurohypophysis these organs from the ventricles. The tanacytes As previously noted, the neurohypophysis is are linked to each other by tight junctions and, the site for the storage and release of vaso- thus, prevent the free exchange between the cir- pressin and oxytocin, which are synthesized in cumventricular organs and the cerebrospinal the supraoptic and paraventricular nuclei. The fluid. nerve terminals of the supraopticohypophyseal Chapter 21 Hypothalmus 385 tract containing these neurohormones are inter- Area Postrema mingled among cells called pituicytes, which The area postrema consists of paired small, are modified glial cells. rounded eminences that occupy the wall of the Organum Vasculosum of the Lamina caudal end, or obex, of the fourth ventricle, Terminalis and Subfornical Organ where it meets the central canal (see Fig. 13.3). It is composed of modified neurons, The organum vasculosum of the lamina ter- astrocytelike cells, and rich overlapping arte- minalis (supraoptic crest and “prechiasmatic rial and sinusoidal network. The terminals in gland”) is a highly vascular region of the lamina the vicinity of the area postrema are of axons terminalis. Its loops of fenestrated capillaries are originating in the vagus nerve, nucleus solitar- surrounded by wide, fluid-filled perivascular ius, and the spinal cord. These endings contain spaces. oxytocin, vasopressin and other peptides not The subfornical organ (intercolumnar tuber- found within the area postrema. It is regarded cle) is an elevation located between the diverg- as an emetic chemoreceptor sensitive to sub- ing columns of the fornix at the level of the stances that are unusual constituents such as interventricular foramina of Monro. It is par- toxins circulating in the blood. The area tially covered by the choroid plexus. Its sinu- postrema acts as a trigger zone that evokes the soids and glomerular loops are supplied by vomiting reflex in response to a host of emetic adjacent blood vessels. agents including apomorphine and digitalis These two organs have nerve endings glycosides. synapsing with their neurons. In addition, the messenger angiotensin II, the production of which is enhanced by a reduction in blood volume, binds to receptor sites of the neurons of SUGGESTED READINGS these organs. The neurons have axons that project to the supraoptic and paraventricular nuclei Berson DM. Strange vision: ganglion cells as circa- of the hypothalamus. The interaction within dian photoreceptors. Trends Neurosci. 2003;26: these organs seems to provide the feedback 314–320. information involved with the hypothalamic Berson DM, Dunn FA, Takao M. Phototransduction control of the posterior lobe of the hypophysis. by retinal ganglion cells that set the circadian This includes roles in drinking behavior clock. Science 2002;295:1070–1073. Burbach JP, Luckman SM, Murphy D, Gainer H. (osmoregulation), release of antidiuretic hor- Gene regulation in the magnocellular hypothal- mone, and the physiological control of body amo-neurohypophysial system. Physiol. Rev. fluid balance. 2001;81:1197–1267. Carpenter DO. Central nervous system mechanisms Subcommissural Organ in deglutition and emesis. In: Schultz SG, ed. The subcommissural organ is located in the Handbook of Physiology. Section 6: The Gas- roof of the cerebral aqueduct just rostral and trointestinal System. Bethesda, MD: American ventral to the posterior commissure. It is com- Physiological Society; 1989:685–714. posed of specialized ependymal cells and glial Conn PM, Freeman ME. Neuroendocrinology in cells in a capillary bed of nonfenestrated Physiology and Medicine. Totowa, NJ: Humana; endothelium. The secretory ependymal cells 2000. Hall JC. Cryptochromes: sensory reception, trans- release a neutral mucopolysaccharide compound duction, and clock functions subserving circa- product directly into the ventricular fluid. It con- dian systems. Curr. Opin. Neurobiol. 2000;10: denses to form Reissner’s fiber, which extends 456–466. through the cerebral aqueduct, fourth ventricle, Harmer SL, Panda S, Kay SA. Molecular bases of and central canal of the spinal cord to coccygeal circadian rhythms. Annu. Rev. Cell. Dev. Biol. levels. Its function is not known. 2001;17:215–253. 386 The Human Nervous System

King DP, Takahashi JS. Molecular genetics of circa- Nauta WJH, Haymaker W. Hypothalamic nuclei and dian rhythms in mammals. Annu. Rev. Neurosci. fiber connections. In: Haymaker W, Anderson 2000;23:713–742. EM, Nauta WJH, eds. The Hypothalamus. Klein DC, Moore RY, Reppert SM. Suprachiamatic Springfield, IL: Charles C Thomas; 1969; Nucleus: The Mind’s Clock. New York: Oxford 136–209. University Press; 1991. Reppert SM, Weaver DR. Coordination of circadian Korf H-W, Usadel K-H. Neuroendocrinology: Ret- timing in mammals. Nature. 2002;418:935–941. rospect and Perspectives. New York: Springer- Sawchenko PE. Toward a new neurobiology of Verlag; 1997. energy balance, appetite, and obesity: the Laemle LK, Hori N, Strominger NL, Tan Y, Carpen- anatomists weigh in. J. Comp. Neurol. 1998;402: ter DO. Physiological and anatomical properties 435–441. of the suprachiasmatic nucleus of an anoph- Sawchenko PE, Li HY, Ericsson A. Circuits and thalmic mouse. Brain Res. 2002;953:73–81. mechanisms governing hypothalamic responses Lowrey PL, Takahashi JS. Genetics of the mam- to stress: a tale of two paradigms. Prog. Brain malian circadian system: photic entrainment, Res. 2000;122:61–78. circadian pacemaker mechanisms, and posttrans- Silverman AJ, Zimmerman EA. Magnocellular neu- lational regulation. Annu. Rev. Genet. 2000;34: rosecretory system. Annu. Rev. Neurosci. 533–562. 1983;6:357–380. Lucas RJ, Hattar S, Takao M, Berson DM, Foster Swanson LW, Sawchenko PE. Hypothalamic inte- RG,Yau KW. Diminished pupillary light reflex at gration: organization of the paraventricular and high irradiances in melanopsin-knockout mice. supraoptic nuclei. Annu. Rev. Neurosci. Science 2003;299:245–247. 1983;6:269–324. Miller AD, Ruggiero DA. Emetic reflex arc revealed Williams RH, Larsen PR. Williams textbook of by expression of the immediate-early gene c-fox endocrinology. 10th ed. Philadelphia, PA: Saun- in the cat. J. Neurosci. 1994;14:871–888. ders; 2003. 22 The Reticular Formation and the Limbic System

Reticular Formation Limbic System Role of the Limbic System

The reticular formation (RF) is a seemingly (area 24) and orbitofrontal and medial pre- diffuse, but actually highly organized, network frontal cortex (areas 10 and 11). The subcorti- of neurons distributed through the tegmental cal centers include the nuclei of the septal area, core of the brainstem. The RF extends rostrally and the nucleus accumbens (portion of the ven- as the intralaminar nuclei of the thalamus and tral striatum). Substantive information is inte- caudally as the gray matter in the vicinity of the grated within the thalamus and amygdala. In central canal of the spinal cord. The RF turn, the amygdala projects its outputs to the receives the summation of sensory information thalamus, hypothalamus, and the brainstem, that flows into the spinal cord and brainstem where they activate the emotional state through via the peripheral nerves. These inputs are the endocrine system and the autonomic nerv- significant in influencing the level of arousal ous system (Chaps. 20 and 21). The networks (i.e., the responsive tone of conscious aware- of the limbic system are linked together by ness and physical performance). The RF con- bidirectional reciprocal pathways. tains assemblies of interacting neurons that Collectively, the limbic system and the retic- integrate reflexes and basic stereotyped action ular formation are neural constructs that have at patterns mediated by cranial nerve input. The least two things in common: (1) Anatomically, basic motor responses range from facial nerve- they both are substantially heteromorphic sys- innervated muscle responses to mechanisms of tems and (2) their actions are woven into the eating, drinking, and breathing. They are cen- fabric of emotional and behavioral expressions trally coordinated and assembled as highly in a way that makes it difficult to define pre- complex behaviors under voluntary control by cisely their individual roles in the totality of higher cerebral motor circuits, including those limbic action. of the limbic system. The precise and subtle patterns of motor behaviors mediated by cranial nerves involve the organized circuitry of RETICULAR FORMATION the brainstem RF. The limbic system (LS) is involved with emotional behaviors, endocrine and autonomic Anatomy regulation, and mechanisms of memory forma- The RF extends throughout the length of the tion. The emotional behaviors comprise activi- brainstem tegmentum. Microscopically, the ties exhibited during satiety, quiescence, prayer, RF appears as gray matter commingled with aggression, fear, rage, and sexual activity. fascicles of ascending and descending axons Anatomically, the limbic system is an intercon- and dendritic arbors imparting the appearance nected neuronal network of neocortical areas of a woven network (Nauta and Fiertig, 1986). and subcortical structures. Neo- and mesocorti- The RF occupies the space in the tegmentum cal areas include the anterior cingulate gyrus not taken up by motor nuclei, nuclei of the sen-

387 388 The Human Nervous System sory pathways (e.g., trigeminal and superior ascending and descending axons that termi- olivary nuclei), cerebellar relay nuclei (e.g., nate primarily in the medial reticular zone. inferior olivary complex) and circumscribed The lateral zone is considered to be an affer- fiber tracts (e.g., medial lemniscus and medial, ent and association area because it receives longitudinal fasciculus). The RF in conjunc- multiple “sensory” inputs from the spinal tion with the nuclei of the raphe (see Fig. 13.6) cord, cranial nerves, and input from the cere- and the periaqueductal gray (see Fig. 13.15) bellum and cerebrum. The medial zone extends rostrally into thalamic areas having (“motor” or “efferent” zone) is characterized visceral functions, consisting in part of the by the presence of many large neurons whose periventricular gray adjacent to the third ven- axons bifurcate into long ascending and long tricle, the parafascicular and central median descending branches. These fibers, which nuclei of the intralaminar thalamic group (see emit numerous collateral branches, form the Fig. 23.1 and Table 23.1), and the zona central tegmental tract of the brainstem incerta and other nuclei near the subthalamic tegmentum. The output from the motor zone is nucleus (see Fig. 24.3). projected rostrally to the hypothalamus and The neurons of the brainstem RF have intralaminar nuclei of the thalamus, caudally extensively branched dendritic trees oriented in to the spinal cord via rubrospinal and reticu- a transverse plane as “segments” and long lospinal tracts, posteriorly to the cerebellum, branching axons that project both rostrally and and laterally to cranial nerve nuclei. The mid- caudally (see Fig. 22.1). These axons form a line zone comprises primarily the nuclei of the widespread network connecting with neurons raphe and the periaqueductal gray (see Fig. of the hypothalamus, thalamus, cerebrum 13.6). These nuclei, along with the locus (including cerebral cortex), cerebellum, and ceruleus, have significant roles in the regula- spinal cord. tion of the levels of consciousness and the Ascending influences from the spinal cord stages of sleep (Chap. 21). are processed and conveyed to and within the RF by ascending reticular projections such as Roles and Connections spinoreticular fibers (Chap. 9) and the central The RF receives a continuous stream of tegmental tract (Chap. 13) and by descending multimodal “sensory” stimuli. Responsiveness influences from the forebrain by direct and to these inputs is expressed through fluctua- indirect downward projections from the cere- tions in the expressions of its output. These are bral cortex, basal ganglia, and forebrain limbic revealed in the variety of nuances associated system. with such behavioral states of the sleep–wake The circuitry essential to various behav- cycle as drowsiness, attentiveness, awareness, ioral states, such as the sleep–wake cycle, is and alertness. The monoaminergic neurons of known as the ascending reticular activating the brainstem, especially those of the raphe system (ARAS). The biochemically defined nuclei and locus ceruleus, have a significant circuits within the ARAS include the adrener- role in the neural activity that evokes these gic (epinephrine), noradrenergic, serotoner- behavioral expressions (Chap. 15). gic, and dopaminergic circuits described in Sleep is not just an absence of wakefulness; Chapter 15. rather, it is the product of active processes The brainstem RF is subdivided at all lev- involving the brainstem “ascending reticular els into three zones (see Fig. 22.1): (1) the lat- activating system” that regulates the level of eral zone (lateral one-third of the tegmentum), activation of the brain. Irreversible coma (per- (2) the medial zone (medial two-thirds of the manent loss of consciousness) resulting from tegmentum), and (3) the midline zone. The severe head injury is associated with extensive lateral zone (also called the “sensory” zone) is damage to the cerebral cortex, midbrain reticu- composed of small cells with relatively short lar formation, or both. A large lesion of the Chapter 22 Reticular Formation and Limbic System 389

Figure 22.1: The central tegmental tract of the ascending reticular pathway system. In general, the multineuronal, multisynaptic relays of the brainstem reticular formation (located in the tegmentum) extend rostrally into two telencephalic regions: (1) dorsally into the intralaminar, ventral anterior (VA), and dorsomedial thalamic nuclear complexes and (2) ventrally into the hypothalamus. The thalamic component projects to the orbitofrontal cortex via VA. The insets at the lower left represent a series of neuropil “segments.” The cross-section through the brainstem (medulla) illustrates the division of the brainstem RF into a midline raphe or paramedian zone, a medial reticular or “efferent” zone, and a lateral reticular or “sensory” zone. Arrows indicate the general direction of flow of neural influences.

midbrain RF produces an animal that is in a and phasic motor actions as expressed in relax- constant behavioral stupor or in a coma. In con- ation and fidgeting. trast, a lesion in the pontine RF results in an animal that is constantly awake. The brainstem Summation RF exerts powerful influences through special- The RF does look chaotic. Its inputs are het- ized nuclear groups for carrying out vital func- erogeneous and dismayingly convergent. Its tions. These include cardiovascular centers for output fibers contain few circumscribed bundles control of blood pressure and respiratory cen- and they tend to be widespread and organized ters for regulation of breathing (Chap. 20). The diffusely. Yet, many of the effector mechanisms RF contributes to postural control through embodied in the reticular formation are highly influences exerted on upper-motoneuron path- specific and precise. The heterogeneity of the ways (reticulospinal and vestibulospinal inputs to the reticular formation can reflect no tracts). This is also demonstrated in such tonic more and no less than the needs to adapt to cir- 390 The Human Nervous System cumstances as diverse as the acidity of blood The mesocortex has a vital role in emotional plasma, the oxygen content of inhaled air, and experiences associated with sensations. The the amount of physical exertion one undertakes perceptions of fear, anger, pleasure, and satis- or anticipates undertaking from moment to factions are considered to be expressions of moment (Nauta and Fiertig, 1986). interactions of the cerebral cortex with subcortical centers focusing on the amygdala and its output. Patients in whom the prefrontal cortex LIMBIC SYSTEM and cingulate gyrus has been ablated illustrate this role in emotional experience. Pain no Anatomically, the limbic system comprises longer bothers them. Pain continues to be felt a complex network of cortical areas and sub- as a sensation and activates the expected auto- cortical structures interconnected by bidirec- nomic responses, but pain is no longer per- tional pathways. One component of the limbic ceived as a decidedly unpleasant experience. system, the hippocampus is important in mech- Stimulation of the anterior cingulate gyrus anisms of memory. In its role as the emotional results in a variety of responses among which processing system (EPS), the limbic system is are pain relief, reduction in obsessive–compul- involved in a variety of functions. (1) Emotion sive behavior, impaired initiation of motor as a conscious feeling is mediated largely by activity, apathy, depression, and reduction in processing within the cingulate and prefrontal anxiety and social awareness. cortices. Emotions are actually bioadaptations that were found to be beneficial during evolu- Substantia Innominata, Basal Nucleus of tion. (2) Emotional reactions to aversive stim- Meynert, and Extended Amygdala uli are responses to sudden danger. The initial Rostral to the hypothalamus and globus pal- reflexive reaction is an alerting pose by evok- lidus and below the anterior commissure is a ing phylogenetically derived programmed region of gray matter called the substantia responses that have survival value (e.g., freez- innominata within which is the basal nucleus ing [playing possum]). This generally is a pre- of Meynert (see Fig. 22.2). The substantia liminary posture prior to a decision for innominata has reciprocal connections with the action—fight or flight. (3) Emotional reactions amygdala, hippocampus, and hypothalamus. to pleasurable and satiety stimuli are such posi- The basal nucleus has reciprocal linkages with tive responses as joyful expressions, elements the hippocampus. Projections from large of love in pair bonding, and family organization cholinergic neurons of the basal nucleus to the along with affirmative social interactions. (4) entire neocortex are regarded as significant Emotional actions are activated by stimuli that because they could have a major role in neural evoke the motivational system to drive and to processing associated with intellectual func- guide goal-directed behavior. These responses tions (Chap. 25). The nucleus could also play a are generally mediated by goals (e.g., food, role in modulating the amygdala and the neo- water, and pain). Goal-directed actions range cortex. The substantia innominata also contains from being motivated by a specific single stim- some neurons that, together with cell groups of ulus to complex abstract ideas or beliefs. the bed nucleus of the stria terminalis located Major limbic centers include the mesocortex in the basomedial forebrain bordering the ante- (cingulate gyrus, orbitofrontal, insular, and rior commissure, are a rostral extension of the medial prefrontal cortices), parahippocampal central nucleus of the amygdala. The contin- gyrus, and subcortical structures, including the uum of central nucleus, substantia innominata, thalamus, septal area, nucleus accumbens, hip- and bed nucleus of the stria terminalis is pocampus, hypothalamus, brainstem and, of referred to as the extended amygdala, which is most significance, the amygdala (amygdaloid next to the ventral striatum and ventral pal- complex). lidum. This emphasizes the close geographic Chapter 22 Reticular Formation and Limbic System 391 relationship of limbic structures with parts of the floor of the temporal (inferior) horn of the the basal ganglia concerned with motor activity lateral ventricle. The ventricular surface is cov- related to emotional stimuli (Chap. 24). These ered by a thin lamina of axons called the could, in part, be reflected by alterations in alveus. The fibers of the alveus arise from the facial expression displaying fear, happiness, hippocampus and from the adjacent subiculum. sorrow, anger, and so forth, and in the connota- These fibers converge to form a flattened band tions of posture such as stooped vs erect. called the fimbria of the fornix, which continues as the fornix. The fornix with its approxi- Hippocampal Formation and the mately 1.25 million fibers is the major output “Papez Circuit” channel of the hippocampus; it also contains The hippocampal formation consists of the some fibers traveling in the opposite direction, hippocampus proper and the dentate gyrus (see particularly from the septal region, that termi- Fig. 22.3). The subiculum is transitional nate in the hippocampus. The hippocampal for- between the hippocampus and entorhinal cor- mation is composed of archicortex (Chap. 25) tex (area 28) of the parahippocampal gyrus, characterized by the presence of three layers: and some consider it to be part of the hip- molecular, pyramidal (granular for the dentate pocampal formation. The hippocampus forms gyrus), and polymorphic (see Fig. 22.3). The

Figure 22.2: Some connections of the limbic system, with emphasis on the circuitry associated with the amygdala. Many of the circuits are reciprocal. Descending fibers terminating in the brainstem reticular formation are not illustrated. 392 The Human Nervous System molecular layer is synaptic and mainly consists dentate gyrus, this middle layer is called the of a meshwork of axonal, dendritic, and glial granular layer because of a dense aggregation processes (neuropil). The pyramidal layer of of small stellate cells. Dendrites of these cells the hippocampus contains several rows of rela- extend into the molecular layer, and their tively large triangular or pyramidal-shaped cell axons, called mossy fibers, terminate within bodies with axons that enter the alveus and are the hippocampus near the base of pyramidal the main output of the hippocampus. Pyramidal cell apical dendrites. The polymorphic layer, cell apical dendrites extend into the molecular covered by the alveus, is composed mainly of layer along with axon collaterals. Interneurons neuropil, like the molecular layer, which also are present in the pyramidal layer. For the includes the extensive basal dendrites as well

Figure 22.3: Diagram of a transverse section through the hippocampal formation (dentate gyrus and hippocampus), subiculum, and entorhinal cortex (area 28) of the parahippocampal gyrus. (1) Input to the entorhinal area and subiculum is derived from several areas of temporal lobe cortex; (2) output from the entorhinal area projects to the dentate gyrus and hippocampus via the alveus (“alvear path”) or via the perforant path; (3) connections of the entorhinal area and subiculum with other cortical areas generally are reciprocal; (4) axons of pyramidal cells of the subiculum and hippocampus pass through the alveus and fimbria into the fornix; and (5) axons of the granule cells in the dentate gyrus terminate in the hippocampus. CA (cornus ammonis) refers to the fields of the hippocampus. Chapter 22 Reticular Formation and Limbic System 393 as axon collaterals of Purkinje cells. The hip- The reciprocal connections of the hippocampal formation is divided into fields pocampus with the many areas of the neocortex CA1, CA2, and CA3. CA1 is continuous with are critical in its presumed role of receiving the subiculum. The designation CA comes novel sensory inputs that are registered as from cornu ammonis (Ammon was an Egypt- short-term memory. Within a limited-time span, ian god with a ram’s head), another name for this memory can become a long-term memory. the hippocampus conferred because of its Memory disorders are characteristic features of shape in the coronal plane. The hippocampal lesions of the hippocampus. Electrical stimula- formation has reciprocal connections with the tion of the hippocampus elicits fear, memories, parahippocampal gyrus, which, in turn, has illusions, and emotions, but this might, in part, widespread reciprocal cortical interconnec- be the result of the activation of other structures. tions. Afferents from the medial part of the The classic Papez circuit for emotions entorhinal area (area 28) traverse the subicu- (1937) comprises the sequence of hippocampus lum and alveus (alvear pathway) and termi- → fornix → mammillary body → mammil- nate on basilar dendrites and cell bodies of lothalamic tract → anterior thalamic nuclear pyramidal cells in the subiculum and CA1 (see group → cingulate gyrus → parahippocampal Fig. 22.3). Afferents from the lateral part of gyrus and neural linkages back to the hip- the entorhinal area pass through the alvear pocampus (see Fig. 22.4). It was recognition of path as the perforant pathway and terminate the closed nature of this loop that led Papez to on apical dendrites of pyramidal cells in the refute the long-held notion that the hippocam- hippocampus and granule cells of the dentate pus served in some obscure way the olfactory gyrus. The hippocampus receives monoamin- sector of functions. Input to the parahippocam- ergic input from the raphe nuclei and the locus pal gyrus and hippocampus is derived from the ceruleus. The output of the subiculum and hip- cingulate cortex and from association areas of pocampus is conveyed via the fornix to the the cerebral cortex (Chap. 25). Papez regarded mammillary bodies, other hypothalamic the cingulate cortex “as the receptive region for nuclei, and nuclei in the vicinity of the septal the experiencing of emotion.” However, the region and the substantia innominata, includ- hippocampus in particular is important for ing the basal nucleus of Meynert. The hip- induction of short-term memory. Long-term pocampus is bilaterally interconnected via potentiation, which facilitates synaptic plastic- fibers that decussate in the fornical (hippocam- ity, a prerequisite for memory, is associated pal) commissure and turn back in the con- with the hippocampus. tralateral fornix; some postdecussational fibers continue rostrally in the opposite fornix. The Functional Subdivisions of the Limbic System fornix divides around the anterior commissure In 1952, Paul MacLean proposed the term into precommissural and postcommissural limbic system (LS) when he reintroduced fibers and it is the latter group, arising from the Papez’ concept that certain limbic structures subiculum, that terminates in the mammillary could be neuroanatomic substrates for emo- body as well as, to a lesser extent, in the ante- tion. On the basis of experimental data, he rior, intralaminar, and lateral dorsal nuclei of established a major foundation for our current the thalamus. The mammillothalamic tract understanding of the limbic system. In brief, projects from each mammillary body to the MacLean proposed that (1) cortical and hypo- anterior thalamic nuclear group; the latter proj- thalamic information is integrated in the LS; ects to the cingulate gyrus (Chap. 25), as does (2) the limbic system is the target of multisen- field CA1 of the hippocampus and the subicu- sory inputs; (3) he downplayed the previously lum. Commencing in the cingulate gyrus, held view that olfaction and the so-called multineuronal linkages terminate in the cortex smell brain played a dominant role in the of the parahippocampal gyrus. functioning of the LS to a significant but sub- 394 The Human Nervous System

Figure 22.4: The “Papez circuit” includes the hippocampus via fornix → mammillary body via mammillothalamic tract → anterior thalamic nuclear group → cingulate gyrus → parahippocampal gyrus → hippocampus. The subiculum is a pivotal cortical area projecting to widespread regions of the cerebrum. Many connections are reciprocal. ordinate position; (4) the amygdala, nucleus tion of the neocortex gives higher mammals accumbens, septal area, and orbitofrontal cor- and especially humans the capacity for prob- tex are vital in the regulation of emotion. lem solving and rational thought. MacLean’s influential theory asserted that the cingulate cortex, along with the neocortex, The Septal and Amygdala Pathways can be identified with forms of emotional MacLean (1955) delimited two functional behavior that illustrate the evolutionary transi- subdivisions within the LS: (1) The septal tion from the primitive brain of therapsid pathway includes the septal area, anterior cin- (mammal-like) reptiles to the early mam- gulate cortex, stria terminalis, hippocampus, malian brain during the geologic Paleozoic and amygdala, which are associated with mem- Era and then to the highly evolved neocortex ory related to social and sexual behaviors, of mammals, including humans during the including mating, procreation, and care of off- Cenozoic Era. According to this theory, the spring. These are important for the preservation evolution of the LS enabled mammals to expe- of the species. Stimulation of the septal area rience and expresses emotions and, thus, results in pleasurable feelings, euphoria, and emancipated them from stereotypic behaviors sexual arousal leading to an orgasm. (2) The dictated by the brainstem (often referred to as amygdaloid pathways, including amygdala and the reptilian brain). In this schema, the evolu- neocortex, have a presumptive role in behaviors Chapter 22 Reticular Formation and Limbic System 395 such as fighting, feeling, feeding, and other Overview of Functional Neuroanatomical appropriate visceral functions that contribute to Organization of the Limbic Circuitry self-preservation. and the Role of the Amygdala The Mesolimbic and The LS is a scattered complex neuroanatom- Mesocorticolimbic Systems ical network of largely bidirectional pathways 1. The mesolimbic dopaminergic pathway linking cortical areas and subcortical structures originating in the ventral tegmental area (see Figs. 22.2 and 22.5) with roles (1) in the (VTA) of the midbrain (see Fig. 13.15) and perception of emotional feeling and motivation projecting to the nucleus accumbens, or ven- and (2) in the regulation of the expression of tral striatum (Chap. 24), is of paramount emotional behaviors (e.g., aggression, fear, and importance because of the extensive connec- sexual behaviors). The anatomical structures tions of the latter to subcortical nuclei of the involved in the limbic circuitry include the LS. Acting at the limbic–motor interface, the cerebral cortex, along with the subcortical sep- nucleus accumbens projects emotion infor- tal area, hippocampus, nucleus accumbens, mation via the stria terminalis to the dorsal dorsomedial thalamic nucleus, striatum, and striatum, where emotions are translated into ventral tegmental area of the midbrain, The ongoing motion actions of the motor-ori- multifaceted processing of “limbic” informa- ented striatum (e.g., at times expressed as tion within the limbic circuitry converges and short phasic bursts of activity). coalesces for additional processing within the 2. The mesocortical dopaminergic system amygdala. Thus, the amygdala emerges as the pathway, which projects directly from VTA defining hub and nodal center that couples the to mesocortex, is involved in emotions, neocortical and mesocortical areas highly memory, and positive reinforcement of processed sensory information with the subcor- emotional behaviors. In turn, the mesocortex tical nuclei of the limbic circuitry. In turn, the has connections with the amygdala, which, amygdala sends its output to the thalamus, via reciprocal connections, links the cortical hypothalamus, and brainstem, where endocrine areas (mesocortex) involved with conscious and autonomic responses associated with emo- feelings (e.g., fear) with the hypothalamus tional expressions are evoked. (Chap. 21) and brainstem circuitry involved The amygdala utilizes a vast array of sen- with somatic and visceral emotional motor- sory information in the performance of its associated expressions (e.g., facial, vocal, functional roles. The neocortex provides the and changes in blood pressure). amygdala with complex highly processed sensory information derived from the visual, The Rostral and Caudal Limbic Systems auditory, somatosensory, and visceral sys- of MacLean tems. Less processed sensory information 1. The rostral limbic system, which is thought received by sensory relay nuclei of the thala- to be functionally involved with emotional mus (e.g., medial geniculate nucleus) from expressions, is anatomically comprised of ascending spinal and brainstem sensory path- the amygdala, septal nuclei, orbitofrontal ways (e.g., lateral lemniscus) is sent directly and medial prefrontal cortex, anterior insula, to the amygdala. This low-level information is and anterior cingulate gyrus. utilized in immediate “essentially reflex” 2. The caudal limbic system, which is pre- responses to aversive stimuli (LeDoux, 2002). sumed to be associated with memory and Information derived from the mesocortex and some visual functions, consists of the hip- the hippocampus is processed within the pocampus, parahippocampal and posterior amygdala for roles in emotion, learning and cingulate gyri, septal area, and the dorsome- memory formation associated with the per- dial thalamic nucleus. ceptions of emotion and feelings. The amyg- 396 The Human Nervous System

Figure 22.5: Some connections of the LS. The medial forebrain bundle is a multineuronal pathway extending from the septal area through the lateral hypothalamus to the brainstem tegmentum. Note the pathway system comprising the sequence of septal area and preoptic area → habenular nucleus → midbrain tegmentum and interpeduncular nucleus. The latter projects to the midbrain tegmentum. dala receives inputs from the olfactory bulb The cingulate gyrus and the orbitofrontal both directly and indirectly via the piriform and medial prefrontal cortex in part mediate the (olfactory) cortex (Chap. 13). Odors are sig- conscious perception of emotion (feelings). nificant energizers of the LS. These cortical areas have reciprocal connec- The amygdala projects output for the tions with the amygdala, which is the neuronal expression of emotion (1) via the stria termi- center that is the hub of the subcortical limbic nalis to the hypothalamus–pituitary complex circuitry. The amygdala through its output is for the regulation of stress hormone release, to responsible for generating emotional states and the lateral hypothalamus for sympathetic regu- mediating peripheral autonomic, endocrine, lation, and to the striatum to modulate the and skeletomotor responses. The amygdala has motor expressions of emotion and (2) via ven- reciprocal connections with autonomic nervous tral amygdalofugal projections to the nucleus system regulatory centers of the brainstem, of the solitary tract, pontine parabrachial including the periaqueductal gray, parabrachial nucleus, and reticular function involved in nucleus, vagal nuclei, and the reticular forma- autonomic regulation (Chaps. 15 and 20). tion. The conscious experience of emotion Thus, the amygdala, through its output, regu- includes fear, anger, fright, pleasure, or con- lates hypothalamic and brainstem effector sys- tentment. The emotional state is evident in a tems and their roles in the expression of variety of responses: increase in blood pres- emotional behaviors involving endocrine hor- sure, dilation of the pupil, inhibition of gas- mone release and the somatomotor and auto- trointestinal contractions, dryness of the nomic nervous systems. mouth, sweaty palms, stress effects from stress Chapter 22 Reticular Formation and Limbic System 397 hormones such as cortisol and somatic motor sadness. Fatigue, lethargy, listlessness, and responses such as nervous tics. unremitting emotional distress relate patho- physiologically to high rates of visceral and The Processing Triangle of Basolateral immune disorders. Pathology of the mesolim- Nucleus of the Amygdala, Nucleus bic network reflects deeply rooted suppression Accumbens, Dorsomedial Thalamic Nucleus of the basic drives to cope with ongoing envi- Within the limbic system, there are many ronmental demands. Severely depressed and complex circuits providing communication suicidal patiens are goal-driven to escape the between centers. Limbic structures, modulated agony of despondency. A behaviorally by dopamine, are referred to as mesolimbic sensitized hyperdriven defense arousal net- because the origin of dopamine is the mesodi- work causes overproduction of hypothalamic/ encephalic ventral tegmental area, located in pituitary/adrenal stress axis hormones such as contiguity with the substantia nigra. It is within cortotropic releasing hormone, resulting in limbic circuitry where emotional and internal increased sympathetic output to the heart, gut, states are coordinated and coupled—the driv- and immune organs. Damasio (2003) defined ing forces behind changes in motivational state. an emotion as a set of changes in body and The mesolimbic network is involved in recog- brain states that occur in many organs, and in nizing incentives that reinforce behavioral some brain circuits, under the control of a ded- response patterns. The following is a schematic icated brain system, which responds to the con- representation of interactions within a pre- tent of one’s thoughts relative to a particular sumed triangular circuit, which includes the entity or event. A story may literally be con- basolateral nucleus of amygdala, mesocortex, structed to explain “adaptive and mal-adaptive” nucleus accumbens, and the dorsomedial action tendencies, variably influencing our nucleus of the thalamus. The amygdala emits moods and affect. Learning from experiences fibers to the neocortex and dorsomedial thala- may permanently alter perceptions and propen- mus which project to the mesocortex forming a sities to think, proact, and act in specific ways. loop. The mesocortex, thalamus, and amygdala each send input to the nucleus accumbens. Stri- Amygdala: The Nodal Processing Center of atopallidal projections go to the dorsomedial the Subcortical Limbic Circuitry (see Fig. 22.2) thalamus/prefrontal cortical circuit and to The almond-shaped amygdala (amygdaloid VTA, the major source of dopamine innerva- complex) is located within the tip of the tempo- tion of the mesolimbic system. In healthy indi- ral lobe deep to the uncus and rostral to the hip- viduals, the mesolimbic striatal networks pocampus. The amygdala is the key structure reinforce drives behind motivation to behav- involved in analyzing and processing the emo- iorally adapt to demands imposed on the organ- tional and motivational significance of an array ism. of sensory stimuli and, in turn, coordinating Positron-emitting tomographic (PET) scan and activating several neuronal systems that imaging of a human with clinical unipolar mediate inborn and acquired responses with an depression revealed abnormal blood flow emotional nuance. The amygdala receives within the three sides of the triangle: the amyg- inputs from several sources: (1) Stimuli signal- dala, orbitofrontal and medial prefrontal cor- ing immediate dangers that are directly and tex, and the DM. The blood flow returned to rapidly conveyed as low-level processed infor- normal following the patient’s subjective mation from the thalamus to the amygdala to recovery from the depression (Brevets and evoke primitive rapid responses. As the center- Raichle, 1999). piece of the limbic defense system, the amyg- Clinically depressed patients formulate dala determines and evaluates whether danger, thoughts of gloom and doom. They ideate innate or learned, is present and then initiates suicide stemming from feelings of sustained bodily responses that were designed during 398 The Human Nervous System evolution to deal with the danger. (2) Signals somatic and visceral sensory experience with conveying highly processed information from emotional significance. The amygdala consists major sensory areas of the cortex are indirectly of three major groups: (1) a corticomedial conveyed to the amygdala to produce more nuclear group, (2) a basolateral nuclear group, measured and modulated emotional responses, and (3) a central nuclear group. The groups as demonstrated by acquired classical condi- have reciprocal connections with the neocor- tioning. (3) Stimuli signal information from the tex, thalamus, hippocampus, hypothalamus, hippocampus, basal ganglia and other subcorti- and brainstem. cal centers to the amygdala that contribute to The corticomedial nuclear group (CMG) the quality of the responses. The amygdala receives major input from the olfactory bulb exerts its motor influences via circuitry to and piriform cortex (Chap. 14) and, in addition, effector centers of the hypothalamus and brain- from other limbic centers via the stria termi- stem (see Fig. 22.5). In general, the amygdala nalis. The CMG projects via the stria terminalis modulates the somatic and visceral compo- to limbic centers such as the septal area and the nents of the peripheral nervous system and hypothalamus. The olfactory input does not fine-tunes the organism’s responses to ongoing involve the perception of smell, but, rather, the stimulation. subtle to intense emotional and motivational The amygdala is essential for sensing and associations evoked by odoriferous stimuli evaluating the affective significance of incom- (e.g., odor-related responses to the smells of ing stimuli and activating the appropriate food and perfume). The olfactory system is responses for its three principal functional more than just a perceiver of odors; it can be an roles: (1) behavior for preservation of self, (2) activator and a sensitizer involved with trigger- learning, and (3) emotion processing. Self- ing behavioral patterns. The perception and preservation behavior is a universal motive in discrimination of smell is associated with the which aversive stimuli are processed by the uncus (see Fig. 1.7). A lesion in the region of amygdala and projected to produce fight or the uncus could cause epileptic seizures known fright activity, including endocrine hormone as “uncinate fits” that are preceded by an olfac- release and somatomotor and autonomic emo- tory aura. The amygdala might have a role in tional responses. As for learning, the amygdala appetite and appetitive behavior through its is in a central position to associate and to coor- projection to the ventromedial nucleus of the dinate a variety of diverse sensory inputs that hypothalamus (Chap. 21). generate new behavioral and autonomic The enlarged basolateral nuclear group responses. This is demonstrated in learning (BLNG) in humans receives significant input classical conditioned emotional responses. pertaining to all of the sensory modalities Emotion processing is a subtle activity. PET from the thalamus and the cortex. Following scan studies show increased activation of the processing within the BLNG, information is amygdala while viewing a motion picture sent to the central nuclear group (CNG), showing an airplane crash. Intracranial record- which is the main source of output from the ing studies of monkeys indicate that amyg- amygdala. The BLNG also receives low-level daloid activity is enhanced with the increasing processed sensory information directly from emotional significance of stressful stimuli. all sensory nuclei of the thalamus (e.g., Amygdalectomized monkeys become socially medial geniculate nucleus and ventral poste- isolated from their troop and are transformed rior nucleus; Chap. 23). The BLNG receives into depressed loners. significant higher-level processed complex information of all modalities involved with The Amygdala Contains Three Major the visual, auditory, and tactile senses from Nuclear Groups. The role of the amygdala is the primary sensory and association cortical to mediate neural processes that encompass areas. The BLNG also is reciprocally con- Chapter 22 Reticular Formation and Limbic System 399 nected with the anterior cingulate gyrus and ulation of the amygdala in the living subject orbitofrontal cortex, important in integration can result in bradycardia, alteration in respira- of emotions such as fear and anxiety into the tion, pupillary dilatation, and urination, influ- various emotional expressions. Thus, the ences mediated via the hypothalamus. amygdala mediates processes that invest sensory experiences with emotional significance. The Mesocorticolimbic System, Mesolimbic In addition, the amygdala influences con- System, and Nucleus Accumbens scious emotion and feeling via its projections The mesocorticolimbic system (MCLS) and to the cingulate gyrus and prefrontal cortex. mesolimbic system (MLS) are dopaminergic The BLNG sends processed information to the systems that gate signals involved in the regu- CNG. The latter gives rise to fibers that proj- lation of motivation and biological drives. ect out of the amygdala via the stria terminalis Motivation is the spontaneous drive or incen- and ventral amygdalofugal pathways. tive that refers to the neuronal and physiologi- The CNG is reciprocally connected with the cal factors that initiate, sustain, and direct mesocortex, nucleus accumbens, hypothala- behavioral responses. The basic and homeosta- mus, and brainstem, including visceral sensory tic expressions of motivation are directed by relay nuclei such as the solitary, parabrachial, such biological drive states as hunger, thirst, and dorsolateral tegmental nuclei and the locus and temperature. Drive states are characterized ceruleus, in addition to being the major recipi- by tension and distortions relevant to a physio- ent of the processed output from the basolateral logic need, followed by the reward of relief nucleus. The CNG is thought to be involved in when the need is consummated. mechanisms associated with both the acquisi- The MCLS and MLS projections to the tion and display of fear and anxiety. It has a nucleus accumbens, striatum, and cerebral cor- significant role in arousal and the conscious tex are conceived as modulatory systems con- perception of emotion. The latter is related to cerned with the process of motivation. The its interconnections with the anterior cingulate MLS is associated with the biological drives gyrus and orbitofrontal cortex. Linkages of the expressed as responses for reward (as positive CNG with the basal nucleus of Meynert in the or incentive reinforcement) or to fear (as nega- basal forebrain and with the hippocampus tive or aversive reinforcement). The MCLS is might contribute to the suggested roles of these involved with normal cognitive functions (e.g., two centers in attention and memory. The cen- attention) and social behavioral responses. tral nucleus of the amygdala has two output Dopamine is the transmitter identified with channels: (1) the stria terminalis and (2) the the MCLS and MLS pathways and has long ventral amygdalofugal pathways (see Fig. been considered to be the critical factor in moti- 22.2). The projection to the mesocortex enables vation and reward. The release of dopamine is the central nucleus to exert an important role in (1) important in the initiation and maintenance arousal and the conscious perception of emo- of anticipatory behaviors in the presence of tion. The output via the stria terminalis to the incentive stimuli, (2) involved in notifying lim- paraventricular nucleus of the hypothalamus bic cortex that something novel or unexpected might be significant in mediating neuroen- has occurred, and (3) involved with the switch- docrine responses during fearful and stressful ing of attention and selection of action. The rel- stimulation. atively few dopaminergic neurons in the human Experimental evidence indicates that, col- brain are all located in the midbrain. They are lectively, all of the nuclear groups of the amyg- equally divided between (1) the substantia nigra daloid complex are critical processing centers that gives rise to the nigrostriatal pathway involved with arousal, conscious perception of (Chap. 24) and (2) the ventral tegmental area, emotion and emotional expressions, olfaction, which activates the MCLS and MLS projections and control of visceral functions. Electric stim- to the nucleus accumbens, amygdala, striatum, 400 The Human Nervous System hippocampus, anterior cingulate gyrus, and area. The nucleus accumbens receives impor- mesocortex. In addition to dopaminergic input tant input from the hippocampus, frontal lobe, from the ventral tegmental area (VTA), the VTA, amygdala and some thalamic nuclei. Fol- amygdala, nucleus acccumbens and other cen- lowing processing, the nucleus accumbens ters receive noradrenergic inputs via the medial projects output to the autonomic regulatory forebrain bundle from the locus ceruleus and centers, the globus pallidus, pedunculopontine serotonergic inputs from the dorsal raphe nuclei nucleus, and hypothalamic nuclei involved in of the brainstem (see Fig. 22.5). emotional expression. Functionally, these systems comprise the The nucleus accumbens is located at the neural network for interactions between the crossroads of emotions and movement, where cerebral cortex information processing and the the limbic emotions are translated into the effectors in the hypothalamus and brainstem movement actions influenced by the striatum. autonomic centers that modulate endocrine- The nucleus accumbens is the recipient of a release and motor-system-regulating behaviors. considerable amount of dopaminergic input The centers are organized as a unified system from the VTA along with inputs from limbic linked together by reciprocal projections. centers involved in emotion processing such as the amygdala. Acting at this regional interface Mesocorticolimbic System. The dopamin- where emotions are translated into actions, ergic mesocorticolimbic system originates in dopamine facilitates synaptic transmission in the VTA and projects to the cortex, particularly the output pathways from the nucleus accum- to prefrontal and the anterior cingulate gyrus. bens to the ventral pallidum (Chap. 24). This This system is involved in the positive rein- modulates the movement control regions of the forcement of such activities as feeding, drink- cortical motor cortex and of the brainstem auto- ing, sexual activity, and drug abuse (cocaine, nomic control centers. These connections are opiates, alcohol, and marijuana). The prefrontal thought to exert a role in planning and integrat- cortex is involved in the organization of activi- ing movement and emotional stimuli. In ties associated with rewards, motivation, plan- summary, the nucleus accumbens and its ning, attention, and social behaviors (Chap. connections with other nuclei regulate motiva- 20). In addition, rostral projections from the tion, biological drives, and reinforcement amygdala to the anterior cingulate gyrus and (strengthening) of goal-directed behaviors. the orbitofrontal cortex contribute to arousal and the conscious perception of emotion. Schizophrenia and the Limbic System Arousal is also enhanced by interconnections Schizophrenia is a mental disorder that fea- with the adrenergic locus ceruleus and the tures a disturbance of cognitive and sensory VTA, as well as by connections with the basal processes leading to hallucinatory experiences, nucleus of Meynert. In humans, dysregulation delusions, and disturbances of thought. In addi- of the MCLS is associated with the positive and tion, the illness shares many features such as negative symptoms of schizophrenia that bear paranoia, suspiciousness, and unrealistic think- some resemblance to the defects seen after sur- ing. This serious disorder is characterized by a gical disconnections of the prefrontal lobes. loss of contact with reality (psychosis). After the loss, subjects are poorly motivated Patients with lesions of the prefrontal cortex and exhibit a flattened affect. have behaviors indicative of a diminished ability to plan and to organize daily activities. In Mesolimbic System. The mesolimbic sys- contrast, their general intelligence, perception, tem projects from the VTA largely to the and long-term memory is essentially intact. nucleus accumbens, amygdala, and, in addi- The prefrontal lobe of humans and primates tion, the bed nucleus of the stria terminalis, lat- have a predominantly mesocorticolimbic dopa- eral hypothalamus, hippocampus, and septal minergic innervation. The depletion of dopa- Chapter 22 Reticular Formation and Limbic System 401 mine from this cortex has effects similar to that more than one pathway; for some the right of lesions. Disturbances of the dopaminergic hemisphere is thought to be more important. systems are presumed to contribute to the symptoms of schizophrenia. Stimulation of Structures Within the Current thinking concerning the etiology of Limbic System schizophrenia involves a genetic component Electric stimulation of the amygdala and and combinations of prenatal and postnatal nearby regions in the unanesthetized monkey insults to the developing brain. A series of produces a number of responses. Activities damages occurring in the developing dopa- associated with feeding and nutrition are minergic system is thought to contribute to the elicited, including sniffing, licking, biting, clinical symptoms of hallucination and delu- swallowing, and retching movements. Mon- sions by the release of excessive amounts of keys exhibit agonistic behavior patterns, which dopamine. comprise behaviors manifested by animals in One theory accounting for the symptoms of an attack-and-defense contest during fight or schizophrenia involves the interactions of dis- fright. The peaceful monkey becomes a furious turbed dopaminergic pathways of the mesocor- and aggressive animal that attacks and bullies; ticolimbic system with the mesolimbic systems once the stimulus is turned off, the peaceful (Weinberger et al., 1992). This concept sug- monkey reappears. Similar observations have gests (1) an increase in the activity of mesolim- been made in humans. In monkeys, increased bic projections involving certain dopamine secretion of digestive juices in the alimentary receptor subtypes can account for positive canal after repeated acute stimulations of the symptoms (e.g., hearing voices), (2) a decrease amygdala might be followed by the appearance in the activity of the mesocortical connections of gastric erosions similar to peptic ulcers. The through the dopamine receptor subtypes in the possibility of psychic factors in the production prefrontal cortex can account for the negative of peptic ulcers in humans is implied. Although symptoms (e.g., flattening of emotions), (3) an the role of the amygdala in aggressive behavior imbalance between mesolimbic and mesocorti- is striking, its role in the acquisition and colimbic dopamine transmission underlies the expression of fear or emotional memories is development of the schizophrenia through meaningful. development time, and (4) the activity of the Stimulation of the hippocampal formation mesocortical pathway to the prefrontal cortex produces respiratory and cardiovascular changes, normally inhibits the mesolimbic pathway by along with a generalized arousal response. In feedback inhibition and that the primary defect addition, the hippocampal formation acting as a in schizophrenia is a reduction in this activity, supplemental motor area activates somatic which leads to disinhibition and overactivity in movements such as facial grimaces, shoulder the mesolimbic pathway. shrugging, and hand movements, characteristic of normal behavioral gestures. Responses indicative of autonomic activity ROLE OF THE LIMBIC SYSTEM are evoked by stimulation of the cingulate gyrus and septal area. These responses, observed in The limbic system is involved with many of humans, include changes in the tone of the blood the expressions that make us human, namely vascular system, in respiratory rhythms, and in emotions, behavior, and states of feeling. How- the activity of the digestive system. ever, the limbic system is not independent: it Aggressiveness can be inhibited or interacts with sensory pathways and primary decreased in monkeys by stimulating the septal and association cortical areas regarded as play- area. Stimulation of a “boss” monkey with ing a primary role in cognitive processes. Dif- implanted electrodes reduces its aggressive ferent feelings and emotions appear to involve behavior. If stimulation is prolonged over a 402 The Human Nervous System period of days, the other monkeys of the colony lation of other sites causes the animal to avoid sense this change. They lose their fear of the further stimulation, an expression of negative “boss” and take new liberties, such as invading reinforcement. Such sites have been named its territory and securing a larger share of food. “punishing centers” or “aversion centers.” The The former situation returns after stimulations so-called pleasure centers are in the septal area, cease. Experimental studies of groups of mon- subcallosal area, cingulate cortex, hippocampal keys reveal that the male boss monkey experi- formation, amygdala, hypothalamus, midbrain ences more stress because of the compulsion to tegmentum, and anterior nuclei of the thala- maintain his dominant status than are the less mus. Punishing centers are in the midbrain dominant members of the group. tegmentum and in certain loci in the thalamus and hypothalamus. Reinforcement and Reward: “Pleasure Several human subjects whose septal areas Centers” and “Punishing Centers” were stimulated experienced feelings of pleas- Reinforcement refers to the ability of certain ure or a “brightening of their attitude.” They events (e.g., stimuli) to strengthen and modify giggled, talked more, and expressed themselves the preceding stimulus–response event. The neu- more freely when the current was on. In ral circuitry involved in intracranial self-stimula- humans, psychomotor seizures, which origi- tion (ICSS) with implanted electrodes underlies nate in or propagate through limbic pathway the natural biological reinforcements and connections, are characterized by an aura of rewards associated with eating, drinking, sex, fear and visceral sensations, loss of conscious- and drug addiction. The stimulation of large ness, and performance of automatic motor acts number of limbic sites can elicit, by direct elec- such a chewing and picking at clothes or nerv- trical stimulation, rewarding effects and ous pacing about. The subject might even drive responses. Among these are the medial forebrain a car or carry on a limited conversation, but bundle, a most responsive pathway, and the sep- will not remember any of these episodes. The tal area, VTA, nucleus accumbens, portions of complex behavioral patterns resulting from the amygdala, anterior cingulate gyrus, hip- limbic stimulation contrast with the relatively pocampus, and dorsal pons. The featured player simple contralateral muscle contractions or in the limbic circuitry of the MCLS and MLS is twitches elicited by stimulation of the precen- dopamine, which has been implicated in the tral motor cortex. motivational processes of reinforcement and reward. In addition, there is evidence supporting Klüver–Bucy Syndrome the concept that dopamine is significant not only Monkeys with the anterior tip of the tem- in mediating ongoing pleasurable aspects of a poral lobes ablated bilaterally exhibit a con- reward but also mediates the arousal effects that stellation of activities and expressions anticipates an impending reward. Dopamine associated with emotion known as the release increases in the nucleus accumbens in Klüver–Bucy syndrome. With bilateral loss of the presence of food, drugs of abuse, and sexual the amygdala, uncus, anterior temporal cortex behaviors. Lesions of the nucleus accumbens or and portions of the hippocampal formation, drugs that block dopamine receptors decrease or the animal is apparently released (“release block reinforced behavior activity. phenomenon”) from expressing fear. Wild and Stimulation by implanted electrodes of cer- aggressive monkeys become tame and docile. tain limbic regions drives an animal to seek The marked absence of emotional responses, further stimulation by tripping a lever over and such as anger, is accompanied by a loss of over again, an expression of positive reinforce- facial expressions and vocal protests usually ment. Such nodal sites have been named noted during aggressive activities. Monkeys “pleasure centers” or “reward centers.” Stimu- are normally afraid of snakes, but, with this Chapter 22 Reticular Formation and Limbic System 403 syndrome, they will now pick up, handle, and defective neural processing (encoding) at the examine a live snake with ease. The animal is time of learning rather than exclusively to a able to see and to locate objects visually, but flaw in memory retrieval. Patients with bilat- is apparently unable to fully recognize the eral lesions involving the uncus and amyg- objects by sight. This visual agnosia in dala, and sparing the hippocampus, do not humans with a comparable ablation is charac- have memory disturbances. Conversely, a terized by the loss of ability to recognize bilateral lesion restricted merely to a portion friends and familiar places (Chap. 25). Ani- of the hippocampus suffices to impair mem- mals in this state probably have auditory and ory without affecting other aspects of cogni- tactile agnosias. Such animals exhibit strong tive activity. oral tendencies, expressed as a compulsion to examine objects repeatedly with their lips and mouth. These overreacting animals are said to SUGGESTED READINGS be stimulus bound with an irresistible impulse to touch, smell, and taste the object many Bechara A, Damasio H, Damasio AR. Role of the times. An explanation for this behavior is that amygdala in decision-making. Ann. NY Acad. because of the agnosia, the animal keeps try- Sci. 2003;985:356–369. ing to obtain additional clues in a concerted Braak H, Braak E, Yilmazer D, Bohl J. Functional attempt to identify the familiar object that it anatomy of human hippocampal formation and related structures. J. Child Neurol. 1996;11: cannot recall. Evidence suggests that the stim- 265–275. ulus-bound behavior occurs with the removal Brady AM, O’Donnell P. Dopaminergic modula- of the amygdala only. Hypersexual behavior is tion of prefrontal cortical input to nucleus marked, with many manifestations of autosex- accumbens neurons in vivo. J. Neurosci. 2004; ual, homosexual, and heterosexual activities. 24:1040–1049. Brodal A. The Reticular Formation of the Brain Korsakoff’s Syndrome and Stem; Anatomical Aspects and Functional Corre- Ablations of the Hippocampus lations. Edinburgh: Oliver and Boyd; 1957. Patients with a form of amnesia, known as Charney DS, Nestler EJ, Bunney BS, eds. Neurobi- Korsakoff’s syndrome, have pathology in neu- ology of Mental Illness. New York: Oxford Uni- ral complexes associated with the limbic sys- versity Press; 2nd ed.; 2003. Damasio A. Feelings of emotion and the self. Ann. tem, namely the mammillary bodies of the NY Acad. Sci. 2003;1001:253–261. hypothalamus and the dorsomedial nucleus of Damasio A. Looking for Spinoza: Joy, Sorrow, and the thalamus. This affliction is the conse- the Feeling Brain. Orlando, FL: Harcourt; 2003. quence of chronic alcoholism and thiamine Darwin C, Ekman P, Prodger P. The Expression of deficiency. The patient displays profound the Emotions in Man and Animals. London: memory loss and becomes easily confused. HarperCollins; 3rd ed.; 1999. People who have undergone bilateral removal Davis M. The role of the amygdala in fear and anx- of the anterior temporal lobe, including the iety. Annu. Rev. Neurosci. 1992;15:353–375. amygdala and the hippocampus, also exhibit de Olmos JS, Heimer L. The concepts of the ventral the symptoms. The patient forgets to answer a striatopallidal system and extended amygdala. question just asked or might reply with an Ann. NY Acad. Sci. 1999;877:1–32. Devinsky O, Morrell MJ, Vogt BA. Contributions of irrelevant answer (called compensatory con- anterior cingulate cortex to behaviour. Brain fabulation). Patients with this psychosis learn 1995:118(Pt. 1):279–306. slowly, but once the subject matter is mas- Gloor P. The Temporal Lobe and Limbic System. tered, they appear to forget at a normal rate. New York: Oxford University Press; 1997. One concept suggests that the memory Grace AA. Gating of information flow within the deficits are the result, in some degree, of limbic system and the pathophysiology of schiz- 404 The Human Nervous System

ophrenia. Brain Res. Brain Res. Rev. 2000; Papez JW. A proposed mechanism of emotion. J. 31:330–341. Neuropsychiatry Clin. Neurosci. 1995;7:103–112 Insel TR, Young LJ. The neurobiology of attach- (reprint of 1937 article). ment. Nat. Rev. Neurosci. 2001;2:129–136. Rolls ET. The Brain and Emotion. New York: Kluver H, Bucy PC. Preliminary analysis of func- Oxford University Press; 1999. tions of the temporal lobes in monkeys. J. Neu- Schachter S. The Interaction of Cogniitive and ropsychiatry Clin. Neurosci. 1997;9:606–620 Physiological Determinants in the Emotional (reprint of 1939 article). State. In: Berkowitz L, ed. New York: Academic; LeDoux JE. Emotion circuits in the brain. Annu. 1994:49–80. Rev. Neurosci. 2000;23:155–184. Scoville WB, Milner B. Loss of Recent Memory LeDoux JE. Synaptic Self: How Our Brains Become After Bilateral Hippocampal Lesions. J. Neu- Who We Are. New York: Viking; 2002. rochem. 1957;20:11–21. MacLean PD. The limbic system (“visceral brain”) Sica AL, Ruggiero DA, Hundley BW, Gootman PM. and emotional behavior. AMA Arch. Neurol. Psy- The sympathetic nervous system of the develop- chiatry 1955;73:130–134. ing mammal. In: Scharf SM, Pinsky, Michael R, MacLean PD, Horwitz NH, Robinson F. Olfactory- Magder S, eds. Respiratory–Circulatory Interac- like responses in pyriform area to non-olfactory tions in Health and Disease. New York: Marcel. stimulation. Yale J. Biol. Med. 1952;25:159–172. Dekker; 2001; 145–181. McGaugh JL. Memory consolidation and the amyg- Swanson LW. The amygdala and its place in the dala: a systems perspective. Trends Neurosci. cerebral hemisphere. Ann. NY Acad. Sci. 2002;25:456. 2003;985:174–184. McGaugh JL. The amygdala modulates the consoli- Tzschentke TM, Schmidt WJ. Functional relationship dation of memories and emotionally arousing among medial prefrontal cortex, nucleus accum- experiences. Ann. Rev. Neurosci. 2004;27:1–28. bens, and ventral tegmental area in locomotion and McGinty JF. Advancing from the ventral striatum to reward. Crit. Rev. Neurobiol. 2000;14:131–142. the extended amygdala. Implications for neu- Vogt BA, Gabriel M, eds. Neurobiology of Cingu- ropsychiatry and drug abuse. Introduction. Ann. late Cortex and Limbic Thalamus: A Compre- NY Acad. Sci. 1999;877:xii-xxv. hensive Handbook. Boston: Birkhäuser; 1993. Moss H, Damasio AR. Emotion, cognition, and the Webster JI, Tonelli L, Sternberg EM. Neuroen- human brain. Ann. NY Acad. Sci. 2001;935: docrine regulation of immunity. Annu. Rev. 98–100. Immunol. 2002;20:125–163. Nauta W, Feirtag M. Fundamental Neuroanatomy. Weinberger DR, Berman KF, Suddath R, Torrey EF. New York: Freeman; 1986. Evidence of dysfunction of a prefrontal-limbic Olds J, Milner P. Positive reinforcement produced network in schizophrenia: a magnetic resonance by electrical stimulation of septal area and other imaging and regional cerebral blood flow study regions of rat brain. J. Comp. Physiol. Psychol. of discordant monozygotic twins. Am .J. Psychi- 1954;47:419–427. atry 1992;149:890–897. 23 Thalamus

Modulation of Thalamic Activity Morphologic and Functional Aspects Neurons and Nuclei of the Thalamus Nuclei of the Thalamus: Major Connections and Functions Limbic Thalamus Thalamic Neurotransmitters Extrathalamic Modulatory Pathways Projecting to the Cerebral Cortex Internal Capsule Functional Considerations Lesions of the Thalamus

The thalamus, also called the dorsal thalamus, is a large, paired, egg-shaped mass of MODULATION OF nuclei located in the diencephalon (see Figs. THALAMIC ACTIVITY 23.1 to 23.3). It is bounded rostrally by the interventricular foramen, dorsally by the trans- Drivers and Modulators verse cerebral fissure, ventrally by the hypo- The terms first, second, and third order gen- thalamic sulcus, and posteriorly by the erally are used to denote a sequence of fibers in posterior commissure, at the midline (see Figs. a sensory pathway. The cell body of a first-order 1.5 and 5.1). Lateral to the midline, it extends neuron usually is in the peripheral nervous sys- further back to overlap the midbrain (see Fig. tem dorsal root or cranial nerve ganglion. By 13.16). Thalamic nuclei process, integrate, and convention, second-order neurons usually proj- relay information for the sensory, motor, lim- ect to the thalamus and third-order project from bic, and motivational systems. Some play a the thalamus to the cortex. The term first order critical role in sensation and motor control. also is used in a different context; “first-order Thalamic nuclei also appear important for relay” refers to a thalamic nucleus that relays transferring information from one part of the or transmits “driver inputs” from sensory path- cerebral cortex to another. The thalamus is so ways, cerebellum, and basal ganglia to the strongly interrelated with the cerebral cortex cerebral cortex for the first time. They drive the that in some senses, it can be regarded as the cortex. These thalamic relay nuclei also are the deepest layer of the cortex (Sherman and sites of reciprocal input from layer 6 of the cor- Guillery, 2001). Activity of thalamic nuclei is tex. This reciprocal input, referred to as “mod- regulated by input from ascending and related ulatory input,” can change the pattern of pathways, the cerebral cortex, and the thalamic transmission, but not significantly alter its reticular nucleus. essential characteristics. Thalamic association

405 406 The Human Nervous System nuclei do not receive input from major ascend- cholinergic receptors, which are sensitive to ing tracts or extrathalamic sources like the acetylcholine. cerebellum or basal ganglia. Instead, these The role of the inhibitory GABAergic neu- nuclei receive major “driver input” from layer rons of the reticular nucleus is to modulate, 5 of the cortex and relay information back to integrate, and “gate” activities and to regulate other cortical areas. Referred to as “higher- transmission of the thalamic nuclei that project order relays,” they also get modulatory input to the cerebral cortex. This is accomplished from layer 6 of the cerebral cortex. Higher- through afferent connections that enable its order thalamic nuclei are considered important neurons to sample the activity of the axons for modulating signals transferred bidirection- passing from the thalamus to the cortex and ally between different parts of the cortex. In from the cortex to the thalamus, and via its addition, there is direct cortico-cortical com- efferents. These terminate directly on thalamic munication. It is thought that a thalamic neuron projection neurons as well as on GABAergic receives more modulatory input than driver interneurons, which constitute up to 25% of the input and that the former may activate slower thalamus. The interneurons, in turn, inhibit the acting metabrotropic receptors, whereas the thalamic projection neurons. Thus, the thala- driver input activates the more rapid ionotropic mic reticular nucleus directly inhibits the neu- receptors. There are conformational differences rons that project to the cortex while providing in the synapses of drivers and modulators some excitation by inhibiting the interneurons, related to their respective functions. allowing for very subtle modulatory effects. The thalamic reticular nucleus also exerts influ- Thalamic Reticular Nucleus ence on the basal ganglia (Chap. 24). This The reticular nucleus of the thalamus is a occurs through interaction with collaterals of thin, two- to three-neuron thick shield located both the thalamostriatal fibers from the within the fascicles of the external medullary lamina just medial to the posterior limb of the internal capsule (see Fig. 23.1). Its major function is to modulate the activity of the other thalamic nuclei. Although derived from the ventral thalamus, it is considered together with the dorsal thalamus because of intimate anatomic and functional relationships. The thalamic reticular nucleus is neither anatomically nor functionally related to the brainstem reticular formation. The input to the reticular nucleus is derived from (1) collaterals of thalamocortical axons projecting from the other nuclei of the thalamus to the cortex and (2) axon collaterals Figure 23.1: The left thalamus. The reticu- of corticothalamic fibers. The outputs of its lar nucleus (R) extends along the lateral aspect neurons are via (a) long axons that extend of the thalamus; only its rostral portion is medially into the thalamus and (b) short axons shown. A, anterior nuclear group; CM, centro- terminating within the nucleus itself. Neurons median nucleus; DM, dorsomedial nucleus; LD, lateral dorsal nucleus; LGB, lateral genic- in localized parts of the reticular nucleus proj- ulate body; MGB, medial geniculate body; P, ect back to the nearby thalamic nucleus from pulvinar; PTh, posterior thalamic nucleus; VA, which each receives input. The thalamic reticu- ventral anterior nucleus; VL, ventral lateral lar nucleus does not project directly to the cere- nucleus; VPL, ventral posterior lateral nucleus; bral cortex. Its neurons are GABAergic. The VPM, ventral posterior medial nucleus. Not nucleus has a high concentration of nicotinic shown: ventral posterior inferior nucleus. Chapter 23 Thalamus 407 intralaminar nuclei and reciprocal pallidothala- which all, except the thalamic reticular mic fibers from the globus pallidus (Chap. 24). nucleus, have reciprocal connections. (2) All influences received by the cerebral cortex are derived from thalamic nuclei, with two excep- MORPHOLOGIC AND tions: pathways of the olfactory system (Chap. FUNCTIONAL ASPECTS 14) and extrathalamic modulatory pathways. (3) Interconnections between thalamic nuclei, The thalamus is located between the third if any, are scarce. Exceptions are extensive ventricle medially and the posterior limb of the interconnections between various intralaminar internal capsule laterally (see Fig. 1.8). The nuclei and with the reticular nucleus. thalamic reticular nucleus (R) forms a thin On a functional basis, thalamic nuclei can be sheet of cells covering its entire lateral side classified as relay, association, or as diffuse- and rostral pole (see Fig. 23.1). The thalamus projecting nuclei (see Table 23.1). (1) Each consists of several groups of nuclei. Although relay nucleus is associated with a distinct sen- different sources present slight variations in this regard, the individual nuclei have consistent designations. The diagonally oriented Table. 23-1: internal medullary lamina, a complex of Organization of Thalamic Nuclei nuclei and fibers, separates the thalamus into a Relay Nuclei (First Order) medial group toward the midline and two tiers Anterior Nuclear Group (A) of nuclei laterally, which form the ventral and Anteroventral nucleus lateral groups. The ventral group includes the Anterodorsal nucleus ventral anterior (VA), ventral lateral (VL), Anteromedial nucleus ventral medial (VM), and ventral posterior Medial Nuclear Group nuclei (VP) (see Table 23.1). The medial Dorsomedial nucleus (DM) or mediodorsal geniculate body (MGB) and lateral geniculate Ventral Nuclear Group body (LGB) are caudal extensions of the ven- Ventral anterior nucleus (VA) Ventral lateral nucleus (VL) tral group; some authors place them separately. Ventral posterior nucleus (VP) The lateral group comprises the lateral dorsal Ventral posterior lateral (VPL) nucleus (LD), lateral posterior nucleus (LP), Ventral posterior medial (VPM) and the pulvinar (P). The medial group con- Ventral posterior inferior (VPI) sists of the dorsomedial nucleus (DM) (or Medial geniculate body (MGB) mediodorsal nucleus). The anterior nuclear Lateral geniculate body (LGB) group (A) is in the rostral thalamus between Posterior Nuclear Group the bifurcated fibers of the internal medullary Posterior thalamic nucleus (PTh) lamina. The intralaminar nuclear group is Ventral medial nucleus (VM) within the internal medullary lamina; one of Association Nuclei (Higher Order) these nuclei, the centromedian (CM) is illus- Lateral Nuclear Group trated in Fig. 23.1. The midline group, also Laterodorsal nucleus (LD known as the periventricular nuclei, are on the Lateral posterior nucleus (LP) medial surface of the thalamus and in the Pulvinar (P) massa intermedia (absent in 30% of human Diffuse Projecting Nuclei brains), which spans the third ventricle. Some Intralaminar Nuclear Group nuclei have subdivisions, which could have Rostral—central medial, central lateral distinct connections. Caudal—centromedian (CM), parafascicular (Pf) All thalamic nuclei receive afferent input Midline Nuclear Group from at least one extrathalamic source: (1) The Thalamic Reticular Nucleus* greatest input is from the cerebral cortex with *Does not project to the cerebral cortex. 408 The Human Nervous System sory modality or with an input derived from a cific thalamic nuclei are characterized as hav- subdivision of the motor or limbic system. ing reciprocal topographic connections with These nuclei match the definition of “drivers.” localized areas of the cerebral cortex. Depend- Projections from a relay nucleus terminate ing on the author, these are restricted to those topographically in a cytoarchitecturally or nuclei associated with sensory and motor sys- functionally defined region (field) of the cere- tems, or to all of the relay and association bral cortex. In turn, each thalamic nucleus nuclei. Nonspecific thalamic nuclei are charac- receives a massive projection from layer 6 of terized as receiving input from the brainstem the same cortical field to which it projects. reticular formation, other thalamic, and basal These recurrent projections are presumed to forebrain nuclei and sending their output to enable the cortex to modulate the input relevant widespread areas of the cerebral cortex as well to ongoing activity. The cortex receives as to the striatum. These comprise the midline “driver” signals from the relay nuclei and the and intralaminar thalamic nuclei. The thalamic latter receives “modulator” connections from reticular nucleus also is classified as nonspe- the cortex. (2) Similar to relay nuclei, associa- cific, although it emits no projections to the tion nuclei have reciprocal topographic connec- cortex. tions with the cortex, but the cortical input is To summarize, each cortical area receives from layer 5 as well as from layer 6. Because both specific and nonspecific thalamocortical this is the first time the association nuclei get projections. The restricted specific projection major input, it is regarded as “driver” input. arises from a thalamic relay or association This distinction is not total in all cases. (3) The nucleus and diffuse nonspecific projections diffuse-projecting nuclei have widespread con- from other thalamic (and even extrathalamic) nections with neurons in other nuclei and the sources including parts of specific relay nuclei, cortex. They exert influences that affect the diffuse projecting thalamic nuclei, and nuclei activity of the neurons in the thalamus and outside of the thalamus. cerebral cortex. They have a role in governing the level of arousal. (4) Fibers projecting (a) from the thalamus to the cortex and (b) from NUCLEI OF THE THALAMUS: the cortex to the thalamus pass through the MAJOR CONNECTIONS internal capsule and corona radiata (see Figs. AND FUNCTIONS 23.2 and 13.5). Major nuclei of the thalamus are illustrated in Figs. 23.3 and 23.4 and listed in Table 23.1. NEURONS AND NUCLEI OF Subdivisions are discussed only insofar as they THE THALAMUS are mentioned in other chapters.

The major thalamic nuclei contain two basic Anterior Nuclear Group types of neuron: projection neurons and The anterior group comprises the anteroven- interneurons. Projection neurons arising from tral, anterodorsal, and anteromedial nuclei, relay and association nuclei have a large axon which form the anterior thalamic tubercle. that goes to layer 4 of the cerebral cortex; each They are major components of the limbic thal- axon has collaterals that terminate in the retic- amus and are integrated in the Papez circuit and ular nucleus. The interneurons have axons that limbic system (Chap. 22). The anterior nuclei terminate locally within the same nucleus. contain the highest concentration of muscarinic They are concerned with information process- receptors of the thalamus. They have reciprocal ing within the nucleus. connections with the (1) hypothalamus, partic- Functionally, thalamic nuclei and their pro- ularly the mammillary body via the mamil- jections are called specific or nonspecific. Spe- lothalamic tract, (2) hippocampal formation in Chapter 23 Thalamus 409 the temporal lobe via the fornix, (3) cingulate connections with the intralaminar nuclei, gyrus of the limbic lobe, and (4) the prefrontal nuclei of the midline, and the lateral posterior cortex. The latter is the neocortical component thalamic nucleus. The magnocellular portion of the limbic system. has reciprocal connections with the amygdala, lateral hypothalamus, and the temporal and Medial Nuclear Group orbitofrontal neocortex. The parvocellular por- (Dorsomedial Nucleus) tion has massive topographically organized The massive dorsomedial nucleus (DM) reciprocal connections with the prefrontal cor- located between the internal medullary lamina tex (areas 8, 9, 10, 11, and 12—all rostral to and the third ventricle is divided into a magno- area 6; Chap. 25). A point-to-point relation cellular (large cell) portion and a parvocellular exists among areas in the amygdala, DM and (small cell) portion. Its principal inputs are frontal lobe. The DM nucleus has massive from the amygdala, olfactory system, and reciprocal connections with the frontal eye field hypothalamus and its primary output is to the (area 8). The ventral caudal part of the nucleus prefrontal lobe. In primate evolution, the rela- (DMvc), involved in mechanisms of pain, tive increase in size of this nucleus parallels receives inputs from the spinothalamic and that of the frontal lobe. The nucleus has rich anterior trigeminothalamic tracts and projects

Figure 23.2: Some component fiber tracts of the internal capsule (shown in horizontal plane) and their cortical connections. Reciprocal projections between a thalamic nucleus and a cortical area are indicated by arrows pointing in two directions. A, anterior limb; G, genu; P, posterior limb; R, retrolenticular portion of posterior limb of internal capsule. 410 The Human Nervous System

Figure 23.3: Major nuclei and some major cortical projections of the thalamus. Thalamic nuclei generally have reciprocal connections (corticothalamic projections indicated by arrows) with the cortex. The medial geniculate body projects to auditory areas 41 and 42, the lateral geniculate body projects to visual area 17, the VPM nucleus projects to the sensory postcentral gyrus (face region of areas 1, 2, and 3) and secondary sensory area, the VPL nucleus projects to the sensory postcentral gyrus (body region of areas 1, 2, and 3) and secondary sensory area, the VL nucleus projects to motor areas 4 and 6, the VA nucleus projects to motor areas 6 and 8 and orbitofrontal cortex, the anterior nucleus projects to the cingulate gyrus, the lateral posterior nucleus and pulvinar projects to the association cortex of the parietal, occipital, and temporal lobes, and the dorsomedial nucleus projects to prefrontal cortex.

to the part of the cingulate gyrus adjacent to the Ventral Nuclear Group rostrum of the corpus callosum (Chap. 9). The ventral nuclear group comprises the Thus, DM, although largely an association ventral anterior, ventral lateral and ventral pos- nucleus, has a subdivision that conforms to the terior nuclei, as well as the medial and lateral definition of a relay nucleus. geniculate bodies, which are a caudal extension. The DM nucleus acts to integrate certain influences from somatic and visceral sources Ventral Anterior Nucleus. The ventral ante- and, in conjunction with the prefrontal cortex, rior (VA) and ventral lateral thalamic nuclei are has roles in various expressions of affect, emo- motor relay nuclei associated with the somatic tion, and behavior. Psychosurgical studies, motor system. The VA nucleus is divided into such as following prefrontal lobotomy or two subdivisions: (1) parvocellular (principal) leukotomy (Chap. 25), indicate that the DM part (VApc) and (2) magnocellular part nucleus and the frontal lobe cortex are involved (VAmc). Each part receives input from differ- with affective behavior. ent sources without overlap. VApc receives Chapter 23 Thalamus 411 afferents from the medial segment of the primarily to VApc and area 8 projects to VAmc. globus pallidus and VAmc receives afferents Fibers from the primary motor cortex do not from the pars reticulata of the substantia nigra. terminate in the VA nucleus. Nonspecific input VA projects selectively to the supplementary from the intralaminar nuclei to the “nonspecific motor area (SMA, area 6) (see Fig. 25.3 and portion” of VA are processed and projected to Chap. 24). Premotor cortical area 6 projects the orbitofrontal cortex.

Figure 23.4: Lateral and medial views of the left cerebral hemisphere illustrating cortical projection areas of some thalamic nuclei. Much of the temporal lobe does not receive projections from the specific thalamic nuclei. Such an area is known as the athalamic cortex. 412 The Human Nervous System

Ventral Lateral Nucleus. The ventral lateral mination of the lateral spinothalamic tract (pain nucleus (VL) is an integral nucleus in the feed- and thermal sense from the body), medial lem- back circuits of (1) cerebral cortex to cerebellar niscus (“pressure” touch and vibratory sense cortex back to cerebral cortex (see Fig. 18.4) from the body), anterior spinothalamic tract and (2) cerebral cortex to basal ganglia to cere- (light touch from the body), and spinocervi- bral cortex (see Figs. 24.5 and 24.6 and Chaps. cothalamic tract (touch, proprioception, and 18 and 24). The VL nucleus receives direct vibratory sense from the body). In addition, the input from the contralateral cerebellar hemi- VPI is a nucleus of the vestibular pathway sphere via the dentatothalamic tract (specifi- (Chap. 16). The VPM is the nucleus of termi- cally from globose, emboliform, and dentate nation of the trigeminothalamic tracts (general nuclei) (Chap. 18). It also receives input from sensory modalities of the head) and of the gus- the medial segment of the ipsilateral globus tatory pathways from the nucleus solitarius. A pallidus. There is apparently no overlap of the somatotopic distribution in the VPL is repre- termination of the input from the cerebellum sented as follows: The pathways from the lower and globus pallidus (Chap. 24). The portion of extremity terminate posterolaterally and from VL receiving input from the cerebellum proj- the upper extremity anteromedially, with fibers ects to the premotor cortex (part of area 6) and from the body in between. The different modal- to the primary motor cortex (area 4; Chap. 25). ities also are topographically localized within The connections with area 4 are somatotopi- the VPM: (1) taste is projected to the medial cally and reciprocally organized with (1) the portion of the nucleus, (2) tactile sense is pro- medial region of VL interconnected with the jected to the lateral portion, and (3) thermal cortical face area, (2) the intermediate region sense is projected to the intermediate portion. interconnected with the upper limb and body The topographic and sensory modality organi- area, and (3) the lateral region interconnected zation is preserved in the thalamocortical pro- with the pelvis and lower limb area. The por- jections. The projections terminate in the tion of VL receiving input from the globus pal- primary somatic sensory cortex (SI, areas 3, 1, lidus projects to the supplementary motor area and 2) and the secondary somatic sensory cor- (portion of area 6) (Chap. 25). Through its pro- tex (SII) (Chap. 25). The entire body is repre- jections to the cortex, VL exerts its role as a crit- sented in the VPI. ical subcortical gateway to the cerebral cortex acting as a prime mover in the motor pathways Medial Geniculate Body. The medial genic- (Chap. 24). Lesions in the VL might ameliorate ulate body (MGB) is a nucleus in the auditory the contralateral tremors and rigidity in patients pathways that receives its main afferent input with Parkinson’s disease (Chap. 24). from the inferior colliculus via the brachium of the inferior colliculus. These ascending fibers Ventral Posterior Nucleus. The ventral pos- terminate in the appropriate isofrequency lami- terior nucleus (VP) of the ventrobasal complex nae, resulting in a highly ordered bilateral tono- is a somatosensory relay nucleus divided into topic projection of the cochlea within the MGB. ventral posterolateral (VPL), ventral postero- This tonotopic organization is projected via medial (VPM), and ventral posteroinferior geniculocortical fibers to the tonotopically (VPI) nuclei. The VP is highly organized with organized primary auditory cortex, where high a precise topographical representation and sep- pitch tones are localized medially and low tones aration of the sensory modalities of the con- laterally (area 41 and 42; Chap. 16). tralateral half of the head and body (Chaps. 9 and 10). Lateral Geniculate Body. The lateral genic- The ventral posterior nucleus is the nucleus ulate body (LGB) is a six-layered nucleus that of termination of somatosensory and gustatory (1) receives input from the retina of both eyes pathways. The VPL and VPI are nuclei of ter- via the optic tract and (2) has reciprocal con- Chapter 23 Thalamus 413 nections via the geniculocalcarine tract (optic nuclei (see Fig. 23.1). These are classified as radiations) with the primary visual cortex (VI, association nuclei. area 17). The LGB has two critical functional roles: (1) the precise transmission of visual Lateral Dorsal Nucleus. The lateral dorsal input from the retina to the primary visual cor- nucleus (LD) is a part of the limbic thalamus; it tex and (2) the modulation and regulation of the is actually a caudal extension of the anterior flow of visual information to the primary visual nuclear group. It has reciprocal connections cortex. The latter expressions involve the with the posterior cingulate gyrus and parahip- extensive corticogeniculate projections from pocampal gyrus. It also receives input from the area 17 to the LGB. These are integrated into septal area. The lateral dorsal nucleus might be feed-forward and feedback inhibitory circuits involved in emotional expression exhibited by (Chap. 3), which process “visual” information the limbic system. and regulate its flow. These connections are thought to be involved in arousal, in regulating Lateral Posterior Nucleus and the Pulvinar. the level of visual attention, and in modulating The lateral posterior nucleus (LP) is considered the flow of information to area 17. to be a rostral extension of the massive pulvinar (P) (see Fig. 23.1). The LP and the pulvinar Posterior Nuclear Group receive significant afferent input from nuclei The posterior nuclear group consists of sev- associated with the visual system such as the eral nuclei caudal to the ventrobasal complex superior colliculus and the pretectal nuclei. that include the posterior thalamic nucleus They are presumed to have a role in the pro- (PTh) (see Fig. 23.1), the ventral medial nucleus cessing of directed visual attention. Both nuclei (VM), and other nuclei not relevant here. The have reciprocal connections with areas 5 and 7 input to PTh is derived from diverse sensory of the posterior parietal cortex and the pulvinar sources including the spinothalamic tracts, with widespread portions of the temporal lobe trigeminothalamic tract, medial lemniscus, infe- as well. The projection field of the pulvinar rior colliculus and ascending reticular pathways. sometimes is referred to as the parieto– Its neurons are multimodal rather than modality temporo–occipital association cortex. specific, in that they respond to combinations of pain, tactile (mechanoreceptive), vestibular, and Intralaminar Nuclear Group auditory stimuli. Physiologically, the neurons of The intralaminar nuclei are structurally and this nucleus respond to high-threshold somatic functionally rostral extensions of the brainstem sensory and auditory stimuli and have properties reticular formation into the diencephalon. They consistent with an involvement in central nerv- are extensively interconnected with each other. ous system pain mechanisms. The PTh nucleus Frequently, they are divided into rostral and projects to the secondary somatic sensory area caudal nuclei, as shown in Table 23.1. of the cerebral cortex (Chap. 25). It is thought to Afferent input is derived from the brainstem have a role in the perception of pain and noxious reticular formation, substantia nigra, superior stimuli. The posterior part of VM, not illustrated, colliculus, pretectum, and spinothalamic tract receives profuse terminals from the spinothala- (pain). The deep cerebellar nuclei project to the mic tract and projects to the anterior end of intralaminar nuclei, with the exception of the insula cortex. It also is important in mechanisms parafascicular nucleus (Pf). The central medial of pain perception. and Pf nuclei receive afferents from the globus pallidus of the basal ganglia. The Pf and central Lateral Nuclear Group lateral nuclei receive input from the spinothal- The lateral nuclear group, located dorsal to amic tract. the ventral group of nuclei, is comprised of the The intralaminar nuclei have rich projec- lateral dorsal, lateral posterior, and pulvinar tions to both the putamen and caudate nucleus 414 The Human Nervous System of the striatum and to widespread areas of the neurons project ascending adrenergic and sero- cerebral cortex, where the fibers are distributed tonergic fibers to the midline nuclei. A role in to all, but particularly, the superficial layers. All visceral activities has been presumed. intralaminar nuclei have reciprocal interconnections with the cerebral cortex. (1) A triangular relation exists among defined regions of LIMBIC THALAMUS the cerebral cortex, intralaminar nuclei, and striatal nuclei. From a common cortical area, The limbic thalamus is generally defined as corticothalamic fibers project to defined regions the nuclei of the thalamus that have connec- of the intralaminar nuclei and corticostriatal tions with limbic lobe cortex and, in particular, fibers project to the striatum. To complete the with the cingulate gyrus (Chap. 22). These triangle, intralaminar–striatal projections inter- include the anterior nuclear group of the thala- connect the same regions of the intralaminar mus and portions of some other thalamic nuclei and the striatum. (2) Each of the nuclei. Area 24 of the cingulate gyrus is a intralaminar nuclei has diffuse and reciprocal major projection site of the anterior nuclear thalamocortical projections to wide areas of the group (see Fig. 25. 6). Areas 25, 29, and 32 also cerebral cortex. The central medial nucleus receive input from this group. Other thalamic projects to rostral portions of the frontal lobe, nuclei with some connections to the cingulate including the limbic areas and cingulate gyrus. gyrus include the dorsomedial, lateral dorsal, The Pf nucleus projects to the lateral and ros- lateral posterior, pulvinar, and the intralaminar tral areas of the frontal lobe. The centromedian nuclei. The limbic thalamus is conceived as nucleus has copious projections to the premo- having a role in visceral emotions, the visceral tor and motor areas, and the central lateral aspects of behavior and even in learning and nucleus has projections to the somatic sensory memory. areas, related parietal areas, and visual association areas of the occipital cortex. The intralaminar nuclei have several roles. THALAMIC NEUROTRANSMITTERS Their widespread cortical projections are involved with the maintenance of arousal, The inhibitory transmitter GABA and the which is integral to the general state of aware- excitatory transmitters glutamate and possibly ness. Their connections to the somatic sensory aspartate are associated with the thalamus areas of the cortex indicate a role in sensorimo- (Chap. 15). GABAergic neurons include virtu- tor integration. The direct spinothalamic, ally all cells of the thalamic reticular nucleus trigeminothalamic and multisynaptic thalamic and interneurons within the thalamic nuclei. In pain pathways do have some terminal connec- addition, GABA is released by axons of neu- tions in these nuclei and presumably have a rons of the globus pallidus and substantia nigra role in arousal and/or in pain perception. that terminate in the ventral anterior and ventral lateral nuclei. The inhibitory interneurons in Midline (Periventricular) Nuclear Group the sensory relay nuclei presumably contribute The midline nuclei are a thin band of nuclei to the enhancement of stimulus contrasts by adjacent to the third ventricle. Dorsal midline lateral inhibition (Chap. 3) and, thus, the selec- nuclei have connections with both the striatum tion of certain types of stimulus and the sup- and the limbic cortex (e.g., prefrontal lobe). pression of others (Chaps. 9 and 10). The Thus, the midline nuclei and intralaminar GABAergic neurons of the reticular nucleus, as nuclei are similar in that they have topographic noted earlier, “gate” the thalamic activity pro- projections to both the cerebral cortex and jected to the cerebral cortex. striatum. Ventral nuclei have connections with Glutamate is the major neurotransmitter the hippocampal region. Brainstem reticular released by thalamic neurons projecting to the Chapter 23 Thalamus 415 cortex as well as by the massive corticothala- neurons and the resultant behavioral state mic projections. (sleep–wake) of the individual.

EXTRATHALAMIC MODULATORY INTERNAL CAPSULE PATHWAYS PROJECTING TO THE CEREBRAL CORTEX The internal capsule is one portion of a continuous massive sheet of fibers projecting to The extrathalamic modulatory pathways and projecting from the cerebral cortex. The comprise systems that arise from cholinergic sheet extends as the crus cerebri of the mid- and monoaminergic nuclei located primarily in brain, the internal capsule of the diencephalon, the brainstem and the basal forebrain. They and the corona radiata of the cerebral white project, without any relays in the thalamus, matter to the cerebral cortex (Chap. 1; Figs. directly to the cerebral cortex, where they exert 1.8, 13.4, 13.5, and 23.3). The fibers of the modulatory control over the excitability level of internal capsule convey almost all of the neural the cortical neurons. They have roles in relation input to and output from the neocortex (Chap. to wakefulness, arousal, and the phases of sleep. 25); they are the direct lines of communication The serotonergic pathway originates in the with the subcortical nuclei, especially the raphe nuclei located in the midbrain and rostral thalamus, brainstem and spinal cord. The inter- pons (Chap. 15). They could be involved with nal capsule is subdivided into an anterior limb sleep and pain control. The noradrenergic located between the head of the caudate pathway originates in the locus ceruleus. These nucleus and the lenticular nucleus, the genu neurons are actively releasing norepinephrine located at the bend (genu) between the anterior during arousal and situations of attention and and posterior limbs, and a posterior limb extreme vigilance. The dopaminergic pathway located between the thalamus and the lenticular arises in neurons of the ventral tegmental area nucleus and extending behind it (retrolenticular and terminates in all areas of the cortex. The portion of the posterior limb) (see Figs. 1.8 densest projections are to the motor cortex. The and 23.2). cholinergic and GABAergic pathways originate The fibers passing through the anterior respectively from the basal nucleus of Meynert (caudatolenticular) limb of the internal capsule and associated nuclei in the basal forebrain. include (1) frontopontine fibers to nuclei in the The cholinergic neurons of the basal nucleus pons, (2) corticostriate fibers to the striatum, project to the cerebral cortex and the GABAer- and the following pathways composed of recip- gic nucleus from the basal forebrain to the hip- rocal connections of fibers between (3) the pre- pocampus. Changes in these acetylcholine frontal cortex and the dorsomedial thalamic terminals of the cortex might contribute in nucleus, (4) the cingulate gyrus and the anterior some degree to the dementia of Alzheimer’s thalamic nucleus, and (5) the septal area and disease. They have a role in cortical arousal. the hypothalamus (medial forebrain bundle). The histaminergic pathway (histamine) arises The genu of the internal capsule contains from neurons in the lateral hypothalamus and corticobulbar and corticoreticular fibers. terminates in all areas of the cortex. The posterior (thalamolenticular) limb is Nuclei of the brainstem reticular formation composed of both motor pathways and sensory and basal forebrain have axons that terminate pathways. Through the rostral half of this limb in the intralaminar thalamic nuclei; the latter, in pass the corticospinal, corticorubral, and corti- turn, have diffuse projections terminating in all coreticular tracts. Through the caudal half of areas of the cortex. Thus, the monoaminergic this limb pass thalamocortical projections from and cholinergic pathways exert continuous the ventral anterior, ventral lateral, and ventral modulatory influences on thalamic and cortical posterior thalamic nuclei. 416 The Human Nervous System

The retrolenticular (postlenticular) portion condition in which there is wakefulness of the posterior limb is composed of optic (arousal) but neither cognition nor awareness. (geniculocalcarine) radiation, auditory (genicu- In her case, the most severe damage was not in lotemporal) radiation, and corticopontine fibers the cerebral cortex, but in the thalamus. Her from the temporal, parietal, and occipital brainstem reticular formation was relatively cortices. intact. “Affect” in sensory appreciation is apparently mediated through the thalamic reticular FUNCTIONAL CONSIDERATIONS system, dorsomedial nucleus, and anterior nuclear group. The affect of an individual An axiom of thalamic organization is that relates to his emotional tone and, somewhat, to the nuclei of the dorsal thalamus provide the the phase of the sleep–wake cycle. Well-being, last subcortical processing stations of the malaise and a state of contentment are expres- ascending pathways before the resultant infor- sions of affect. The degree of agreeableness or mation is projected to the neocortex. This disagreeableness of any stimulus depends on might be the initial critical stage in generating the state of an individual. The same objective each sensory modality into a sensation. degree of pain, temperature, or touch can evoke The thalamus is a major neural processor a remarkable variety of subjective degrees of and integrator involved in essentially all activ- reactivities. This variety is an expression of ities of the forebrain. All general and special affective sensory mechanisms. sensory systems, except for the olfactory sys- Through the interaction of the nonspecific tem, project their major output to the thalamus nuclei and specific nuclei, the thalamus exerts a before the processed information is relayed to regulatory drive upon the cerebral cortex. the cerebral cortex. The intralaminar nuclei, These nuclei act as modulators and modifiers nuclei of the midline, and part of the ventral of thalamic processing. In addition, the syn- anterior nucleus are essential components of chronization and desynchronization of thala- the reticular system acting as linkages in the mic activity are considered to be dependent, in circuitry between the brainstem reticular path- part, on recurrent collateral branches of thala- ways and the higher centers of the limbic lobe mic neurons feeding back on interneurons; in and the neocortex. Thalamic output is the turn, these connections modulate the neurons chief source of input to the cerebral cortex; projecting to the cortex. The thalamus is essen- these connections are, to a large degree, inte- tial to such expressions of synchrony (or desyn- grated into circuits comprising (1) reciprocal chrony) as (1) the rhythmic brain wave activity connections between thalamic nuclei and the observed in an electroencephalogram and (2) cerebral cortex and (2) circuits among the the phasic and tonic movements mediated by cortex, basal ganglia, thalamus, and cortex the motor pathways. The thalamus is consid- (Chap. 24). The thalamus has a critical role in ered to be a “prime mover” of motor pathways. somatic motor activity through its strategi- The modulatory effects are exerted in concert cally located nuclei (VA and VL), which with the VL and VA nuclei through (1) the cere- receive inputs from the cerebellum and basal bellothalamocortical pathway (Chap. 18) and ganglia and project influences to the motor (2) the globus pallidus–thalamocortical path- cortex (Chaps. 18 and 24). way (Chap. 24). Through integrative, modula- The thalamus is conceived as being essential tory, and synchronizing activities, the thalamus for cognition and awareness and can also be exerts a major effect upon the motor expres- critical for arousal. The neuropathological find- sions via the cerebral cortex and its projection ings in the brain of Karen Ann Quinlan support pathways, including the corticospinal, corti- this view; she was in a persistent vegetative corubrospinal, corticostriate, and corticoreticu- state for 10 years (9 without a respirator)—a lospinal tracts, among others. Chapter 23 Thalamus 417

relayed rhythmically through the dentatothala- LESIONS OF THE THALAMUS mic pathway. Without these influences, the abnormal movements are expressed. The ame- Lesions of the thalamus (as a consequence lioration of cerebellar dyskinesias in man can of vascular impairment) can produce signs occur following a surgically placed lesion in known as the thalamic syndrome. All general the contralateral VL nucleus. somatic modalities can be diminished on the contralateral half of the head and body without complete anesthesia (lesion of ventral posterior nucleus), all general modalities from the face SUGGESTED READINGS can be normal (the VPM not damaged), tactile sense from the face can be intact (bilateral pro- Jones EG. Thalamic circuitry and thalamocortical jections from principal trigeminal nucleus), synchrony. Phil. Trans. R. Soc. Lond. B. Biol. Sci. and some pain and temperature sense on the 2002;357:1659–1673. contralateral side can be retained (these modal- Jones EG. A pain in the thalamus. J. Pain. ities can be bilaterally represented in the thala- 2002;3:102–104. mus or some qualities of these modalities can Kinney HC, Korein J, Panigrahy A, Dikkes P, Goode be felt in the midbrain). In this syndrome, the R. Neuropathological findings in the brain of Karen Ann Quinlan. The role of the thalamus in threshold for pain, temperature, and tactile sen- the persistent vegetative state. N. Engl J. Med. sations is usually raised on the side contralat- 1994;330:1469–1475. eral to the lesion. In addition to the diminution Morel A, Magnin M, Jeanmonod D. Multiarchitec- of sensations, mild stimuli might evoke dis- tonic and stereotactic atlas of the human thala- agreeable sensations (dysesthesias). The feel- mus. J Comp Neurol. 1997;387:588–630. ings elicited from a pinprick might be an Price DD, Verne GN. Does the spinothalamic tract intolerable burning and agonizing pain. Heat, to ventroposterior lateral thalamus and somato- cold, and pressure from one’s clothes can be sensory cortex have roles in both pain sensation exceedingly uncomfortable. Intractable pain, and pain-related emotions? J. Pain. 2002;3: which does not respond to analgesics, can be a 105–108. consequence. In response to environmental Sherman SM, Guillery RW. On the actions that one nerve cell can have on another: distinguishing stimulation, affect qualities are expressions of “drivers” from “modulators.” Proc. Natl. Acad. modified and exaggerated stimuli during emo- Sci. USA 1998;95:7121–7126. tional stress. For example, the application of a Sherman SM, Guillery RW. Exploring the Thala- warm object to the hand can evoke a range of mus. San Diego, CA: Academic; 2001. feelings from pain to pleasure. Sherman SM, Guillery RW. The role of the thalamus These highly overactive sensory responses in the flow of information to the cortex. Phil. are probably the result of alterations in fre- Trans. R. Soc. Lond. B. Biol. Sci. 2002;357: quencies and patterns of input to the thalamus, 1695–1708. irritation of injured neurons, and changes in the Treede RD. Spinothalamic and thalamocortical quality of the output to the cerebral cortex. In nociceptive pathways. J. Pain 2002;3:109–112. addition, the release from some cortical influ- Walker AE. The Primate Thalamus. Chicago, IL: The University of Chicago Press; 1938. ences upon the thalamus might be contributory Willis WD Jr, Zhang X, Honda CN, Giesler GJ Jr. A (release phenomena). critical review of the role of the proposed VMpo A neocerebellar lesion results in cerebellar nucleus in pain. J Pain. 2002;3:79–94. dyskinesia. This is an expression of a release Zhang L, Jones EG. Corticothalamic inhibition in phenomenon, in which the VL nucleus is the thalamic reticular nucleus. J. Neurophysiol. released from the normal cerebellar influences 2004;91:759–766. 24 Basal Ganglia and Extrapyramidal System

Organization of the Basal Ganglia General Circuitry Associated With the Basal Ganglia Parallel Organization of Functionally Segregated Circuits Linking Basal Ganglia, Thalamus, and Cortex Side Circuits Summary Functional Considerations

The cerebrum exerts control of voluntary tems is anatomically, functionally, and inextri- somatic motor activity through several cably interconnected with the basal ganglia. descending pathways. The direct pathway is via the pyramidal system, which includes the corticospinal (pyramidal) tract together with ORGANIZATION OF THE fibers that diverge from it to innervate cranial BASAL GANGLIA nerve motoneurons, the corticobulbar tract (see Fig. 24.1). The cortical neurons that form The basal ganglia are nuclear complexes in the tract are upper motoneurons. There are the cerebrum and midbrain that play a critical two other major descending pathways that role in the integration of motor activity. Along arise from the cortex: the corticorubral/ with the cerebellum, the basal ganglia act at the rubrospinal tract and the corticoreticular/ interface between the sensory and motor sys- reticulospinal tract, but these are less direct. tems. The basal ganglia integrate and process They involve a synapse in the red nucleus and afferent input from the cerebral cortex and send in the reticular formation of the lower brain- the modified signals to the thalamus, which, stem, respectively. Before evolution of the after further alteration, relays the output back cerebral cortex in mammals, voluntary to specific areas of the cerebral cortex. somatic motor activity was mainly mediated Although this chapter emphasizes the role of by upper motoneurons in the red nucleus and the basal ganglia in somatic motor function, the brainstem reticular formation. These this group of nuclei also is of great importance nuclei together with the corpus striatum, the in mechanisms involving emotional and cogni- major component of the basal ganglia and the tive behaviors. The following information is most important forebrain center for motor meant to provide a basic understanding of how control in premammalian vertebrates, were the basal ganglia participates in a variety of designated as components of the extra- activities and is a simplification of their func- pyramidal system whose descending fibers tional organization and complex circuitry. pass through the tegmentum rather than the Clinically, resting movement disorders medullary pyramid. However a dichotomy (dyskinesias), which occur when a patient is between a pyramidal and an extrapyramidal not purposefully moving, are generally system does not really exist. The cortex that ascribed to malfunctioning of the basal ganglia. gives rise to all of these descending tract sys- Parkinson’s disease and Huntington’s chorea

419 420 The Human Nervous System are two well-known expressions of basal gan- The basal ganglia are considered to include glia dysfunction. In order to understand the the corpus striatum, subthalamic nucleus, sub- mechanisms involved, it is important to know stantia nigra, and the ventral tegmental area the structures that comprise the basal ganglia, (see Table 24.1). This is based on the interrela- fundamentals of the circuitry, and whether the tionships of these structures and their roles in various links excite or inhibit their targets or somatic motor function. The pedunculopontine do both. nucleus probably should be added to this list

Figure 24.1: The core circuit linking the cerebral cortex, basal ganglia, thalamus, and motor cortex to the descending pathways. The sequence comprises the (1) cerebral cortex to (2) striatum (putamen and caudate nucleus) to (3) globus pallidus to (4) thalamus (ventral anterior and ventral lateral nuclei) to (5) supplementary, premotor, and motor cortices, where (6) the corticospinal, corticorubrospinal, corticoreticulospinal, and corticobulbar pathways originate. Chapter 24 Basal Ganglia and Extrapyramidal System 421

Table 24-1: Basal Ganglia and Related Centers

Caudate nucleus Dorsal striatum Striatum (neostriatum) Putamen Nucleus accumbens Ventral striatum

Corpus striatum Medial (internal) segment Globus pallidus Dorsal pallidum Lateral (external) segment (pallidum, paleostriatum) Ventral pallidum

Pars compacta Substantia nigra Pars reticularis

Subthalamic nucleus Ventral tegmental area (VTA) because of its extensive interrelations with ment of the globus pallidus and substantia nuclei listed in the table. nigra, pars reticularis (SNr), form two paired The corpus striatum is divided into the stria- units; each pair has similar inputs and outputs tum (neostriatum) and the globus pallidus (pal- (see Fig. 24.2). The ventral tegmental area lidum or paleostriatum). The striatum is (VTA) is a cluster of neurons in the midbrain divided into the putamen (about 55% by vol- tegmentum located just medial to the substantia ume), caudate nucleus (about 35% by volume), nigra, pars compacta (SNc). The substantia which together form the dorsal striatum (see nigra, pars compacta, and VTA both are Fig. 1.8), and the nucleus accumbens (ventral dopaminergic. striatum). The globus pallidus (GP) is divided into medial (GPm) and lateral (GPl) segments, Ventral Striatum and Ventral Pallidum and ventral pallidum. The substantia nigra con- (see Table 24.1) sists of two parts, called the pars reticularis and The ventral striatum, which we equate to the pars compacta based upon differences in neu- nucleus accumbens although it does encompass ronal densities. The two parts have different some of the adjacent area, is located ventral to connectivity and neurotransmitters and, hence, the anterior limb of the internal capsule at the are functionally distinct. During development, junction of the caudate nucleus and putamen. Its the fibers of the internal capsule pass through the cytoarchitecture and histochemistry are similar territory of the basal ganglia and separate (1) the to that of the dorsal striatum, which commonly putamen from the caudate nucleus and (2) the is referred to simply as striatum. The ventral subthalamic nucleus and the substantia nigra striatum projects to the ventral pallidum. It from the globus pallidus. The putamen and the serves as a link with the limbic system through globus pallidus are collectively called the afferent input from the amygdala and hippocam- lenticular (lentiform) nucleus. The (1) caudate pal formation and output via the ventral pal- nucleus and putamen and the (2) medial seg- lidum to the dorsomedial thalamic nucleus. 422 The Human Nervous System

Figure 24.2: Structures involved in the circuitry of the basal ganglia. (B) the location of the basal ganglia in relation to the lateral ventricle; (A) some efferent projections of the basal ganglia and cerebellum. The pallidofugal fibers from the globus pallidus form three bundles: ansa lenticularis, lenticular fasciculus, and subthalamic fasciculus. The former two bundles and the projections from the dentate nucleus of the cerebellum join to form the thalamic fasciculus that terminates in the thalamus. L and M refer to the medial and lateral segments of the globus pallidus, respectively. VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nuclei; CM, centrum medianum; ZI, zona incerta.

The substantia innominata (see Fig. 22.2) is be a ventral extension of the globus pallidus. an area located ventral to and extending ros- The ventral pallidum has projections that trally from the basal ganglia. It is associated eventually affect descending motor systems. with the substantia innominata is the basal Through these connections, the ventral pal- nucleus of Meynert (Chap. 25) and the ventral lidum together with the ventral striatum are pallidum composed of neurons considered to linked to the limbic system and exert a role in Chapter 24 Basal Ganglia and Extrapyramidal System 423 planning and integrating movements that are ganglia → thalamocortical loops that convey related to motivational and emotional stimuli. functionally distinct information from different cortical regions. Each circuit combines a “closed loop” and an “open loop.” The “closed GENERAL CIRCUITRY ASSOCIATED loop” comprises the input from a specific corti- WITH THE BASAL GANGLIA cal area (e.g., supplementary motor cortex) back to the same region (e.g., supplementary The cerebral cortex, basal ganglia, and thala- motor cortex). The “open loop” component mus are interconnected via several complex comprises input from other cortical areas (e.g., neural circuits. Until recently, it was thought premotor area, primary motor cortex, and pri- that the basal ganglia primarily integrated and mary somatosensory cortex) and terminates in processed diverse inputs from wide areas of the the cortical area of origin of the closed-loop neocortex and relayed signals to “motor nuclei” supplementary motor cortex in the example. of the thalamus, which projected back to motor regions of the cortex. However, It has become clear that the circuitry of the basal ganglia is in PARALLEL ORGANIZATION OF a dynamic state. Components are differentially FUNCTIONALLY SEGREGATED activated, depending on conditions, and interact CIRCUITS LINKING BASAL GANGLIA, as required. Inhibitory and excitatory transmit- THALAMUS, AND CORTEX ters, involving numerous comodulators, which act on neurons with a variety of receptor sub- The basal ganglia–thalamocortical circuits types to produce smooth coordinated move- include (1) a motor circuit (see Fig. 24.5A), (2) ments and behavioral responses, exquisitely an association circuit (see Fig. 24.5B), (3) an modulate activity throughout the system. oculomotor circuit (see Fig. 24.5C), and (4) a Pathology of an anatomical or chemical nature limbic circuit (see Fig. 24.5D). As indicated, can cause profound functional disturbances. the basic design of each circuit incorporates a The following representation is abstracted central “closed loop” and an “open loop,” which from more complex circuitry. The basal ganglia receives input from several partially overlap- are composed of a core circuit, which is divisi- ping functionally related cortical areas. These ble into at least four functionally segregated multiple inputs are progressively integrated in parallel circuits (motor, association, oculomo- their passage through the pallidum and thala- tor, limbic), and two side loops, one with the mus and back to one specific cortical area. subthalamic nucleus and the other with the sub- None of the loops is a rigid self-contained stantia nigra. pathway but, rather, receives diverse influences from the nuclei of the circuit. Generalized Core Circuit The significance of the parallel circuits is The basic core circuit comprises the cerebral that they express another level of organization cortex → striatum → globus pallidus → thala- and functional specificity. Subsidiary inputs mus → cerebral cortex. Processed information and circuits modify and modulate the flow of then is transmitted via upper motoneuron path- information that passes through the major basal ways (e.g., corticospinal tract) to the lower ganglia–thalamocortical circuits and, thus, motoneurons. Some structures associated with provide additional routes for influences to be this circuit are illustrated in Figs. 24.1–24.4. A exerted on these processing centers. feedback loop goes back to the striatum via thalamostriate fibers from the intralaminar Circuit 1: Motor (see Fig. 24.5A) nuclei. Widespread areas of the cerebral cortex, The general core circuit serves as a template including the motor areas, project corticostriate for the other parallel cerebral cortex → basal fibers in a topographically organized arrange- 424 The Human Nervous System

Figure 24.3: Main circuits associated with the basal ganglia are illustrated in (A) a coronal section through the cerebrum and (B,C) transverse sections through the upper and lower midbrain. Note: (1) circuit 1: cerebral cortex to striatum to globus pallidus to VA and VL of thalamus (via Chapter 24 Basal Ganglia and Extrapyramidal System 425

Figure 24.4: Circuits associated with the basal ganglia. Note: circuit 2: striatum (caudate nucleus and putamen) to substantia nigra to striatum and to VA and VL thalamic nuclei to motor cortex; circuit 3: globus pallidus to subthalamic nucleus to globus pallidus. ment to the ipsilateral striatum, particularly the sule and appears as a prominent band as it con- putamen. The motor cortices (areas 4 and 6) tinues medially along the dorsal and rostral sur- and primary somatosensory cortex (areas 3, 1, faces of the subthalamic nucleus (see Fig. and 2) project bilaterally to the putamen. The 24.3). In this location, the lenticular fasciculus closed-loop portion of the motor circuit begins forms the ventral border of the zona incerta, and ends in the supplementary motor cortex. which is an extension of the brainstem reticular The open-loop portion involves the other areas. formation into the diencephalon. Fibers of the Striatopallidal fibers arising from all parts of lenticular fasciculus and ansa lenticularis coa- the striatum terminate in both the medial and lesce medial to the zona incerta and subthala- lateral segments of the globus pallidus. The mic nucleus, where they are just rostral to the medial segment is the origin of two fiber bun- red nucleus in what is referred to as the pre- dles, both of which terminate in the thalamus. rubral field. The combined fascicles pass later- Fibers from the ventral portion of the globus ally and rostrally along the ventral border of the pallidus form the ansa lenticularis, which thalamus (dorsal to the zona incerta) as the loops under the internal capsule, whereas fibers thalamic fasciculus (see Fig. 24.3). It should be from the dorsal portion enter the lenticular fas- noted that dentatothalamic fibers from the cere- ciculus, which passes across the internal cap- bellum, as well as fibers of the medial lemnis- ansa lenticularis, lenticular fasciculus, and thalamic fasciculus) to motor cortex; (2) circuit 2: striatum via GABAergic fibers to substantia nigra to striatum via dopaminergic fibers; (3) circuit 3: globus pallidus to subthalamic nucleus and back via subthalamic fasciculus; and (4) circuit 4: striatum to globus pallidus to centrum medianum to striatum. ZI, zona incerta. 426 The Human Nervous System cus and spinothalamic tract, also pass through region (areas 9 and 10). Further, striatopallidal the prerubral field and join the thalamic fasci- connections to the medial segment of the culus. Pallidal efferent fibers turn dorsally and globus pallidus terminate in portions of the terminate in the ventral anterior (VA), ventral nucleus that project preferentially to intralami- lateral (VL), and centro median (CM) nuclei of nar nuclei other than the CM, as well as to the the thalamus. The VA and VL nuclei project VA and VL. In addition to diffuse cortical col- somatotopically to lamina IV of the motor cor- laterals, these other intralaminar nuclei project tex (area 4), supplementary motor and premo- back to the caudate. Also, the parts of the VA tor cortices, which occupy area 6, frontal eye and VL receiving input forward the information field (area 8), and prefrontal cortex (areas 9 to the prefrontal cortex (areas 9 and 10). Other and 10). features of this circuit are similar to those of the Other connections of this circuit add to the motor circuit. complexity of interactions involving the nuclei of the basal ganglia (see Fig. 24.3). The globus Circuit 3: Oculomotor (see Fig. 24.5C) pallidus, for example, projects to CM and other The closed-loop component of the oculomo- intralaminar thalamic nuclei; the former, in tor circuit begins and ends in the frontal eye turn, projects to the putamen as well as dif- field (area 8). The open loop receives input fusely to the cortex. Thus, the intralaminar from the prefrontal cortex (areas 9 and 10) and nuclei are incorporated into a circuit of stria- from the posterior parietal region (area 7). tum to globus pallidus to intralaminar nuclei Fibers arising from these cortical areas project and back. In addition, the globus pallidus has preferentially to the body of the caudate reciprocal connections with the pedunculopon- nucleus, from which, after processing, infor- tine nucleus of the midbrain (see Fig. 24.3). mation is sent to the globus pallidus and the The latter does not project caudally. This is substantia nigra, the pars reticularis. In addition consistent with the evidence that none of the to projections from these nuclei to the thalamus basal ganglia has fibers projecting to the lower as in the other circuits (VL, VA, intralaminar), brainstem or spinal cord. Rather, the output nigral efferents also go to the frontal eye field from the basal ganglia is directed toward the (area 8) via relays in the dorsomedial nucleus cerebral cortex. Several neurotransmitters have of the thalamus and directly to the superior col- been identified with these circuits. liculus to participate in control of saccadic eye movements. Circuit 2: Association (see Fig. 24.5B) The association circuit is different from the Circuit 4: Limbic (see Fig. 24.5D) motor and oculomotor circuits in that the wide- There are several separate circuits that can spread association areas of the frontal, parietal, be described as limbic, but they have been occipital, and temporal lobes project primarily combined into one for simplification. The to the ipsilateral caudate nucleus. The closed closed-loop portion of a limbic circuit begins loop commences and ends in the prefrontal and ends in the anterior part of the cingulate

Figure 24.5: Schematic representation of segregated parallel circuits (loops) among the cerebral cortex, basal ganglia, and thalamus. (A) Motor loops. The closed loop commences with and terminates in the supplementary motor cortex (area 6). The open loop involves input to the closed loop from somatosensory cortex (areas 3, 1, and 2), primary motor cortex (area 4), and premotor cortex (area 6). (B) Association loops. The closed loop commences with and terminates in the prefrontal cortex (areas 9 and 10). The open loop involves input from premotor cortex (area 6) and posterior parietal cortex (area 7). (C) Oculomotor loops. The closed loop commences with and terminates in the frontal eye field (area 8). The open loop involves input from the prefrontal cortex (areas 9 and Chapter 24 Basal Ganglia and Extrapyramidal System 427

10) and posterior parietal cortex (area 7). The projection to the superior colliculus has a role in the control of saccadic eye movements. (D) Limbic loops. The closed loop commences with the anterior cingulate gyrus (area 24) and orbitofrontal cortex (areas 10 and 11) and terminates in these areas. The open loop involves input from the medial and lateral temporal lobe, hippocampus, amygdala, and entorhinal area (area 24). Ant, anterior; caudlat, caudolateral; DM, dorsomedial thalamic nucleus; mc, magnocellular part; GPl, GPm, globus pallidus, lateral, and medial segments; Hippo, hippocampus; parvo, parvocellular; SNr, substantia nigra, pars reticularis; SS, somatosensory; VA, ventral anterior thalamic nucleus; VL, ventrolateral thalamic nucleus. 428 The Human Nervous System gyrus (area 24) and orbitofrontal cortex (areas are some terminals in ventral parts of the pars 10 and 11). The open-loop component receives compacta. The projections from the substantia input from the medial and lateral temporal lobe nigra are directed rostrally via (1) nigrostriatal cortex, including the entorhinal area (area 28), fibers from the pars compacta to the striatum the amygdala, and hippocampus. These regions and (2) nigrothalamic fibers from the pars retic- send excitatory signals (glutamatergic) to the ularis to the VA and VL thalamic nuclei. These ventral striatum (nucleus accumbens) and part thalamic nuclei project to portions of the motor of the head of the caudate nucleus, from which, cortical areas. The nigral efferent projections to after processing, information is forwarded to the VA and VL nuclei terminate in different the ventral pallidum, globus pallidus and retic- regions of these thalamic nuclei than do projec- ular part of the substantia nigra. Fibers from tions from the globus pallidus and from the these nuclei project to the magnocellular divi- cerebellum (dentatothalamic fibers); current sions of the ventral anterior and dorsomedial evidence indicates that no overlap occurs thalamic nuclei, which project to the cortex of among these three projections. the closed loop. The substantia nigra, pars reticularis, GPm, and the cerebral cortex are sources of descending fibers to the pedunculopontine SIDE CIRCUITS nucleus (PPN) in the caudal midbrain (see Fig. 24.2). These fibers are the most caudal Circuit 5: Substantia Nigra projections from the basal ganglia. Other afferents come from the cerebellar nuclei via Striatum → substantia nigra → thalamus → the superior cerebellar peduncle. Different (VA and VL nuclei) portions of the motor cells in PPN express acetylcholine and gluta- cortex (see Figs. 24.2 and 24.4). mate. Efferents from the pedunculopontine This circuit involves the substantia nigra. nucleus, which are directed rostrally, mainly In brief, the substantia nigra (1) receives input go to the substantia nigra, pars compacta, with from the ipsilateral striatum, subthalamic some to the subthalamic nucleus and to GPm. nucleus, and globus pallidus and (2) projects to Thus, PPN is an interface between the cere- the ipsilateral VL and VA thalamic nuclei (see bellum and the basal ganglia. Fig. 24.5) as well as back to the striatum (see The nigrostriatal fibers from the pars com- Fig. 24.2). pacta form a dopaminergic system, which The substantia nigra is divided into the ven- releases dopamine in the striatum. The sero- trally located pars reticularis, or SNr (adjacent to tonin in the pars reticularis is derived from the the crus cerebri) and the dorsally located pars dorsal tegmental nucleus of the midbrain raphe. compacta (SNc) (see Fig. 13.15). The pars retic- The striatonigral fibers and the nigrothalamic ularis has iron-containing glial cells, serotonin, fibers release GABA. and gamma aminobutyric acid (GABA), but lacks the melanin pigment. The pars compacta Circuit 6: Subthalamic Nucleus has dopaminergic neurons that contain melanin Globus pallidus ↔ subthalamic → globus pallidus (hence, its dark appearance). Neuromelanin pig- (lateral segment) nucleus (medial segment) ment is a polymer of the catecholamine precur- ↓ sor dihydrophenylalanine (Dopa) and is absent substantia nigra in patients with Parkinson’s disease as well as in (pars reticularis) infants. There is linkage between the two parts (see Figs. 24.2 and 24.4). of the nigra via dendrites of pars compacta neu- The subthalamic nucleus receives input rons, which extend into the pars reticularis. from the ipsilateral globus pallidus (lateral The striatonigral fibers project almost segment), motor cortex, and pedunculopon- entirely to the pars reticularis, although there tine nucleus. It projects output to both seg- Chapter 24 Basal Ganglia and Extrapyramidal System 429 ments of the ipsilateral globus pallidus and to laris), and ventral pallidum comprise the output the pars reticularis of the substantia nigra, nuclei. The GABAergic projections from these with which it is reciprocally interconnected; nuclei are largely directed to the thalamus and this is another side circuit. The fibers that are inhibitory (see Fig. 24.6). reciprocally interconnect the globus pallidus and the subthalamic nucleus form the subthal- Cytoarchitectural and Compartmental amic fasciculus, which passes through the Organization of the Striatum posterior limb of the internal capsule. Neu- Cell Types. The striatum contains two rons of the subthalamic nucleus release gluta- major neuronal population projection neurons mate, which is an excitatory transmitter. The whose axons terminate in other nuclei and subthalamic nucleus is the driving force regu- interneurons whose axons remain within the lating the output of the globus pallidus and striatum. The medium spiny neuron, which substantia nigra by increasing or decreasing receives most of the extrastriatal input, is, by the amount of inhibition they exert on the far, the most numerous cell type, constituting thalamus (see later). over 90% of the total population. These cells have axons that project out of the striatum; General Organization of the Basal Ganglia GABA is the major neurotransmitter. Two On the basis of their neural connections, the classes of this cell type, with different projec- nuclei of the basal ganglia are organized as tions, are recognized. Striatonigral neurons, input nuclei, intrinsic nuclei,andoutput nuclei including those with collaterals to the medial (see Table 24.2). The input nuclei receive pallidal segment, corelease substance P and afferent information from outside the basal dynorphin; this is referred to as the direct path- ganglia and project their output to the intrinsic way to the output nuclei. Striatopallidal neu- nuclei. The intrinsic nuclei interact and have rons to the lateral segment (indirect pathway) connections with both other input nuclei and corelease enkephalin. Both types of spiny neu- output nuclei. After neural processing within ron have dopamine receptors. There are several the basal ganglia, the output nuclei send different dopamine receptor subtypes; D1 and inhibitory signals to nuclei outside the basal D2 receptors, which activate different intracel- ganglia. lular pathways, have been studied most. Recent

The striatum (caudate nucleus, putamen, evidence shows that D1 and D2 receptors are and nucleus accumbens) comprises the input colocalized on most spiny neurons, supersed- nuclei. It receives its major input from the cerebral cortex as well as afferents from the intralaminar nuclei of the thalamus; both path- Table 24-2: ways are glutamatergic. The globus pallidus Categories of Basal Ganglia Nuclei (lateral segment), subthalamic nucleus, substantia nigra (pars compacta), and ventral Input nuclei tegmental area comprise the intrinsic nuclei. Caudate nucleus Putamen The circuitry linking these nuclei together and Nucleus accumbens with the input and output nuclei is mainly Intrinsic nuclei inhibitory, with GABA as the major neuro- Globus pallidus (lateral segment) transmitter; an important exception is the sub- Subthalamic nucleus thalamic nucleus, whose glutamatergic output Substantia nigra (pars compacta) is entirely excitatory (see Fig. 24.6A). A sec- Ventral tegmental area (VTA) ond rather unusual and very important excep- Output muclei tion, to be discussed, involves the substantia Globus pallidus (medial segment) nigra, pars compacta. The globus pallidus Substantia nigra (pars reticularis) (medial segment), substantia nigra (pars reticu- Ventral pallidum 430 The Human Nervous System

Figure 24.6: Simplified model depicts functional connections of the basal ganglia with the thalamus and cortex whence to lower motoneurons and shows relative balance/imbalance of activity in different parts of the circuitry in normal and various pathological states. Open arrows, excitatory Chapter 24 Basal Ganglia and Extrapyramidal System 431 ing the notion that spiny neurons giving rise to has been divided into smaller patch compart- the direct pathway have D1 receptors, whereas ments (15% of the total) embedded in a matrix. those giving rise to the indirect pathway have The matrix, in contrast to patches, contains high

D2 receptors. The two receptor subtypes inter- levels of the enzyme acetylcholinesterase. Only act. The dopaminergic input from the substan- matrix cells contain the calcium-binding protein φ tia nigra presumably differentially modulates calbindin D28k and only matrix cells have opi- the two classes of spiny projection neuron, pro- oid receptors. Spiny projection neurons viding the basis for explaining various forms of expressing primarily substance P or enkephalin basal ganglia-induced motor disturbances (see occur in both compartments, but the cortical below). Spiny projection neuron axons emit inputs to the compartments differ. Corticostriate copious collaterals, which inhibit other spiny projections from cells in more superficial parts projection neurons. This is another example of of lamina V go principally to the matrix com- lateral inhibition. In addition, strionigral fibers partment. Although most of the cortex projects form presynaptic terminals on the collaterals, to the matrix, afferents from sensory and motor adding to the complex modulatory influences cortex are differentially distributed to it. Patch on these cells. Collaterals also synapse on compartments receive terminals from neurons interneurons, which terminate on spiny projec- in deep parts of lamina V in the cortex related to tion neurons and other interneurons. Interneu- the limbic system (anterior cingulate and rons, whose axons do not leave the striatum, medial frontal gyri), where this lamina is well are of several types. All have dopamine recep- developed. The two compartments emit distinct tors. Large aspiny neuron are cholinergic and striatonigral projections. The matrix sends form excitatory synapses on the projection neu- fibers to the GABAergic parts of SNr, whereas rons. In addition, there are two separate classes the patches provide input to dopaminergic neu- of intrinsic medium aspiny neurons whose rons located in the ventral part of SNc and in major neurotransmitter is GABA. One type islands within SNr. also colocalizes somatostatin, nitric oxide, and neuropeptide Y. Thus, different classes of interneurons directly excite or inhibit the pro- SUMMARY jection neurons. Inhibitory interneurons also can indirectly disinhibit them by acting on The basal ganglia are subcortical nuclei that other inhibitory interneurons, which, in turn play a primary role in the integration of somatic synapse upon the projection neurons. motor activity. The amygdala and hippocampus, nuclear complexes of the limbic system Patch-Matrix Compartments. Based on dif- (Chap. 22) with connections to the ventral ferences in neurochemical markers, the striatum striatum, involve the basal ganglia in somatic connections; solid arrows, inhibitory connections. Increased excitation or inhibition, thick arrows; diminished effect, thin arrows. (A) Normal: all connections are in balance (arrows are the same width throughout). The major neurotransmitters are shown. (B) Destruction of the substantia nigra, pars compacta (SNc), as in Parkinson’s disease. (C) Destruction of the subthalamic nucleus (STN), as in ballism. (D) Selective loss of gabaergic striatal projection neurons to the lateral segment of the globus pallidus (GPl), as occurs in early-stage Huntington’s chorea. Those projecting directly to the globus pallidus, medial segment (GPm) and to the substantia nigra, pars reticularis (SNr)— the output nuclei of the basal ganglia—also undergo degeneration in later stages. GABA is the major neurotransmitter of spiny striatal projection neurons. Those giving rise to the direct pathway coexpress dynorphin (Dyn) and substance P (Sub P). Those giving rise to the indirect pathway coexpress enkephalin (Enk). LMNs, lower motoneurons; VL/VA, ventral lateral and ventral anterior thalamic nuclei. The striatum contains three types of interneurons. See text for description. 432 The Human Nervous System movements associated with responses to moti- thalamic neurons receiving these inputs do not vational and emotional stimuli. exert major effects on the primary motor cortex The striatum is the receptive complex of the (area 4), but, rather, mainly project their out- corpus striatum (see Table 24.2); its input is puts to premotor and supplementary motor derived from widespread areas of the neocortex, areas (Chap. 25). The pallidothalamic and intralaminar nuclei (centrum medianum and nigrothalamic fibers primarily exert inhibitory parafascicular nucleus) of the thalamus, sub- effects on the thalamus. stantia nigra, VTA, and dorsal raphe nucleus of The substantia nigra receives input from the midbrain. The afferent corticostriate influ- both the striatum and globus pallidus of the ences are mediated by the excitatory transmitter corpus striatum, subthalamic nucleus, pedun- glutamate (see Fig. 24.6A). The intrinsic local- culopontine nucleus, and dorsal nucleus of the circuit neurons of the striatum are cholinergic midbrain raphe. A major output from the sub- and GABAergic. The striatum is divided into stantia nigra (pars compacta) terminates as two compartments: 85% consists of a “matrix” dopaminergic endings in the striatum. The sub- and 15% consists of small “patches.” The con- thalamic nucleus receives input from the lateral centration of acetylcholine is much higher in the segment of the globus pallidus and the motor matrix than in the patches. The matrix receives cortex and projects to both segments of the major input from the motor and sensory cor- globus pallidus, the substantia nigra (pars retic- tices. Patches receive major input from the lim- ularis), and ventral pallidum. Excitatory influ- bic cortex. Two classes of GABAergic medium ences from the glutamatergic subthalamic spiny projection neurons give rise to two sepa- nucleus acting on the medial segment of the rate striatal output pathways: direct and indi- pallidum and on the substantia nigra (pars rect. The direct pathway, which arises from reticularis) is regarded as the driving force reg- neurons that coexpress substance P and dynor- ulating the output of the basal ganglia. phin, makes monosynaptic connections with the The basal ganglia along with the cerebellum output nuclei of the basal ganglia, the medial act as the interface between our sensory sys- segment of the globus pallidus, and the substan- tems and many motor responses. The palli- tia nigra (pars reticularis). The indirect pathway, dothalamic projections in the thalamus do not which arises from neurons that coexpress overlap the cerebellar projections from the enkephalin, goes to the lateral segment of the deep cerebellar nuclei. No convergence from globus pallidus. The GPl sends fibers to the sub- the pallidal and cerebellar inputs has been thalamic nucleus, whose glutamatergic excita- demonstrated on a single thalamic neuron. tory efferents go to the output nuclei. Striatal The precise role of the basal ganglia in the projection neurons and interneurons have regulation of normal movements is still a mat- dopamine receptors. Although there are a vari- ter of speculation. They are thought to be ety of subtypes of dopamine receptor, the D1 involved in the regulation of background mus- and D2 subtypes, which appear to be colocalized cle tone and posture and in the initiation, con- in virtually all projection neurons, have been trol, and cessation of automatic movements most thoroughly studied. They are associated such as in locomotion (running) and in athlet- with second-messenger systems (Chap. 3). The ics (throwing a ball). The basal ganglia are

D1 receptors act to increase and the D2 receptors apparently involved in the transfer and modi- to decrease cAMP formation. fication of information from widespread neo- The output of the basal ganglia is derived cortical areas to the motor cortex, especially from neurons of the medial segment of the GP, the premotor and supplementary motor areas. the substantia nigra (pars reticularis), and ven- Via circuitry linking the ventral striatum with tral pallidum. The projections from these the limbic system, the basal ganglia partici- sources to VL and VA thalamic nuclei are dis- pate in behavioral responses related to the tinct and their terminations do not overlap. The emotions. Chapter 24 Basal Ganglia and Extrapyramidal System 433

is associated with hyperactive static fusiform FUNCTIONAL CONSIDERATIONS gamma motoneurons. In contrast, spasticity (Chap. 12) is a form of hypertonus in which the Formerly, the cerebral cortex, especially the muscles are in phasic hyperactive activity when motor cortex, was hierarchically placed at the the muscles are stretched. This is associated highest level for orchestrating motor integra- with hyperactive dynamic fusiform gamma tion, and subcortical structures were placed at motoneurons. another level and thought to function solely in a feedback capacity. The newer view states that Clinical Manifestations both the basal ganglia and the cerebellum are The abnormal involuntary movements called crucial in the initial and early processing stages dyskinesias can be rhythmic or arrhythmic, resulting in motor activity. The circuitry involv- generally without paralysis of the muscles. ing the sensory cortical areas, basal ganglia, They can be classified as hypokinetic or hyper- and cerebellum act through the ventral anterior kinetic. The motor disorders result from and ventral lateral nuclei, known as the motor improper functioning of the basal ganglia, and nuclei of the thalamus. They serve as the main associated nuclei, including, among others, gateway through which these circuits become paralysis agitans (Parkinson’s disease), atheto- involved in generating activity in the motor sis, choreas, and ballism. cortical areas; they fire well in advance of and Paralysis agitans (Parkinson’s disease, during each volitional movement. In addition, parkinsonism), which has a mean onset at age these circuits act as bridges between the sen- 60, is characterized by rigidity and tremor. The sory cortical areas and the motor cortical areas. rigidity is essentially the same in all muscles; it In a real sense, these circuits are active partici- is accompanied by poverty of movements and pants during all phases of a movement, from cogwheel rigidity. Cogwheel rigidity is initiation to completion. expressed when the examiner flexes and As we have seen, the role of the basal gan- extends a limb joint of the patient; during glia, cerebellum, and associated nuclei is to movement, an increased resistance suddenly modulate motor activities through circuits, gives way, and as the movement continues, this which directly and indirectly feed back to the sequence is repeated, as in a cogwheel. From a cerebral cortex. In turn, the cortex projects its standing position, a patient has difficulty taking influences to the brainstem and spinal levels initial steps. The subject also has the same through the descending motor pathways, upon problem arresting a movement. During forward the local circuitry that activates the alpha and locomotion, short, shuffling steps are taken. gamma motor neurons. The malfunction of var- The “masked” face has a fixed expression, ious nuclear complexes results in an imbalance accompanied by no overt spontaneous emo- in the interactions within the circuitry of the tional response. The tremor, with a regular fre- basal ganglia, disrupting the output, which ulti- quency (three to six per second) and amplitude, mately is manifest at the level of the motor occurs while the subject is at rest; it is lost or units. This is a plausible explanation for the reduced during voluntary movement. Degener- variety and assortment of symptoms and signs ative changes in the nigrostriatal pathway, noted in the disorders involving control of pos- raphe nuclei, locus ceruleus, and motor nucleus ture and movements. In some disorders, there is of the vagus nerve are present in parkinsonian an increase in muscle tone to a similar degree patients; in addition, there is a marked reduc- in the agonists and antagonists of a muscle tion to absence of dopamine, serotonin, and group without an accompanying increase in norepinephrine. It has been shown that Parkin- reflex activity, called rigidity. Rigidity (Chap. son-like symptoms can be elicited by toxins, 8) is a form of hypertonus in which the muscles such as 1-methyl-4-phenyl-1,2,3,6-tetrahy- are continuously or intermittently tense, and it dropyridine (MPTP), that selectively destroy 434 The Human Nervous System nigrostriatal dopamine neurons. Administration the drug. Suggested causes include alteration of of L-dihydroxyphenylalanine (L-dopa) in low the dopaminergic receptors, resulting in their doses can ameliorate the rigidity, and in high hypersensitivity to dopamine. The consequen- doses, it can ameliorate the tremors. L-Dopa is tial alteration in the balance among the a precursor of melanin and dopamine. dopaminergic, intrastriatal, cholinergic, and Although the placement of small lesions in GABAergic agents results in the involuntary the globus pallidus and VA nucleus of the thal- movements. amus in some patients alleviates the symptoms Choreas (dances) are characterized by jerky, of rigidity and tremor, slowness in the initiation irregular, brisk, graceful movements of the and execution of movement (bradykinesis) does limbs accompanied by involuntary grimacing not change. Moreover, the tremor and rigidity and twitching of the face. Primarily, the distal often recur a few years after surgery. Modern segments of the extremities express these therapy for parkinsonism includes administra- movements. In advanced cases, the patient is tion of can -dopa, certain anticholinergics, almost always in motion when awake. There is and/or other agents. Another therapeutic no reduction in muscle power. Huntington’s approach being explored is the transplantation disease (chorea) is a hereditary autosomal of fetal midbrain tissue, including the substantia dominant disorder (chromosome 4). From its nigra into the striatum. In primate models of initial subtle symptoms that might not appear Parkinson’s disease, caused by injecting MPTP, until the late thirties, the affliction features pro- subsequent lesions produced in the subthalamic gressive increases in the severity of chorea nucleus have been shown to reverse the signs. (choreiform movements) and dementia. Death This is attributed to re-establishment of the generally occurs 15–20 years after onset. The appropriate balance of activity within the cir- early stages of the disease have been correlated cuitry of the basal ganglia. A newer treatment with a preferential loss, mainly in the caudate option involves deep brain stimulation, in which nucleus, of the neurons that express enkephalin high-frequency electrical currents are delivered that project to the lateral segment of the globus via electrodes implanted bilaterally in the sub- pallidus, with a relative sparing of those that thalamic nucleus. This produces overexcitation project to the substantia nigra and to the medial of the globus pallidus, causing it to increase its pallidal segment. The latter are affected in later inhibition of the thalamus and reduce activity in stages. Although not markedly degenerated, the the thalamocortical and descending corticofugal cholinergic interneurons clearly are damaged pathways to the lower motoneurons. Clinical in later stages, as evidenced by a significant trials also have been initiated using gene ther- reduction in the amount of striatal cholines- apy. One strategy is to transfer glutamic acid terase. A reduction in substance P and enkepha- decarboxylase, which catalyzes synthesis of lin in the globus pallidus and substantia nigra GABA, into neurons of the subthalamic nucleus also occur. The involuntary choreiform move- that normally produce glutamate. Increased ments are presumed to result from disturbances excitation of the output nuclei is regarded as in metabolism and outputs of the neuronal one aspect causing Parkinson’s disease. loops involving the GABAergic spiny projec- Tardive dyskinesia is a form of dyskinesia tion neurons, dopaminergic nigrostriatal, and that occurs in some patients following the cholinergic intrastriatal neurons. The impaired chronic administration of phenothiazines cognitive function is attributed to a concomi- (antipsychotic and tranquilizing drugs) as ther- tant loss of neocortical neurons. apy for such psychoses as schizophrenia. The The movements of athetosis are slow and symptoms can include facial grimacing, lip exaggerated by voluntary movement. The slow, smacking, and choreoathetotic movements of writhing character of the involuntary move- the limbs and trunk. Treatment is to stop giving ments of the neck, trunk, and extremities Chapter 24 Basal Ganglia and Extrapyramidal System 435 appear wormlike. The alternating adduction Alterations of Inhibitory/Excitatory Activity and abduction of the shoulder joint is accom- in Movement Disorders panied by flexion and extension of the wrist As indicated earlier, motor activity is and fingers. Usually, the wrist is flexed, and the modulated by the basal ganglia via their fingers hyperextended. Facial grimaces might inhibitory output to the thalamus and excitatory occur during the limb movements. This dyski- thalamocortical–upper motoneuronal path- nesia could be the result of a lesion in the stria- ways. Smooth, coordinated “normal” move- tum, mainly in the putamen. Athetosis is ments require a proper balance of excitatory frequently associated with cerebral palsy. It and inhibitory activity throughout the basal occurs as the result of brain lesions during or ganglia (see Fig. 24.6A). Anything that alters prior to birth. the usual pattern of inhibition exerted upon the Ballism (“throwing”) is characterized by thalamus is in a position to disrupt normal violent, high-amplitude, flaillike movements motor function. Thus, increased inhibition of originating mainly from the activity of the the thalamus might be expected to diminish proximal appendicular muscles of the shoulder excitatory activity of the thalamocortical–upper and pelvis. The movements cease during sleep. motoneuronal pathways and reduce or other- There is a reduction of muscle tone. These wise impoverish motor activity. Conversely, symptoms are exhibited unilaterally with a decreased inhibition of the thalamus might be lesion in the contralateral subthalamic nucleus. expected to increase excitation of the thalamo- Because, clinically, ballism almost always cortical– upper motoneuronal pathways and occurs on one side only and is usually the result produce an excess of motor activity. of a vascular accident, it is also known as Based on the circuitry of the basal ganglia hemiballism. Symptoms associated with mal- and the interplay of inhibitory and excitatory functioning of the basal ganglia are usually neurotransmitters, the bradykinesis characteris- observed bilaterally. However, like hemibal- tic of parkinsonism is attributed to increased lism, lesions on one side are manifest on the activity of the basal ganglia output nuclei opposite side because the output of the basal (medial segment of the globus pallidus; substan- ganglia is directed toward the ipsilateral cere- tia nigra, pars reticularis), which inhibit the VA bral cortex whose descending pathways pre- and VL nuclei of the thalamus (see Fig. 24.6B). dominantly innervate lower motoneurons on An unusual feature of the circuitry of the basal the contralateral side. ganglia is that dopamine in the nigrostriatal The abnormal movements resulting from pathway presumably inhibits the enkephalin- lesions in the basal ganglia circuitry are an expressing striatal spiny projection neurons that expression of release phenomena, in which the give rise to the indirect pathway and excites the inhibitory influences on such structures as the substance P- and dynorphin-containing neurons globus pallidus or ventral lateral nucleus of the that form the direct pathway. Following this thalamus are lost or reduced. Surgical lesions scheme, loss of dopaminergic nigrostriatal neu- of these “released structures” (globus pallidus rons, an attribute of this disease, causes reduced and VL) are known to ameliorate the symptoms inhibition selectively of the striatopallidal fibers in many patients. In this context, the loss of to the lateral segment of GP). Thus, the GPl dopamine, noted in patients with parkinsonism, receives greater than usual inhibitory input, accounts for the reduction or loss of inhibitory causing its inhibitory influence on the subthala- influences upon the striatum. A likely underly- mic nucleus to be reduced. As a consequence, ing cause of disorders of the basal ganglia is the excitatory influence of the subthalamic that disruptions in transmitter metabolism nucleus upon GPm/SNr is increased. These out- result in an abnormal output from the circuitry put nuclei inhibit the VL and VA to a greater of the basal ganglia. than customary degree, ultimately reducing the 436 The Human Nervous System activity of the lower motoneurons. Diminished dopamine receptor colocalization in neostriatal excitation of the striatal neurons that project neurons. Nature Neurosci. 2000;3:226–230. directly to the GPm/SNr simultaneously occurs. Bates G, Harper PS, Jones L. Huntington’s Disease. This reduces inhibition on the GPm/SNr, leading New York: Oxford University Press; 2002. to increased inhibition of the thalamus, as via the Brady AM, O’Donnell P. Dopaminergic modulation of prefrontal cortical input to nucleus accumbens indirect pathway. neurons in vivo. J. Neurosci. 2004;24:1040–1049. Conversely, lesions of the subthalamic Gerfen CR. D1 dopamine receptor supersensitivity nucleus decrease excitation of GPm/SNr, in the dopamine-depleted striatum animal model resulting in diminished inhibition of the thala- of Parkinson’s disease. Neuroscientist mocortical part of the circuit (see Fig. 24.6C). 2003;9:455–462. Thus, activity of the lower motoneurons is Guzman JN, Hernandez A, Galarraga E, et al. increased above usual levels, as occurs in bal- Dopaminergic modulation of axon collaterals lism. Following this line of reasoning, lesions interconnecting spiny neurons of the rat striatum. of the subthalamic nucleus, produced in J. Neurosci. 2003;23:8931–8940. MPTP-induced models of parkinsonism, Haber SN, Fudge JL, McFarland NR. Striatonigros- should restore the balance of activity in the triatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. internal circuitry of the basal ganglia. Indeed, J. Neurosci. 2000;20:2369–2382. this has been demonstrated to occur. With Kawaguchi Y. Neostriatal cell subtypes and their lesions of the substantia nigra, there is exces- functional roles. Neurosci. Res. 1997;27:1–8. sive activity in the subthalamic nucleus, Kelly RM, Strick PL. Macro-architecture of basal regarded as an important factor in the genera- ganglia loops with the cerebral cortex: use of tion of Parkinson’s disease. In the primate rabies virus to reveal multisynaptic circuits. model, this excessive activity is eliminated Prog. Brain Res. 2004;143:449–459. with the secondary lesion. Luo J, Kaplitt MG, Fitzsimons HL, et al. Subthala- As noted, Huntington’s chorea in the early mic GAD gene therapy in a Parkinson’s disease stages is associated with lesions of the striatum rat model. Science 2002;298:425–429. (mainly caudate) selectively involving the Matsumura M, Kojima J. The role of the pedunculopontine tegmental nucleus in experimental enkephalin-expressing GABAergic projection parkinsonism in primates. Stereotact. Funct. neurons whose axons terminate in the lateral Neurosurg. 2001;77:108–115. segment of the pallidum. Reduced inhibition Obeso JA. The Basal Ganglia and New Surgical upon the GPl would cause greater inhibition of Approaches for Parkinson’s Disease. Philadel- the subthalamic nucleus (see Fig. 24.6D). In phia, PA: Lippincott-Raven; 1997. turn, excitation of GPm/SNr would be reduced, Obeso JA, Rodriguez-Oroz MC, Rodriguez M, causing less inhibition of VL and VA, as after Arbizu J, Gimenez-Amaya JM. The basal ganglia lesions of the subthalamic nucleus directly. and disorders of movement: pathophysiological Thus, the end result would be increased activ- mechanisms. News Physiol. Sci. 2002;17:51–55. ity of the lower motoneurons, expressed as a Onn SP, West AR, Grace AA. Dopamine-mediated hyperkinetic movement disorder. However, the regulation of striatal neuronal and network interactions. Trends Neurosci. 2000;23:S48–S56. pattern as well as amount of activity might be Parent A, Levesque M, Parent M. A re-evaluation of expected to be different from that elicited by the current model of the basal ganglia. Parkin- other pathologies, accounting for the dissimi- sonism Relat Disord. 2001;7:193–198. larities in movement disorders. Plenz D. When inhibition goes incognito: feedback interaction between spiny projection neurons in striatal function. Trends Neurosci. 2003;26: SUGGESTED READINGS 436–443. Reynolds JN, Wickens JR. Dopamine-dependent Aizman O, Brismar H, Uhlen P, et al. Anatomical plasticity of corticostriatal synapses. Neural and physiological evidence for D1 and D2 Netw. 2002;15:507–521. Chapter 24 Basal Ganglia and Extrapyramidal System 437

Rodriguez-Oroz MC, Rodriguez M, Guridi J, et al. West AR, Floresco SB, Charara A, Rosenkranz JA, The subthalamic nucleus in Parkinson’s disease: Grace AA. Electrophysiological interactions somatotopic organization and physiological between striatal glutamatergic and dopaminer- characteristics. Brain 2001;124:1777–1790. gic systems. Ann. NY Acad. Sci. 2003;1003: Steiner H, Gerfen CR. Role of dynorphin and 53–74. enkephalin in the regulation of striatal output Wichmann T, DeLong MR. Functional neu- pathways and behavior. Exp. Brain Res. roanatomy of the basal ganglia in Parkinson’s 1998;123:60–76. disease. Adv. Neurol. 2003;91:9–18. Tunstall MJ, Oorschot DE, Kean A, Wickens JR. Wise SP, Murray EA, Gerfen CR. The frontal Inhibitory interactions between spiny projection cortex–basal ganglia system in primates. Crit. neurons in the rat striatum. J. Neurophysiol. Rev. Neurobiol. 1996;10:317–356. 2002;88:1263–1269. 25 Cerebral Cortex

Organization of the Neocortex Motor Areas of the Neocortex Sensory Areas of the Neocortex Higher Cortical Association Areas Blood Flow in the Cortex Split-Brain Man and Cerebral Dominance Memory

The highest of human functions involve the tion (hippocampus and dentate gyrus), and the intricate circuitry of the cerebral cortex, which paleocortex, composed of the six-layered para- has crucial roles in language, conceptual think- hippocampal gyrus, and the olfactory cortex or ing, creativity, planning, and the ways in which uncus. A form of the neocortex that might have we give form and substance to our thoughts. features not as advanced as the bulk of this type Our abilities in this realm are the result of the is sometimes referred to as the mesocortex; it enlargement of the neocortex, particularly of includes the cingulate gyrus, fasciolar gyrus, the association cortex, one of the most striking and the isthmus (see Fig. 1.7). The allocortex features of mammalian evolution. The cortex and mesocortex incorporates the limbic lobe enables us to appreciate the fine qualities of (Chap. 1), an artificial construct formed from sensation and to organize skilled motor activi- parts of other lobes, located on the medial ties. Our multifaceted patterns of response aspect of the hemisphere, where it forms a ring require a continuous stream of sensory input around the corpus callosum and rostral brain- and interactions of the cortex with the thalamus stem. The neocortex consists of the cortex of and subcortical nuclei such as the basal gan- the frontal, parietal, occipital, temporal, and cen- glia. Conscious awareness of self, both internal tral lobes, excluding the allocortex (Chap. 1). and in relation to the environment, is cortical The neocortex has been parceled in several expressions. ways; the most commonly used scheme is that The cerebral cortex is the 600-g gray cover- of Brodmann (1909), who numbered areas con- ing of the cerebrum, constituting about 40% of secutively, based on cytoarchitectural differ- the brain by weight and containing 100 billion ences visualized in Nissl-stained preparations. or more neurons. Of the total mass, the neurons More than 40 areas, out of a total of 52, are dis- weigh about 180 g and the glial cells and blood cernable on the lateral and medial surfaces of vessels weigh about 420 g. the brain (see Figs. 25.5 and 25.6). Nonadja- The cerebral cortex is divided into the phy- cent areas frequently express the same features. logenetically older allocortex, about 10% of Later, von Economo (1920) categorized the the total, and in mammals, the more recently neocortex into a continuum of five different evolved six layered neocortex (isocortex), cytoarchitectural types. The two extremes are about 90% of the cortex in humans. The allo- referred to as heterotypic and include the pri- cortex, which does not receive thalamic input, mary sensory cortices and motor cortex. The consists of the ancient three-layered archicor- former is the thinnest cortex (about 2 mm from tex, which is limited to the hippocampal forma- pial surface to white matter), and because of a

439 440 The Human Nervous System large population of small stellate-shaped peri- nae elsewhere in cortex. The input to the neo- karya in a particularly well-developed layer IV cortex, aside from association and commissural that resemble sand, it is called hypergranular. fibers, is derived primarily but not entirely The heterotypic motor cortex is more than from the thalamus. The output from the neo- twice as thick and is called agranular because cortex to subcortical regions is relayed via pro- of the lack of a well-defined layer IV. In addi- jection fibers—corticobulbar, corticoreticular, tion, layer IV of this region is characterized by corticopontine, corticothalamic, corticostriate, the presence of small pyramidal cells, and layer corticorubral, corticonuclear, and corticospinal. V is enlarged. The great majority of cortex, comprising the association areas, is referred to Neurons of the Neocortex as homotypic and includes the middle three (see Figs. 25.1 and 25.2) gradations. The six layers are more readily dif- Five basic neuronal cell types (pyramidal, ferentiated in this type of cortex. stellate, stellate [star] pyramidal, Martinotti, horizontal) are representative of the numerous cortical neurons. The shape of the cell body, ORGANIZATION OF THE dendritic organization, and course taken by its NEOCORTEX axon are among the criteria used to characterize a cell. Pyramidal cells, present in all but the The neocortex is conventionally described first layer, constitute the majority of cortical as being organized in six horizontal laminae neurons. Each pyramidal cell has a cell body oriented parallel to the cortical surface (see shaped like an isosceles triangle with a single Fig. 25.1). Individual laminae are somewhat branched apical dendrite extending toward the obscured in the heterotypic cortex, where some cortical surface and several horizontally laminae are highly developed and others are directed branched basilar dendrites. The axon attenuated. In some areas, different laminae are typically arises from the base and, except for subdivided. Although lamination is its most some in layer II, enters the subcortical white conspicuous feature, the basic functional units matter; usually, there is a collateral branch of the cerebral cortex are physiologically (recurrent collateral) going back toward the defined vertical columns or modules extending pial surface. The main axonal branches of the from the pial surface to the white matter (see pyramidal cells form the association fibers, Fig. 25.2). These are not columns in the archi- commissural fibers, and projection fibers listed tectural sense, but, rather, are long three- above. Pyramidal cells, depending on the size dimensional slabs up to 0.5 mm in width. Most of the soma, are described as small, medium, cortical columns are (1) the terminus of affer- large, or giant. The latter, called Betz cells,are ent fibers from other cortical areas and the about 100 μm high and are restricted to cortical thalamus and (2) the source of efferent fibers lamina V of area 4 (Chap. 11). The designa- terminating in other cortical columns of the tions external (III) and internal (V) pyramidal same hemisphere (association fibers), in the layers are derived from the neurons that char- same cortical area of the contralateral hemi- acterize them. Although layer II is called the sphere (commissural fibers passing through the external granular layer, it is actually largely corpus callosum or anterior commissure), and populated by small pyramidal neurons. Stellate in subcortical nuclei of the cerebrum, brain- cells are multipolar interneurons with a star- stem, and spinal cord (projection fibers). In shaped body, short-branched dendrites, and a general, the main input layers of the cortex are short axon that arborizes and synapses with laminae I through IV. The main output is from other cortical neurons in the immediate vicin- laminae V and VI. However, both association ity. Stellate cells, which are local circuit (Golgi and commissural fibers take origin from lami- type II) neurons, comprise two distinct mor- nae II and III and terminate in the same lami- phological and functional populations, namely Chapter 25 Cerebral Cortex 441

Figure 25.1: Vertical columnar organization of the neocortex. Roman numerals indicate the six horizontal laminae. The cell bodies of the pyramidal neurons and stellate (granule) neurons are present in laminae II through VI. Each pyramidal neuron is oriented in a vertical plane, with its apical dendrite extending to lamina I and its basilar dendrites extending horizontally. Its axon extends out of the cortex into the white matter and has recurrent branches projecting back to the cortex. The dendrites and axon of each stellate neuron (S) arborize and terminate within the immediate column. The axon of each Martinotti neuron (M) has an axon that extends from lamina VI to laminae II and I. A, axon of a pyramidal neuron; A-AC, axon of an association or commissural neuron; AD, apical dendrite of pyramidal neuron; A-P, axon of projection neuron; A-T, corticopetal axon from a neuron of a specific relay or association nucleus in the thalamus; BD, basilar dendrites of a pyramidal neuron; RC, recurrent collateral. excitatory neurons and inhibitory ones. The lat- and sometimes are referred to with names such ter, referred to as aspiny neurons because of a as double bouquet cells, tuft cells, chandelier lack of dendritic spines, are mainly GABAergic cells, and basket cells (see Fig. 25.2). Except (GABA is the major inhibitory neurotransmit- for the double bouquet cells, they are all ter). Spiny stellate cells are glutamatergic. Glu- regarded as aspiny inhibitory interneurons. tamate is regarded as the major excitatory Stellate pyramidal neurons are large cells that neurotransmitter of the cerebral cortex. Many combine the features of both stellate and cortical neurons have comodulators. Stellate pyramidal cells. These neurons have a stellate cells are particularly conspicuous in lamina IV, shape with an apical dendrite together with and because of their appearance in the Nissl numerous dendrites radiating from the cell stain, this lamina is called the internal granular body. Stellate pyramidal neurons are character- layer. Stellate cells exhibit a variety of shapes istic of lamina VI and have an axon that enters 442 The Human Nervous System the subcortical white matter. Martinotti cells or rare in adults; its axon is oriented parallel to are multipolar interneurons with short- the cortical surface. Lamina I is referred to as branched dendrites and a branching axon that the molecular layer because it mainly consists ascends toward the cortical surface, forming of neuronal processes and contains relatively synapses with other cortical neurons. The hori- few cell bodies. Except for the pyramidal and zontal cell (of Cajal) is a small neuron of the the stellate pyramidal cells, all cortical cells are most superficial cortical lamina that is absent intracortical interneurons.

Figure 25.2: (A) Modular organization of the neocortex as formed by the afferent inputs from specific thalamic nuclei, commissural and association fibers. Note (1) the vertical cylindrical distribution of the axons of the intrinsic neocortical interneurons and (2) that all neurons and fibers illustrated have putative excitatory synaptic connections with the pyramidal neurons. (B) Cortical interneurons that have putative inhibitory synaptic connections that inhibit the pyramidal neurons; the cells illustrated are varieties of aspiny Golgi type II neurons. Different interneurons inhibit various segments of the pyramidal neurons; the inhibitory axoaxonic synapses of the axoaxonic cells just distal to the axon hillock of the pyramidal cell can act as the final processing mechanism regulating the discharge of the pyramidal neuron (Dendrite–Cell Body Unit, Chap. 3). The processing also includes the disinhibition of interneurons by inhibitory synapses from other interneurons (not illustrated). Fibers from the pyramidal neurons of (1) lamina VI project to the thalamus, (2) those of lamina V project to thalamic association nuclei and other subcortical structures (e.g., striatum, brainstem, and spinal cord), and (3) those of laminae II and III project to other areas of the cerebral cortex. DBC, double bouquet cell; MgC, microgliaform cell; MC, Martinotti cell; PC, pyramidal cell; SS, stellate cell. (Adapted from Szentagothai, 1978. Chapter 25 Cerebral Cortex 443

The input to the columns of the neocortex is Functionally defined areas of the neocortex derived primarily from other cortical areas comprise the (1) sensory areas, including pri- (largest), thalamus, substantia innominata, mary sensory areas, secondary sensory areas locus ceruleus, brainstem raphe nuclei, and and association areas, (2) motor areas, includ- basal nucleus of Meynert; there are other ing primary motor area, premotor areas, and sources of corticopetal fibers. In general, fibers supplementary motor area, and (3) “psychical” from the thalamic relay nuclei terminate in a and prefrontal areas. rich arborization within lamina IV, fibers from nonspecific nuclei terminate mainly in layers I, V, and VI, and afferents from other cortical MOTOR AREAS OF THE NEOCORTEX areas terminate primarily in layers II and III. The axon collaterals of the pyramidal cells and Primary Motor Cortex the axons of many interneurons are oriented vertically. The lateral spread of the axons and The primary motor cortex is located in area dendrites is minimal. These neurons are inter- 4 of the precentral gyrus (see Fig. 25.3). Direct connected into numerous chains of small and electric stimulation of this region evokes move- long loops. The locus ceruleus and, possibly, ments of the voluntary muscles on the opposite the raphe nuclei are excited by novel stimuli in side. A map of this electrically excitable motor the environment; each adrenergic fiber from the cortex produces a motor homunculus. Figure locus ceruleus arborizes widely in the output 25.4 depicts both the motor and sensory cortical laminae V and VI, whereas each sero- homunculi. The homunculus is upside down, tonergic fiber from the raphe nuclei arborizes with the head region near the lateral fissure and widely in the input cortical laminae I to IV. The the lower extremity on the medial surface in the result is that the diffuse projections from these paracentral lobule. The amount of motor cortex nuclei have global effects upon both the limbic devoted to specific body regions is roughly pro- system and cerebral cortex (see Prefrontal portional to the delicacy of control and inner- Cortex). vation density of that region (e.g., large areas for fingers, thumb, lips, and tongue). Ablation Functional Aspects of this cortex results in marked contralateral The cerebral cortex has been subdivided into paresis, flaccidity, hyperactive deep tendon areas described in terms of several structural reflexes, and positive Babinski reflex and is and functional criteria. The functions of the followed by moderate motor recovery. (Note cortex are inferred from subjective accounts similarities to and differences from upper- and objectively observed responses of subjects motoneuron paralysis; Chap. 12.) (1) who have had areas of cortex damaged by lesions or surgical ablation, (2) in whom corti- Premotor Cortex and Supplementary cal sites were stimulated electrically, and (3) Motor Area (see Figs. 25.3 and 25.4) who have irritative lesions resulting in epileptic The premotor cortex consists of areas 6 and seizures. Evidence based on ablation generally 8. The supplementary motor area is in area 6 on reveals how the nervous system functions with- the medial aspect of the frontal lobe. Stimula- out the ablated part, but does not necessarily tion of this supplemental area elicits responses reveal more than the general role of the part. An that are largely bilateral synergistic movements enormous amount of information concerning of a tonic or postural nature, affecting primarily the function of different areas of the cortex has the axial muscles and proximal muscles of the been generated in recent years using imaging extremities. The responsive area outlines a techniques such as positron-emission tomogra- small homunculus with its head located ros- phy (PET) and functional magnetic resonance trally. Stimulation of area 6 on the lateral cere- imaging (MRI). bral surface produces aversive movements; 444 The Human Nervous System

Figure 25.3: The location of several functional areas of the cerebral cortex. The representation of body parts of the primary motor and somatic sensory (somatosensory) cortices includes the head (H), upper extremity (UE), trunk (T), and lower extremity (LE). Numbers represent areas of Brodmann. these “orientation” movements are generalized by lesions of both the primary motor cortex and actions, such as turning of the head and eyes, supplementary cortex, but not of either sepa- twisting movements of the trunk, and general rately. This suggests that the symptoms of flexion or extension of the limbs. Bilateral UMN paralysis are probably the result of inter- ablation of the supplementary motor area in the ruption of fibers from the primary motor monkey results in hypertonus of flexor muscles cortex, supplementary motor cortex, and pre- and increased resistance to passive movements motor cortex as they pass through the internal in the limbs, but it does not cause paresis. capsule. Note that the symptoms of an upper- The primary motor cortex participates in the motoneuron (UMN) paralysis can be produced initiation of skilled, delicate, and agile volun- Chapter 25 Cerebral Cortex 445 tary movements. Although the primary motor gramming of patterns and sequences of move- cortex has a critical role in the control of the ments. For example, electrical stimulation of distal limb muscles on the contralateral side of this area activates complex patterns of move- the body, it also contributes to the regulation of ments not only of the contralateral limbs but of axial and proximal limb musculature. The pre- the ipsilateral limbs as well. The premotor cor- motor cortex on the lateral surface of the tex and the supplementary motor cortex project frontal lobe has (1) a primary role in the control some fibers to the primary motor cortex. of proximal limb and axial musculature and (2) Two additional coextensive motor and an essential role in the initial phases of orienta- somatic sensory areas are present. In both, tion movements of the body and upper limb direct stimulation produces a somatotopic directed toward a target (tennis player’s adjust- arrangement of motor responses as well as ments prior to the stroke). The supplementary somatic sensations. These are the second motor motor cortex has a significant role in the pro- area and secondary somatic sensory area

Figure 25.4: The multiple homunculi in the cortex include those in the primary somatic sensory cortex (SI), primary motor cortex, supplementary motor cortex, and combined secondary somatic sensory cortex (SII) and second motor area. 446 The Human Nervous System located at the base of the precentral and post- into 3a (located within the posterior bank of the central gyri (see Fig. 25.3). All four of the central sulcus in continuity with area 4 on the motor areas contribute fibers to the descending anterior bank) and 3b. This region receives motor pathways, including the pyramidal tract. input from the ventral posterior nucleus of the Stimulation of area 8 results in conjugate thalamus, which conveys influences mostly saccadic movements of the eyes to the opposite from the opposite side of the head and body. side. This frontal eye field mediates voluntary The projection to this area can be represented eye movements (called eye movements on com- somatotopically as an upside-down sensory mand; Chap. 19). homunculus, with the head located ventrally near the lateral sulcus and the lower extremity Motivation and Control of Movement in the paracentral gyrus (see Fig. 25.4). It is In a broad context, the initiation and regula- clear from Fig. 25.4 that the greatest represen- tion of volitional movements involves (1) tation is given to input from the face, tongue, motivation and (2) control. Although how and lips, and hand, especially the thumb and index where movements are initiated is, as yet, finger. unknown, it is probable that those related to The cortical map of areas 3, 1, and 2 (post- motivation are generated within the limbic sys- central gyrus) comprises detailed somatotopi- tem and that control is in the province of the cally organized modality-specific columns that basal ganglia. Following this concept, the represent various submodalities. Area 3a drive and behavioral states expressed as moti- receives information from muscle spindle vation activate the neural circuits involved afferents and is closely related to the adjacent with the actual control of motor activity (Chap. motor cortex. Somatosensory cortex is hierar- 24). The processing centers where the linkage chically organized. Area 3b gets input from between the limbic system and the striatal sys- both rapidly and slowly adapting cutaneous tem is thought to occur is in the basal fore- receptors important for determining features brain, probably the ventral striatum (nucleus such as size, shape, and texture and distributes accumbens) and ventral pallidum. These com- this information to areas 1 and 2 for further ponents of the basal ganglia through their con- processing. Thus, area 1 receives input from nections with the amygdala, hippocampus, area 3 as well as from rapidly adapting cuta- ventral anterior, and dorsomedial thalamic neous receptors, and it mediates perception of nuclei have ties with the limbic system (Chap. textures. The input to area 2 is from area 3 and 22). Functionally, a distinction between moti- deep pressure receptors; it serves to differenti- vation and control is expressed in patients with ate the size and shape of objects and position of abnormal movement disorders (e.g., choreas joints. In essence, each of these areas has a and Parkinson’s disease). In these individuals, complete sensory homunculus, reflecting dif- motivation is intact and intense, but execution ferent response properties. The postcentral is faulty. gyrus also is associated with the characterization of pain and temperature, but these modalities have only a slight representation here. SENSORY AREAS OF THE Following unilateral lesions to the primary NEOCORTEX somatic sensory cortex, sensations of touch, position sense, and pressure are impaired on General Somesthetic Cortex the contralateral side of the body, but pain and The primary somatic sensory (somatosen- temperature, except for their localization, are, sory) cortex (SI) includes the postcentral gyrus at most, minimally affected. and its medial extension in the paracentral The secondary somatic sensory area (SII) is gyrus (areas 3, 1, and 2 of the parietal lobe) located on the superior bank of the lateral fis- (see Figs. 25.3 and 25.5). Area 3 is subdivided sure below the primary motor and sensory Chapter 25 Cerebral Cortex 447

Figure 25.5: Lateral surface of the human cerebral cortex with numbers indicating the areas of Brodmann. areas. SII is topographically organized with shape, and roughness by touch on the con- respect to such general sensory modalities as tralateral side of the body. touch, position sense, pressure, and pain. This area receives input from SI as well as bilateral Gustatory and Vestibular Cortices inputs from the ascending pathways. Taste is represented in area 43, located just Further neural processing of the multisen- above the lateral fissure. Two areas are associ- sory somesthetic input takes place before being ated with the vestibular system—one located integrated into the levels where perception of adjacent to the face area of SI and the other on shape, size, and texture and the identification of the superior temporal gyrus adjacent to the pri- objects by contact occur (e.g., stereognosis— mary auditory cortex. The feelings of dizziness recognition of an object, such as a key or fork, and rotation occur during direct electrical stim- after handling it). This is accomplished in the ulation of these areas. association areas of the superior parietal lobule (sensory areas 5 and 7) and in the supramar- Visual Cortex ginal gyrus (area 40). These areas have well- The primary visual cortex (area 17), also developed reciprocal connections with the known as visual area I, is the striate area of the pulvinar of the thalamus. Lesions in area 40 occipital lobe (see Figs. 25.5 and 25.6). It can result in tactile agnosia (see below). Func- occupies both banks of the calcarine sulcus and tional activity of this area is essential for the is the cortical terminus of the optic radiations perception of the general senses. Areas 5, 7, from the lateral geniculate body of the thala- and 40 of the parietal lobe comprise the mus (Chap. 19). The two principal roles of the somatosensory association cortex. striate cortex are (1) to perform the act of Electrical stimulation of SI can evoke pares- fusion of the inputs from both eyes into one thesias (numbness and tingling) and pressure image for binocular vision and (2) to analyze sense from the corresponding part of the body. the visual world with respect to the orientation A lesion of SI results in deficits in position of stimuli in the visual fields. Simple and com- sense and in the ability to discriminate size, plex cells are localized within the striate cortex; 448 The Human Nervous System

Figure 25.6: Medial surface of the human cerebral cortex with numbers indicating the areas of Brodmann. they detect straight lines, each having a specific different areas are important for perception of orientation and position in the retina. The different kinds of visual information. visuotopically organized striate cortex contains Through corticotectal fibers, the so-called ocular dominance columns and orientation occipital eye field of areas 18 and 19 mediate preference columns (Chap. 19). slow pursuit and vergence eye movements The extrastriate association cortex includes (Chap. 19). Electrical stimulation of the former visual area II (area 18), visual area III (area 19), results in a conjugate eye movement to the angular gyrus (area 39), and inferotemporal opposite side. cortex (areas 20 and 21) (see Figs. 25.5 and The inferotemporal cortex of the tectal sys- 25.6). Actually, almost 40 separate visual areas tem (Chap. 19) has a role in higher visual func- have been identified. Complex and hypercom- tions. It reacts to such stimulus features as size, plex cells are found within visual areas II and shape, contrast, and color. Monkeys with infer- III (Chap. 19). Complex cells respond opti- otemporal cortical lesions demonstrate a deficit mally to linear environmental stimuli, whereas in the performance of some visual discrimina- hypercomplex cells respond optimally to cur- tion tasks. vatures or angular changes in the direction of a line. Lesions in area 39 of the dominant hemi- Auditory Cortex sphere can result in patients being unable to The primary auditory cortex (area 41) is comprehend the symbols of language and located in the temporal lobe in the transverse express themselves through them. This area is gyri of Heschl on the floor of the lateral fissure essential to the comprehension of a visual (see Fig. 25.3). It is the cortical terminus of the image. These association areas are integrated auditory radiations from the medial geniculate with the “psychical cortex” (see below) and the body (Chap. 16). Neurons in this area respond thalamus (pulvinar) through reciprocal connec- to broad bands of the audible spectrum; it is tions. As yet, the manner in which visual tonotopically organized. The primary cortex is images are perceived is unknown, but clearly essential for the detection of changes in pattern Chapter 25 Cerebral Cortex 449 and in the location of the source of a sound. et al., 1992). A competitive balance is continu- Auditory area II (area 42) has a higher thresh- ally taking place within and between cortical old to sound intensity than the primary cortex. columns in which changing cortical inputs are There are at least five auditory cortical areas in associated with collateral sprouting and the the temporal lobe, including area 22 of the loss, additions, rearrangement, and alterations superior temporal gyrus. Patients with lesions of synaptic connections. of area 22 on the dominant side have profound Plasticity, at the cortical level, can, in part, difficulty in the interpretation of sounds; the explain the increased functional capability of spoken language might be meaningless or the feet and toes in performing complex motor extremely difficult for them to comprehend. acts in cases where the arms fail to develop, or the enhanced acuity in one sensory system Plasticity in the Structure of when another is rendered dysfunctional. It is Cortical Columns functionally significant that brain damage at an A basic question in neurobiology concerns early age is less deleterious than similar lesions whether synaptic connections in the adult nerv- in adulthood. ous system are static or dynamic. There is direct evidence that neural connections are dynamic in response to functional circum- HIGHER CORTICAL stances. It has been amply demonstrated that ASSOCIATION AREAS the organization of the neocortex in perinatal Language Circuitry animals is determined in part by its input from peripheral receptors. For example, Woolsey A Conceptual Model for Language and and his collaborators showed that removal of a Speech. The cortical areas associated with lan- mystacial vibrissa (whisker) from a neonatal guage are conceived as being organized follow- rodent prevents development of a cortical struc- ing a model proposed by Geschwind, which ture referred to as a barrel in a specific location. elaborated on circuitry diagramed in 1874 by A barrel is a circular aggregation of neurons in Wernicke (see Fig. 25.7). According to this lamina IV that forms part of a column repre- scheme, neural channels originating in the sen- senting a particular receptive field. Similarly, sory association areas (visual, somatic sensory, evidence indicates that the structural organiza- and auditory) coalesce at Wernicke’s area (pos- tion of adult primate neocortex exhibits terior language area) located in the posterior changes in response to alterations in its input. portion of area 22, which occupies parts of the Merzenich has shown electrophysiologically superior and middle temporal gyri. Some that the cortical receptive field of adjacent fin- authors also include the supramarginal (area gers, which is spatially completely separated 40) and angular gyri (area 39). This entire under normal circumstances, in time becomes region is part of the parieto–temporal–occipital overlapping after the two fingers are surgically association cortex. Area 22 is critical for the joined together (syndactyly). If the fingers are processing of the basic elements for the pro- subsequently separated, the cortical representa- duction of language. Representations visual- tion ultimately reverts to the original discontinu- ized as words or images are conveyed from the ous condition. Merzenich also has demonstrated visual cortex (occipital lobe) to the angular in monkeys that the cortical representation of a gyrus (area 39). Constructs of form, size, and single digit expands with repeated use of that body image are projected from the somatosen- finger. Evidence from human amputees sug- sory cortex (parietal lobe) to the supramarginal gests an even more extensive cortical reorgani- gyrus (area 40). Auditory information of zation in which the area representing the face sounds and words is thought to be conveyed expands to include the adjacent area that had from the auditory cortex (temporal lobe) to the represented the missing limb (Ramachandran angular gyrus (area 39). Information then is 450 The Human Nervous System

Figure 25.7: Probable sequence of neural transmission within the neocortex that occurs from the perception of an object within the visual areas to the formulation of the spoken language (i.e., naming an object seen). The presumed sequence comprises (1) the visual cortex (areas 17, 18, and 19) to (2) the angular gyrus (area 39) to (3) Wernicke’s area (area 22) via (4) the arcuate fasciculus to (5) Broca’s speech areas 43 and 44, and, finally, (6) to the motor area 4, where the descending motor pathways involved with vocalization originate. conducted to area 22. In essence, sensory sys- about 95% of individuals (left hemisphere tems converge on Wernicke’s area for further dominance) and the remaining 5% have either processing. a right hemisphere dominance or a mixed right The words to be spoken originate and are and left dominance (see later. generated in Wernicke’s area and then transmitted via the arcuate fasciculus to Broca’s Aphasias (see Fig. 25.7) speech area (anterior language area; areas 44 Aphasia, or the disruption of language or and 45 of the inferior frontal gyrus). Within speech, can occur following a stroke involving Broca’s area, a detailed coordinated program the cortex of the left (major) hemisphere. Lan- for vocalization is formulated and activated for guage is the body of words and systems and controlling articulation through the sequencing their combinations used and understood by of the musculature of the vocal cords, pharynx, groups of people, whereas speech refers to tongue, and lips. This information is then trans- facility in the formulation of language. There mitted to the motor areas (areas 4 and 6), where are several forms of aphasias. the appropriate motor pathways are activated Wernicke’s or receptive aphasia results from for the production of the spoken language. Key a lesion of Wernicke’s area. Although hearing elements of this circuitry have been demon- and vision are normal, individuals with this strated with PET, which also shows that the disability show an essentially total failure to scheme is oversimplified (see Fig. 25.8). With comprehend either spoken and/or written lan- regard to language and speech, the left hemi- guage. Speech of such patients has the correct sphere of the brain assumes the critical role in rhythms and normal nuances of articulation, Chapter 25 Cerebral Cortex 451 but conversations are devoid of content and full might lose the ability to read (called alexia) or of nonsense words. Their speech is fluent but to write (agraphia) even though they can meaningless. Afflicted subjects seem unaware understand the spoken language and can speak. that their speech is meaningless. Thus, Wer- These lesions interfere with the transfer of nicke’s area has an important role in the mech- information from the visual (occipital lobe) and anisms of language, including reading, writing, general somatic sensory (parietal lobe) cortices and the production and comprehension of the to Wernicke’s area. spoken word. Global or total aphasia is associated with Conduction aphasia results from lesions in widespread damage of the cortex on either side the lower parietal lobe that damage the fibers of of the lateral (Sylvian) sulcus, damaging Wer- the arcuate fasciculus that connect Wernicke’s nicke’s and Broca’s areas and the arcuate fasci- area to Broca’s area. In individuals with this culus. Such patients are unable to speak or disconnection syndrome, speech is fluent but comprehend language. In addition, they have a quite meaningless. They show a poor ability to severe impairment of language-related func- repeat phrases and spoken language. tions in that they cannot read, write, or name an Anomia aphasia occurs following a lesion of object. the posterior portion of the left superior tempo- When Broca’s area on the left side is dam- ral gyrus near the angular gyrus. Patients aged by a stroke, Broca’s aphasia (expressive demonstrate an inability to think of a specific aphasia) can result. It is primarily a failure in word or the name of a person or an object. In a the formulation of speech, which is labored, lesion limited to the angular gyrus, patients slow, and poorly articulated. Patients have great

Figure 25.8: Positron-emission tomographs show areas with increased blood flow elicited by language-related activities. Note the relationships between these areas and those illustrated in Fig- ure 25.7, including Wernicke’s area. (Courtesy of Dr. Steve Petersen and Dr. Marcus Raichle, Washington University.) 452 The Human Nervous System difficulty expressing themselves. They are fully coordination and the sensory pathways are aware of the disability. The muscles involved functioning normally. Lesions in various corti- with speech are not paralyzed, demonstrated by cal areas (supramarginal gyrus, other regions of the fact that they function normally in other the parietal and occipital lobes, premotor cor- tasks such as chewing, swallowing, and laugh- tex, and Broca’s speech areas 44 and 45), the ing. Many patients can often sing a formerly association fibers interconnecting many of known song rapidly, correctly, and even with these cortical areas, and in the corpus callosum feeling. In responding to a question, a patient can result in several types of apraxia. Among gives a comprehensible answer, but it is these are (1) an inability to perform skilled expressed with difficulty and with the omission learned movements, ranging from the clumsy of small words (“a” and “the”) and endings. It execution of writing and drawing to agraphia, might be delivered in a disjointed style. The a condition in which the subject cannot write, comprehension of written matter and the ability (2) an inability to carry out a sequence of com- to write are unimpaired. plex motor acts (often called transmissive apraxia) (e.g., subjects who are able to brush Agnosias their teeth, comb their hair, wash their fac,e and Agnosia (Greek, lack of knowledge) refers tie their shoes automatically, are unable, upon to an inability to recognize or to be aware of an command, to perform the same tasks in a spec- object when using a given sense (sight) even ified sequence [lesion in the supramarginal though this sense is essentially functionally gyrus]), and (3) the loss of articulate speech intact. (sometimes called oral aphasia) with other- Tactile agnosia (astereognosis), the inability wise normal musculature of the tongue, lips, to recognize familiar objects through the senses larynx, and palate. Subjects have use of only a of touch and proprioception, can result from few words in conversation and mispronounce lesions of the supramarginal gyrus (area 40) of common words or repeat them over and over the major hemisphere. Patients with tactile again (lesion in Broca’s areas 44 and 45 and in agnosia might have a disturbance of the body other regions). image; for example, they might not recognize their individual fingers and might confuse the Prefrontal Cortex left from the right side of the body. The prefrontal cortex (areas 9 through 12) Visual agnosia, the inability to recognize and its rich reciprocal connections with the objects by sight, can result from a lesion in dorsomedial nucleus of the thalamus, hypothal- areas 18 and 19 of the major hemisphere. These amus, and limbic system are well developed in individuals are able to characterize the objects man. The prefrontal lobe has been conceived as by the use of other senses such as touch. being a regulator of the depth of feeling of an Auditory agnosia, the inability of an individ- individual. It is not involved in the perception ual with unimpaired hearing to recognize of sensations, but, rather, in the “affect” associ- familiar sounds, music, and words, results from ated with sensations. The complex responses of bilateral lesions in the posterior parts of the an individual, from calmness to ecstasy, from superior temporal gyrus (area 22). Such gloom to elation, from friendliness to disagree- patients have reasonable ability to comprehend ableness, have their roots in areas 9 to 12. the spoken language and show good reading The bilateral ablation of areas of the pre- ability. frontal cortex or interruption of the subcortical white matter (prefrontal lobotomy, leukotomy) Apraxia can produce subjects who are less excitable, Apraxia is the inability to perform certain but also less creative. Relief from anxiety is skilled and complex movements, even though accompanied by a change in the patient’s out- there is no paralysis or disturbance in motor look and disposition. Drive, not intelligence as Chapter 25 Cerebral Cortex 453 measured by IQ tests, is altered. Goal-directed ging qualities, and signals that normal activity activity and planning for the future are dis- should be curtailed and attention should be turbed and generally neglected. The ability to paid to the pain. The “fast” system is relatively remember information such as a sequence of “free of emotional content,” whereas the slow numbers for a short period (“working mem- system contributes to the emotional quality of ory”) is impaired, particularly when lesions the insult. Both the limbic system and the pre- involve dorsolateral parts of the frontal lobes. frontal lobes contribute to the emotional col- The landmark case of Phineas Gage exempli- oration of the pain. fies the above. Gage was a foreman working on Relief from intractable pain can be obtained a project to lay track for the Rutland and following prefrontal lobotomy. Although the Burlington Railroad in Vermont, when, in pain persists, the patient is unconcerned 1848, a tamping iron was blown through his because the psychic feeling associated with its head, producing a prefrontal lobotomy. Only intensity is lost. Data show that the prefrontal transiently stunned, he survived for some 12 cortex is the neocortical representative of the years. Although his brain was not recovered, limbic system. the skull was preserved and recent reconstruc- tions with neuroimaging techniques have con- firmed that the prefrontal areas were damaged BLOOD FLOW IN THE CORTEX bilaterally, particularly medial and ventral parts; other parts of the frontal lobes (i.e., The mean blood flow in the brain of normal Broca’s area and areas 6 and 4) were spared. individuals is 50 mL per 100 g of tissue per His personality changes were so profound that minute. However, at any given moment, the friends said “Gage was no longer Gage.” blood flow through a specific region might be Whereas he was physically as before and greater or less than the mean, as illustrated in showed no apparent changes in memory, learn- Fig. 25.8. The brain is similar to other body tis- ing, or intellect, he became profane and irre- sues in that the blood flow varies with the level sponsible to the point of being unable to hold of metabolism and functional activity within down a job. the tissue. An increase in blood flow takes There is support for the view that some of the place, for example, in the primary and associa- expressions are, at least in part, associated with tion auditory cortices (areas 41 and 42) in both interactions between the locus ceruleus, pre- hemispheres and in Wernicke’s areas in the left frontal lobe, and limbic system. The locus hemisphere during a conversation. Dynamic ceruleus, with adrenergic projections, imposes movements of the hand evoke blood flow excitatory influences on both the prefrontal cor- increases in several cortical areas involved with tex and the limbic system. In turn, the prefrontal hand movements and with sensory signals in cortex, through its inhibitory influences, modu- the skin, joints, and muscles associated with lates the activity of the limbic system. Thus, fol- the movements. Blood flow increases occur in lowing prefrontal lobotomy, the limbic system, the contralateral “hand” region of the motor now partially released from some prefrontal cortex (area 4) and postcentral gyrus constraints, has freer rein for expression. (somatosensory cortex) and of both ipsilateral The perception of pain includes both the and contralateral premotor and supplementary sensation of pain and the emotional reaction to motor cortices (areas 6 and 8). The motor and it. The neospinothalamic or fast pain pathway, sensory activities involved with the acts of involving the somatosensory cortex, is the reading aloud and listening result in an increase warning system informing the individual of the of blood flow in both the ipsilateral and con- presence, extent, and location of an injury caus- tralateral auditory cortices, motor and ing the pain. The paleospinothalamic or slow somatosensory cortices (“face” and “mouth” pain pathway involves the unpleasant and nag- areas), premotor and supplementary motor cor- 454 The Human Nervous System tices, Broca’s speech area, frontal eye fields learned information and of learned motor activ- (area 8), and visual association cortices of both ities are apparently confined to the hemisphere sides. to which the sensory information was relayed and from which the motor output was projected. If the corpus callosum is intact, this SPLIT-BRAIN MAN AND CEREBRAL memory is utilized for motor expression by DOMINANCE both hemispheres. Apparently, the engram,or memory trace, laid down in the directly trained The presence in the cerebrum of the corpus hemisphere is transferred via the callosal fibers callosum, with its 300 million fibers in humans, to the opposite hemisphere, and a second and of the anterior commissure suggests that engram is created in the contralateral hemi- interhemispheric commissural fiber pathways sphere. are of crucial functional significance. Most of In common usage, dominance as applied to the callosal fibers interconnect with mirror- a hemisphere is imprecise, as each hemisphere image sites of both hemispheres. In addition, is dominant for certain functions (see Fig. many fibers terminate in cortical areas different 25.9). For example, the left hemisphere is dom- from the areas of origin (e.g., area 17 of one inant for language and the right hemisphereis hemisphere projects to areas 18 and 19 of the dominant for spatial construction (stereogno- other). Several areas do not receive callosal sis). Neither hemisphere should be regarded as fibers; these include the hand and foot areas of subordinate overall. The “dominant” hemi- the primary motor cortex (area 4), second sphere is also called the major hemisphere and motor area, somatosensory cortex (SI and SII), the “nondominant” hemisphereis also called and primary visual cortex (area 17). The com- the minor hemisphere. In most individuals, the missural fibers to and from the temporal cortex, major hemisphere is the left hemisphere and particularly the middle and inferior temporal the minor hemisphere is the right hemisphere. gyri, pass through the anterior commissure (see In human beings, speech and the language Fig. 1.7). In essence, the cortices of the two symbolisms of the written and spoken word are hemispheres are in continuous communication lateralized in the major hemisphere. Both the with each other through the fibers of the corpus major (or “talking”) hemisphere and the minor callosum and anterior commissure. (“mute”) hemisphere can comprehend, but nor- Yet, when the corpus callosum is completely mally only the major hemisphere “talks”. Lin- transected, no functional alterations can be guistic expression resides exclusively within detected by the usual neurologic and psycho- the major hemisphere, whereas the comprehen- logic examinations. Complex activities, such as sion of both the written and spoken language is playing musical instruments and writing, are represented in both hemispheres. performed with the same dexterity as before The minor hemisphere can perceive tactile, surgery. auditory, and visual information, but is unable An experimental animal or human being to communicate through verbal language. with the corpus callosum and other commis- However, it can respond and communicate by sures (anterior and hippocampal commissures) gestures (e.g., pointing) or emotional activity transected has, in a way, two brains; the term (e.g., fidgeting or blushing). The minor hemi- twin brain or split brain applies. They behave sphere is specialized to appreciate spatial normally, are alert and curious, perceive, learn, dimensions, to grasp the totality of a scene, and and retain learned activities. to recognize the faces of people better than the Studies of split-brain monkeys and human major hemisphere. This mute hemisphere is beings have been conducted whereby the input presumed to have an essential role in creative from the periphery is projected to only one acts associated with musical, poetic, and imag- hemisphere. The memories of perceptually inative expressions. Chapter 25 Cerebral Cortex 455

Human split-brain subjects exhibit some of the corpus callosum or of cortical associa- interesting and curious disturbances of higher tion areas giving rise to commissural fibers, brain function. When these result from lesions they are known as disconnection syndromes.

Figure 25.9: Some of the roles of the major and minor cerebral hemispheres as established in “twin-brain” humans. General senses from one hand and from half of the visual field are projected to the contralateral hemisphere. The olfactory sense is conveyed to the ipsilateral hemisphere. Hear- ing is largely projected to the contralateral hemisphere. (Adapted from Sperry, 1985.) 456 The Human Nervous System

The ultimate expression of the general sensory speech functions are lateralized to the left information conveyed from the right hand to hemisphere in most adults regardless of hand the left or major hemisphere can differ dramat- preference. Roughly 80% of adults are right- ically from that which is conveyed from the left handed, 10% are left-handed, and 10% are hand to the right or minor hemisphere. The ambidextrous. In right-handers, the left cortical right hand might be “unaware” of what the left motor areas control the right hand, whereas in hand is doing; for example, the right hand left-handers, the right cortical motor areas con- might be buttoning a shirt while the left hand is trol the left hand. About 90% of right-handers unbuttoning it. The subject can name an object have speech centers in the left hemisphere, and held in the right hand, but cannot name an the other 10% have speech centers in the right object held in the left hand; the act of naming hemisphere. About 65% of left-handers also is a function of the major hemisphere. These have speech centers in the left hemisphere, patients can perform certain tasks better with 20% in the right hemisphere, and the remaining the left hand than with the right hand. This 15% have speech centers located bilaterally. indicates that the minor hemisphere does have Naturally ambidextrous subjects have their some superior roles over the major hemisphere. speech centers located as follows: 60% in the For example, better performances are executed left hemisphere, 10% in the right hemisphere, by the left hand than by the right hand in tasks and 30% in both hemispheres. involving spatial relations such as arranging In general, injuries of the brain in infants blocks, drawing simple three-dimensional and children are often accompanied by less objects (cubes), and matching up designs. severe neurological impairment and greater Several basic conclusions concerning the recovery of function (expression of more plas- roles of the cerebral hemispheres obtained from ticity) than similar injuries in the adult. This studies of “twin-brain” subjects (see Fig. 25.9) “infant lesion effect” is dramatically demon- are that (1) perception and memory can be per- strated following unilateral damage to the cere- formed independently in both hemispheres, (2) brum. In a child, after extensive cerebral language and speech are almost exclusively the damage as a consequence of a cerebral infarc- roles of the major hemisphere, (3) the minor tion or hemispherectomy for relief from hemisphere is superior to the major hemisphere intractable seizures, there is marked compensa- in the recognition and appreciation of spatial tory recovery of functional deficiencies. The dimensions, (4) the primary role of the cerebral intact hemisphere can assume the ability to per- commissures is in the bilateral integration of the form many of the impaired skilled movements two hemispheres for linguistic functions, (5) it and language functions. is through the major hemisphere that humans can express thoughts and knowledge through language, and (6) the commissures are essential MEMORY for maintaining the unity of the higher sensory and motor functions of the cerebrum. The fol- Learning and memory are expressions of lowing is a rather simplistic summary of the neuronal processing. Learning is the means by roles of the two hemispheres. The left (major) which we realize new knowledge and percep- hemisphere can be considered to be the analyti- tions about events and experience. Memory is cal, rational, and verbal half of the cerebrum. It characterized as the consequence of the acqui- is analytic, as used in language recognition. The sition, storage, and recall of previously learned right (minor) hemisphere is the synthetic, intu- experiences. itive, and nonverbal half. It is nonanalytical and A general framework of neuronal circuitry used in perceptive recognition. of both parallel and hierarchical components The lateralization of Broca’s speech area is relevant to memory in the primates, including not causally related to handedness. Actually, humans, was proposed by Mishkin and Appen- Chapter 25 Cerebral Cortex 457 zeller (1987). The presence and presumed roles channels from the parietal lobe cortex (cross- of different parts are based on studies of neuro- modality interactions). Other cortical pathways logic patients with impaired memories and of conveying information from the auditory, primates with selectively placed lesions (Squire somatosensory, and gustatory association areas and Zola-Morgan, 1988, and others). In converge in the anterior temporal neocortex. essence, the sequence of feed-forward process- Neurons in anterior temporal lobe neocortex ing connections and their functional correlates are responsive to a wide variety of features of in the cerebral cortical and subcortical circuits the visual, auditory, tactile, and taste spheres. leading to memory (1) commences with sen- They integrate these diverse inputs from the sory association cortical areas, (2) proceeds world, which bombard the individual. Confir- through channels converging to the neocortex matory evidence has been obtained from elec- of each anterior temporal lobe, (3) continues to trical stimulation of this cortex in conscious the parahippocampal cortex and its projections patients that can evoke associations relative to to the amygdala and hippocampus, (4) pro- “experiences” (Thompson and Krupa, 1994). It ceeds via their diffusely distributed circuits can also elicit the recall of objects seen, music including the basal forebrain area, and, finally, heard, or objects touched. Visual and auditory (5) completes the “circle” with projections hallucinations can be produced, such as a clear from the basal nucleus of Meynert to broad re-enactment of an experience of the recent or areas of the neocortex (see Fig. 25.10). distant past. The evoked experiences might be Neuronal channels comprise pathways from a symphonic melody that the subject thinks is the visual, auditory, and somatic sensory asso- being played on a phonograph or radio. The ciation areas (including angular gyrus, supra- patient with temporal lobe tumors might have marginal gyrus) that converge to the cortex of auditory or visual hallucinations and see vivid the anterior temporal lobe (see Fig. 25.10). scenes and friends not present and hear songs Each of these pathways consists of a number of not sung. The patient is cognizant of the converging and diverging processing channels hallucinations that are consistent with experi- and subsets of neuronal pools. Each subset is ences seen or heard in the past (deja vu). In a involved with a specific visual, auditory, or sense, a neuron or small group of neurons in somatic sensory feature or combination of fea- this area are “windows to our internal and tures. external worlds.” There are two pathways from primary visual From this temporal lobe, cortex channels cortex: (1) One pathway consists of processing project to the limbic lobe cortex on the medial sequences directed toward the temporal lobe. It aspect of the temporal lobe (parahippocampal is involved with the “broader context” of the gyrus and subiculum). Reciprocal circuits visual world. Its neurons respond to such envi- interconnect the medial temporal lobe cortex ronmental stimuli as shape and color basic to with two major processing structures, the “object vision.” A portion of the superior tem- amygdala and the hippocampus, which are part poral gyrus has a role in analyzing visual of the limbic system. The amygdala also motion related to the subjective perception of receives direct input from the olfactory system. movement during a visual task. (2) Another Bilateral removal of the medial portions of pathway directed toward the posterior temporal the temporal lobes, including the amygdala and lobe is involved with visual attention and the hippocampus result in severe memory deficits spatial relations of the object or the scene (even total amnesia), specifically with a loss of observed. The “spatial system” is associated capacity to consolidate or retain short-term with the perception of an object in context with (recent) memory. Thus, these patients lose the the other landmarks in the visual field, capacity to form and to store new long-term so-called object and pattern discrimination. memories; however, long-term memories This pathway is thought to interact with tactile acquired before surgery remain essentially 458 The Human Nervous System

Figure 25.10: Possible sequence of neural transmission that is involved with the formulation of memory. (A) Neocortical pathways converge from the sensory association areas via several neural circuits to the neocortex of the anterior temporal lobe. These circuits include the (I) “broader concept” visual pathway from the occipital lobe, (II) “spatial” visual pathways from the posterior parietal lobe, (III) somatosensory pathways from the parietal lobe, (IV) auditory pathways from the temporal lobe, and (V) the gustatory pathways from the superior temporal lobe cortex. These pathways converge to the anterior temporal lobe cortex (VI). (B) From the anterior temporal lobe cortex, information is conveyed (VI) to the subiculum and parahippocampal gyrus of the paleocortex (VII). From this paleocortex, circuits project to the amygdala (VIII) and hippocampus (IX), both of which project widely (Chap. 22) to the basal forebrain area, including the basal nucleus of Meyn- ert (X). In turn, projections from the basal area “complete” the overall circuitry via fibers from the basal nucleus of Meynert back to the neocortical sensory association areas somehow to fix a new memory or to elicit an old memory. “Working memory” (memory retrieved and temporarily held) is extracted from “long-term memory” that is consolidated, dispersed, and stored at multiple sites in the brain. Chapter 25 Cerebral Cortex 459 intact and can be recalled, often vividly, many sites (Chap. 22) and (2) reciprocally to the years later. As generally used, short-term mem- medial temporal lobe and, hence, via associa- ory comprises the information and awareness tion bundles to the neocortical association that one retains for only a short time-span. Uni- areas of the four lobes, especially the prefrontal lateral removal of the amygdala and hippocam- cortex. Evidence indicates that the hippocampus does not result in impairments of memory pus is implicated in memory mechanisms such (see Klüver-Bucy Syndrome, Chap. 22). as to make it possible for humans to compare This region of the temporal lobe has great the present circumstance with previously expe- importance in learning and memory functions. rienced events. Lesions of the fornix or of the The hippocampus is an essential component in mammillary bodies (formerly thought to result establishing memory. Amnesia ensues follow- in amnesia) results in a negligible and transient ing bilateral lesions of the hippocampus and loss of memory. surrounding cortical regions that spare the Some evidence suggests that the medial amygdala. These observations indicate that the thalamus, possibly the medial (dorsomedial) ablated structures are in some way involved thalamic nucleus, is also involved in the formu- with the consolidation of memory but not with lation of memory. Bilateral damage of the mid- its storage. line diencephalon can result in profound Bilateral ablation limited to the amygdala amnesia in humans and severe memory impair- (monkey) has no detectable effect on memory. ment in monkeys. In essence, the reciprocal The widespread connections that the amygdala neural linkages between the hippocampus and has with the neocortex and its strategic location the neocortex are envisioned as being involved as a major processing center suggest that the in the dynamics of memory. They are involved amygdala plays a role in the modulation of in the initial phase of learning (e.g., impression incoming sensory information. In addition, it of novel image, namely short-term memory). might be important in establishing associations Then, followed by a limited period, the image, to events and in correlating information from if retained, gradually becomes independent of different modalities. Thus, the amygdala might the hippocampus and goes into the long-term affect performance of memory tasks that memory domain. depend on these functions. Another view is that In general, the hippocampus seems to be both the amygdala and the hippocampus are more involved with registering cognitive infor- essential for recognition memory (recognizing mation than with emotion, whereas the amyg- an object such as a glass) and associative mem- dala has an essential role in the expression of ory (e.g., a glass can be associated with a glass emotion rather than with cognition. of water or milk, or a bark with the image of a Another link in the memory channels barking dog). The connections of the amygdala involves the substantia innominata and the with the limbic system, including the hypothal- basal nucleus of Meynert (Chap. 22; see Fig. amus, enables sensory events and perceptions 22.2). This region receives afferent input from to develop emotional associations and expres- the amygdala, insula, and parts of the parahip- sions (the latter through the autonomic nervous pocampal gyrus; it projects diffusely to such system). Thus, the amygdala can act as an centers as the amygdala, hippocampus, hypo- intermediary between the sensory systems and thalamus, and some brainstem nuclei. Impor- emotions. tantly, the basal nucleus contains cholinergic As to neural connections, the amygdala has neurons whose fibers are distributed widely to reciprocal circuits with the cerebral cortex, the entire neocortex in a quite orderly topo- striatum, hypothalamus, brainstem, thalamus, graphic manner and are regarded as a major and hippocampus. The hippocampus projects source of cortical acetylcholine. Its neurons its output via two major efferent circuits (1) via have excitatory synapses with muscarinic the fornix to the mammillary body and other receptors of cortical neurons. This nucleus is 460 The Human Nervous System thought of as acting as the final linkage (along expressed in the visual system, where several with the output of the hippocampus to many anatomically and physiologically documented areas of the neocortex) to close the loop that is modules, including cortical areas, are embed- involved with the processing and storage of ded within the system. Each module processes acquired information (the “stored memories in different dimensions of visual information such the neocortex”). One concept postulates that as color, depth perception, and motion (Chap. this link in the loop evokes changes in the neu- 19; Hubel, 1987). Higher degrees of processing rons and local circuits of the sensory areas that within functionally specific anatomic modules fix a perception so that it is stored in memory of the cerebral cortex involved with memory and, in addition, possibly releases previously have been demonstrated in the monkey (noted stored memories in the neocortex to our con- in this chapter; Mishkin and Apenzeller, 1987). scious self. Another complex of modules present in the Alzheimer’s disease (presenile dementia), as human brain are those involved with a variety well as senile dementia, which is the same of language processes. entity except for age of onset, is an affliction At higher levels, the human brain appears to with initial signs of forgetfulness leading to pro- have a modular organization consisting of iden- gressively more severe mental deterioration. tifiable components that participate in the gen- Patients exhibit a loss of memory and become eration of the cognitive state, including the confused and disoriented. They are incapable of appreciation of the surrounding world and past abstract thought. In advanced stages, they can- events, perception, reasoning, and the unitary not recognize even close friends and relatives. experience of conscious awareness (Gazzaniga, Diffuse cerebral atrophy, particularly involving 1989). the frontal and temporal lobes, is a constant attribute. Alzheimer’s disease is a degenerative Dynamic Maintenance of Cortical Areas disease with an established genetic predisposi- Cortical areas such as the V4 color area are tion characterized by having senile plaques and functionally distinct divisions that are precisely neurofibrillary tangles. These plaques are found localized. The circuitry of the neuronal organi- throughout the cerebral cortex and hippocam- zation within each area is (1) nurtured during pus. Each plaque is composed of enlarged development by “self-organization” and active degenerating cholinergic axonal endings sur- neural activity patterns generated by inputs and rounding a core composed mainly of extracellu- (2) maintained during adulthood by active lar amyloid. The filaments of the tangles are dynamic inputs (Kaas, 1987). Hence, cortical primarily 20-nm wide components of the tan- maps are shaped and sustained by neural gle. The symptoms might be the result, in part, activity. of the massive destruction of these neurons. The micro-organization (local circuitry) of Alzheimer patients have reduced neocortical the cortex is in a constant state of flux, depend- acetylcholine and its precursor enzyme, acetyl- ing on a variety of competitive inputs. Stability choline transferase. in a cortical area results from a balance of these inputs. Increased input from greater usage Modular Organization of the Brain tends to increase the amount of cortical space “An emerging view is that the brain is struc- dedicated to a specific modality, whereas turally and functionally organized into discrete decreased usage tends to decrease its cortical units or `modules’ and that these components representation (Chap. 6). It is clear that mental interact to produce mental activities” (Gaz- activity and physical exercise associated with zaniga, 1989). In a broad sense, the major sen- stimulation derived from sensory receptors and sory systems, such as the visual system, are the activation of reflexes and movements exert complexes of modular systems. In turn, each positive roles in sustaining and maintaining the system comprises several modules. This is integrity of cortical areas throughout life. Chapter 25 Cerebral Cortex 461

The preceding has provided merely a brief Douglas R, Keyan AC. Neuronal Circuits of the Neo- introduction to the vast topic of cognition, cortex. Ann. Rev. Neurosci. 2004;27:419–451. memory, and language about which a vast liter- Ferrari PF, Gallese V, Rizzolatti G, Fogassi L. Mir- ature exists. References are provided to guide ror neurons responding to the observation of readers interested in pursuing this subject, ingestive and communicative mouth actions in the monkey ventral premotor cortex. Eur. J. Neu- which has been moving rapidly since the rosci. 2003;17:1703–1714. advent and refinement of functional imaging Funnell MG, Corballis PM, Gazzaniga MS. Tempo- techniques. Intriguing new insights have ral discrimination in the split brain. Brain Cogn. evolved since the discovery of what are 2003;53:218–222. referred to as “mirror neurons.” Mirror neu- Gazzaniga MS, Ivry RB, Mangun G.R. Cognitive rons, first described in the monkey ventral pre- Neuroscience: The Biology of the Mind. New motor cortex, which is homologous to Broca’s York: Norton; 2002. area, “discharge both when the monkey grasps Gazzaniga MS. Organization of the human brain. or manipulates objects and when it observes the Science 1989;245:947–952. experimenter making similar actions” (Rizzo- Goldman-Rakic PS. The prefrontal landscape: lati and Arbib, 1998). It is thought that this implications of functional architecture for under- matching of codes for observation and execu- standing human mentation and the central execu- Phil. Trans. R. Soc. Lond. B: Biol. Sci. tion of movements was a crucial precondition tive. 1996; 351:1445–1453. for the development of language in that it Goldman-Rakic PS. The cortical dopamine system: enabled utterances to have the same meaning role in memory and cognition. Adv. Pharmacol. for both the speaker and listener. Future studies 1998;42:707–711. in this area should prove to be very exciting. Grezes J, Armony JL, Rowe J, Passingham RE. Activations related to “mirror” and “canonical” neurones in the human brain: an fMRI study. SUGGESTED READINGS Neuroimage 2003;18:928–937. Hamzei F, Rijntjes M, Dettmers C, Glauche V, Arbib MA. Language evolution: the mirror system Weiller C, Buchel C. The human action recog- hypothesis. In: The Handbook of Brain Theory nition system and its relationship to Broca’s and Neural Networks. 2nd ed. Arbib MA, ed. area: an fMRI study. Neuroimage 2003;19: Cambridge, MA: MIT Press; 2003:606–611. 637–644. Arbib MA, Billard A, Iacoboni M, Oztop E. Syn- Handy TC, Gazzaniga MS, Ivry RB. Cortical and thetic brain imaging: grasping, mirror neurons subcortical contributions to the representation of and imitation. Neural Netw. 2000;13:975–997. temporal information. Neuropsychologia 2003; Blake DT, Byl NN, Merzenich MM. Representation 41:1461–1473. of the hand in the cerebral cortex. Behav. Brain Harris JC. Social neuroscience, empathy, brain inte- Res. 2002;135:179–184. gration, and neurodevelopmental disorders. Borsook D, Becerra L, Fishman S, et al. Acute plas- Physiol. Behav. 2003;79:525–531. ticity in the human somatosensory cortex follow- Haxby JV, Petit L, Ungerleider LG, Courtney SM. ing amputation. Neuroreport 1998;9:1013–1017. Distinguishing the functional roles of multiple Brodmann K, Garey LJ. Brodmann’s Localisation in regions in distributed neural systems for visual the Cerebral Cortex. (Translated from 1909 pub- working memory. Neuroimage 2000;11:145–156. lication with editorial notes and introduction by Hubel DH. Eye, Brain, and Vision. New York: Scien- Laurence Garey.) London: Imperial College tific American Library; 1987. Press; 1999. Jenkins WM, Merzenich MM. Reorganization of Damasio AR, Damasio H. Brain and language. Sci. neocortical representations after brain injury: a Am. 1992;267:88–95. neurophysiological model of the bases of recovery Damasio H, Grabowski T, Frank R, Galaburda AM, from stroke. Prog. Brain Res. 1987;71: 249–266. Damasio AR. The return of Phineas Gage: clues Kaas JH. The organization of neocortex in mam- about the brain from the skull of a famous mals: implications for theories of brain function. patient. Science 1994;264:1102–1105. Annu. Rev. Psychol. 1987;38:129–151. 462 The Human Nervous System

Kelleher RJ, Crowdon JH. Alzheimer’s disease. In: Mishkin M, Appenzeller T. The anatomy of mem- Kelleher LH, et al., eds. Diseases of the Nervous ory. Sci. Am. 1987;256:80–89. System, Clinical Neuroscience and Therapeutic Nicolelis MA. Brain-machine interfaces to restore Principles. 3rd ed. New York: Cambridge Uni- motor function and probe neural circuits. Nature versity Press, 2002; 237–251. Rev. Neurosci. 2003;4:417–422. Keysers C, Kohler E, Umilta MA, Nanetti L, Oztop E, Arbib MA. Schema design and implemen- Fogassi L, Gallese V. Audiovisual mirror neurons tation of the grasp-related mirror neuron system. and action recognition. Exp. Brain Res. 2003; Biol. Cybern. 2002;87:116–140. 153:628–636. Penfield W, Roberts L. Speech and Brain Mecha- Kroll NE, Yonelinas AP, Kishiyama MM, Baynes K, nisms. Princeton: Princeton University Press. Knight RT, Gazzaniga MS. The neural substrates Ramachandran VS, Stewart M, Rogers-Ramachan- of visual implicit memory: do the two hemi- dran DC. Perceptual correlates of massive corti- spheres play different roles? J Cogn Neurosci. cal reorganization. Neuroreport 1992;3:583–586. 2003;15:833–842. Rizzolatti G, Arbib MA. Language within our grasp. Levy R, Goldman-Rakic PS. Association of storage Trends Neurosci. 1998;21:188–194. and processing functions in the dorsolateral pre- Solso RL. Mind and Brain Sciences in the 21st Cen- frontal cortex of the nonhuman primate. J. Neu- tury. Cambridge, MA: MIT Press; 1997. rosci. 1999;19:5149–5158. Squire LR and Schacter DL. Neuropsychology of Liu X, Robertson E, Miall RC. Neuronal activity Memory. New York: Guilford Press; 2002. related to the visual representation of arm move- Squire LR, Zola-Morgan S. Memory: brain systems ments in the lateral cerebellar cortex. J. Neuro- and behavior. Trends Neurosci. 1988;11:170–175. physiol. 2003;89:1223–1237. Szentagothai J. The neuron network of the cerebral Merzenich M. Cognitive neuroscience. Seeing in the cortex: a functional interpretation. Proc. R. Soc. sound zone. Nature 2000;404:820–821. Lond. B: Biol. Sci. 1978;201:219–248. Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Thompson RF, Krupa DJ. Organization of memory Schoppmann A, Zook JM. Somatosensory cortical traces in the mammalian brain. Annu. Rev. Neu- map changes following digit amputation in adult rosci. 1994;17:519–549. monkeys. J. Comp. Neurol. 1984;224: 591–605. Turk DJ, Heatherton TF, Kelley WM, Funnell MG, Merzenich M, Wright B, Jenkins W, et al. Cortical Gazzaniga MS, Macrae CN. Mike or me? Self- plasticity underlying perceptual, motor, and cog- recognition in a split-brain patient. Nature Neu- nitive skill development: implications for neurosci. 2002;5:841–842. rorehabilitation. Cold Spring. Harbor Symp. Van Horn JD, Gazzaniga MS. Opinion: Databasing Quant. Biol. 1996;61:1–8. fMRI studies towards a discovery science’ of brain Miall RC. Connecting mirror neurons and forward function. Nature Rev. Neurosci. 2002; 3:314–318. models. Neuroreport 2003;14:2135–2137. Xerri C, Merzenich MM, Jenkins W, Santucci S. Miller MB, Van Horn JD, Wolford GL, et al. Representational plasticity in cortical area 3b Extensive individual differences in brain activa- paralleling tactual-motor skill acquisition in tions associated with episodic retrieval are reli- adult monkeys. Cereb. Cortex. 1999;9:264–276. able over time. J. Cogn. Neurosci. 2002;14: Zeki S. Inner Vision: An Exploration of Art and the 1200–1214. Brain. New York: Oxford University Press; 1999. Index 463

Index

A Amygdala, Abducent nerve, 248, 250 anatomy, 395 Accessory cuneate nucleus, 232 autonomic control, 364, 365 Accessory nerve, 256, 257 circuitry, 395, 396 Accommodation, 329 learning and memory, 457, 459 Acetylcholine (ACh), limbic system processing, 397–399 basal forebrain group projections, 269 nuclear groups, 398, 399 brainstem tegmental group projections, overview, 2 269, 270 taste function, 265 metabolism, 268, 269 Amyotrophic lateral sclerosis (ALS), 216 neuromuscular junction synapse, 54, 56, Anesthesia, 210 58, 269 Angular gyrus, 449 sympathetic nervous system, 353 Anomia aphasia, 451 Acetylcholine receptors, Anopsia, 347 movement in plasma membrane, 19 ANS, see Autonomic nervous system myasthenia gravis autoimmunity, 208, 210 Ansa lenticularis, 425 types, 269 Anterior cerebral artery, 79, 83 ACh, see Acetylcholine Anterior choroidal artery, 79 Action potential, 45–48, 52, 53 Anterior spinal artery syndrome, 215 Active transport, 43 Anterior spinothalamic tract crude touch Adaptation, and movement sensation system light, 333 (ASTT), 166, 182 receptors, 177, 178 Anterodorsal nucleus, 408 Adenosine, 282 Anterograde transport, 116 Adrenal gland, 354 Anterolateral pathway, 160, 225 Afferent inhibition, 74 Anteromedial nucleus, 408 Aging, Anteroventral nucleus, 408 brain neuron loss, 101, 102, 119, 120 Aphasias, 450–452 neuron plasticity, 102, 103 Apical dendrite, 440 Agnosias, 452 Apoptosis, Agraphia, 451, 452 neurodegenerative disease, 119 Alexia, 451 neuron development, 117, 118 Allocortex, 439 regulators, 119 Alpha motoneuron, 134, 141, 144, 151, Appetite, hypothalamic regulation, 380 152, 194 Apraxia, 452 ALS, see Amyotrophic lateral sclerosis Aqueduct of Sylvius, 220 Alternating hemianesthesia, 306, 310 Aqueous humor, 330 Alternating hemiplegia, 306, 307, 311, 312 Arachnoid, 89 Alveus, 391, 393 Archicerebellum, 316 Alzheimer’s disease, 460 Arcuate nucleus, 233 Amblyopia, 125 Area postrema, 385 L-Aminobutyric acid (GABA), 15, 271, 414 Argyll–Robertson pupil, 344

463 464 Index

Aspiny neuron, 441 Barrington’s nucleus, 368 Association fibers, 440 Basal body, 291 Astereognosis, 191, 452 Basal ganglia, Asthenia, 326 circuits and connectivity, Astrocyte, 28–30 association circuit, 426 ASTT, see Anterior spinothalamic tract core circuit, 423 crude touch and movement limbic circuits, 426, 528 sensation system motor circuit, 423, 425, 426 Asynergia, 326 oculomotor circuit, 426 Ataxia, 191 substantia nigra, 428 Athetosis, 434 subthalamic nucleus, 428, 429 Auditory agnosia, 452 nuclei, 429 Auditory system, organization, 419–423, 429 auditory cortex, 448, 449 overview, 6, 419, 431, 432 clinical considerations, 294, 295 pathology, 433–436 cochlear duct, 289, 290 striatum, ear anatomy and physiology, 288, 289 cell types, 429, 431 hair cells, 290–292 patch-matrix compartments, 431 pathways, ventral striatum, 421, 422 ascending pathways, 292–294 ventral pallidum, 422, 423 descending pathways, 294 Basal nucleus of Meynert, 390, 459 overview, 225 Basilar artery, 78 sound reception, 289 Basilar dendrite, 440 Autonomic nervous system (ANS), Basilar membrane, 289 cardiac nervous system, 358 Basilar pons, 219, 235 central control circuits, 363–367 Basket cell somata, 317 denervation sensitivity and Basolateral nuclear group (BLNG), sympathectomy, 367, 368 397–399 enteric division, 356, 358, 359 BBB, see Blood–brain barrier general organization, 351 BDNF, see Brain-derived neurotrophic Hirschsprung’s disease, 368 factor parasympathetic division, 354, 356 Benedikt’s syndrome, 312, 313 sensory and humoral systems, Betz cell, 440 cotransmission, 363 BLNG, see Basolateral nuclear group effector organ responses, 361, 363 Blood–brain barrier (BBB), visceral sensory systems, 359, 361 carrier-mediated transport, 86 somatic motor system comparison, diffusion, 86 349–351 structure, 84, 86 sympathetic division, 351, 353, 354 Blood–cerebrospinal fluid barrier, 96, 97 urinary bladder control, 368 Bouton, 11, 24 Axonal sprouting, 37 Brain, see also specific regions, Axonal transport, 21, 23 brainstem, 9 Axon reaction, 33, 34 cerebrum, 2, 5–7, 9 circulation, B arterial supply, 78–81 Babinski reflex, 212, 213 blood–brain barrier, 84, 86 Ballism, 435 functional considerations, 81, 83 Index 465

requirements, 77 Carotid body reflex, 257 venous drainage, 81 Carotid sinus reflex, 257 development, Cauda equina, 130 cerebellum, 113, 114 CCK, see Cholecystokinin congenital defects, 125 Central pain syndrome, 173 fetal development, 120–123 Central reticular nucleus, 230 genetic factors, 124 Cerebellar ataxia, 191 nutrition, 124, 125 Cerebellopontine angle syndrome, 309, 310 patterning, 105, 106 Cerebellum, postnatal growth, 123, 124 circuitry, nerve regeneration, 217 cerebrocerebrum, 324 subdivisions, 1, 2 inputs, 320, 321 ventricles, 1, 90–92 internal feedback circuit, 325 weight, 1 outputs, 321 Brain-derived neurotrophic factor paravermal zone, 324 (BDNF), 25 vermal zone, 323, 324 Brainstem, vestibulocerebellum, 324, 325 blood supply, 307 development, 113, 114 cranial nerves, 9, 222, 223, 305 functional overview, 319–323 internal landmarks, 224–228 gross anatomy, 315 lesions, see Brainstem lesions lesions and neurodegenerative disease, longitudinal organization, 219, 220 325–327 surface landmarks, 220–222 peduncles, 221, 315, 320 transverse sections, 228–242 proprioceptive pathways, Brainstem auditory evoked potential, 295 anterior spinocerebellar tract, 189 Brainstem lesions, cuneocerebellar tract, 189 Benedikt’s syndrome, 312, 313 indirect pathways, 190 cerebellopontine angle syndrome, 309, posterior spinocerebellar tract, 189 310 retrospinocerebellar tract, 189, 190 medial longitudinal fasciculus, 310, 311 subdivisions, medulla, cortex, 317–319 medial zone, 307 hemispheres, 315, 316 posterolateral region, 307–309 lobes, 315, 316 Parinaud’s syndrome, 313 Cerebral cortex, pons, agnosias, 452 lateral half of midpons, 311, 312 apraxia, 452 medial and basal portion of caudal blood flow, 453, 454 pons, 310 dynamic maintenance, 460, 461 unilateral lesions, 305, 306 hemispheric dominance, 454–456 Weber’s syndrome, 312 language and speech, Broca’s aphasia, 451, 452 aphasias, 450–452 Brown Sequard syndrome, 213, 214 circuitry, 450, 451 Bulbar palsy, 306 learning and memory, 456–460 modular organization, 460 C motor areas, Caloric test, 302 movement control, 446 Carbon monoxide (CO), 282 premotor cortex, 443–445 466 Index

primary motor cortex, 443 Climbing fiber, 319 supplementary motor area, 445, 446 Clonus, 212 organization, CMG, see Corticomedial nuclear group functional aspects, 443 CO, see Carbon monoxide neocortical neurons, 441–443 Coactivation, lower motoneurons, 151, 152 overview, 439, 440 Cochlear duct, 286, 289, 290 prefrontal cortex, 452, 453 Cochlear implant, 295 sensory areas, Collateral sprouting, nerves, 217 auditory cortex, 448, 449 Coma, 311, 312 gustatory cortex, 447 Combined system degeneration, 216 plasticity, 449 Commissural fibers, 440 somatosensory cortex, 446, 447 Commissural interneuron, 152 vestibular cortex, 447 Conductance, 42 visual cortex, 447, 448 Conductile segment, 50, 52, 53 split-brain subjects, 454–456 Conduction aphasia, 451 Cerebrocerebrum, 321, 324 Cone, 32, 331–333 Cerebrospinal fluid (CSF), Corpus callosum, 454–456 blood–cerebrospinal fluid barrier, 96, 97 Corticobulbar tract, 200, 224, 419 clinical aspects, 98, 99 Corticomedial nuclear group (CMG), flow, 97 398, 399 functions, 93, 94 Corticopontine tract, 224 hydrocephalus, 98 Corticoreticulospinal pathway, 201 pressure, 97, 98 Corticorubral tract, 201 volume, 94, 96 Corticorubrospinal pathway, 201 Cerebrum, Corticospinal tract, 199, 200, 224, 419 basal ganglia, 6 Corticotectal tract, 202 diencephalon, 6, 7 Corticotropin-releasing hormone gyri, 5, 6 (CRH), 377 hemispheres, 2 Cough reflex, 258 internal capsule, 7, 9 Cranial nerves, see also specific nerves, lobes, 2, 5 brainstem nuclei, 246, 247 topography, 2, 5, 6 classification, Chemesthesis, 157 branchiometric nerves, 244, 245 Chemoreceptor, 157 general somatic afferent nerves, 244 Chief cell, 32 special somatic afferent nerves, 243 Cholecystokinin (CCK), 281 ganglia in head, 246 Chorea, 434 motor nerves, 228 Choroid plexus, 96, 97 sensory nerves, 228 Cingulate gyrus, 396, 409 types, 9, 222, 223, 245 Circadian rhythm, Cretinism, 125 melatonin control, 383 CRH, see Corticotropin-releasing hormone overview, 381 Crossed reflex, 143, 152 sleep–wake cycle, 382, 383 Crude touch, sensation pathways, 185, 187, suprachiasmatic nucleus control, 382 190, 191 Circle of Willis, 79–81 Crus cerebri, 219, 240, 241, 415 Circumventricular organs, 98, 383–385 CSF, see Cerebrospinal fluid Cisterns, 89 Cuneiform nuclei, 238, 241 Index 467

Cuneocerebellar tract, 189 EGF, see Epidermal growth factor Emissary veins, 81 D Endolymphatic duct, 287 Deep tendon reflex, 143, 149, 214 Endolymphatic sac, 287 Dendriole, 318 Endorphins, 172, 280 Dendrite, Enkephalins, 172, 280 function, 68, 70, 71 Enterochromaffin cell, 32 regulation, 71 Ependyma, 31, 32 spines and synaptic plasticity, 116 Epidermal growth factor (EGF), 25 structure, 11, 23, 24 Epidural space, 129 Dendrite–cell body unit, 50–52 Epinephrine, Denticulate ligaments, 129 metabolism, 272, 273 Depolarization, 45 projections, 274, 275 Dermatomal vasodilatation, 211 EPSP, see Excitatory postsynaptic potential Dermatome, 160 Excitatory postsynaptic potential (EPSP), Diabetes insipidus, 380 47, 50–52, 63 Diencephalon, 1, 6, 7 Extended amygdala, 390, 391 Dissociated sensory loss, 211 Exteroceptor, 157 DLF, see Dorsal longitudinal fasciculus Extrapyramidal system, 200, 201 Dopamine, Eye, extrathalamic modulatory pathways, 415 anatomy, 329 metabolism, 272, 273 movement, projections, 275–277 retinotectal pathways, 344, 345 prolactin release inhibition, 377 types, 345 reticular formation neurotransmission, retina, 330, 331, 333, 335, 336 227, 228 schizophrenia and dopamine hypothesis, F 227 Facial colliculus, 221, 236, 237 Dorsal column–medial lemniscus pathway, Facial nerve, 252–254 182 Facial nucleus, 246 Dorsal longitudinal fasciculus (DLF), 379 Fasciculation, 208 Dorsal motor vagal nucleus, 231 Fasciculi, 137, 138 Dorsal root, 210, 211 Fasciculus cuneatus, 182 Dorsal root ganglia, 130, 132 Fasciculus gracilis, 182 Dorsomedial nucleus, 261, 397, 409, 410 Fast-twitch fibers, 135 Down syndrome, 124 Feed-forward inhibition, 72–74 Ductus reuniens, 286 Feedback inhibition, 72–74 Dura mater, 89, 129 FGF, see Fibroblast growth factor Dural sinuses, 81 Fibrillation, muscle, 208 Dysarthria, 327 Fibroblast growth factor (FGF), 25 Dysdiadochokinesis, 326 Fibronectin, 109 Dyskinesia, 433, 434 First messengers, 61–63 Dysmetria, 326 Fissures, cerebral, 2 Flexor reflex, 143, 150, 151 E Flocculi, 316 Ear, anatomy and physiology, 288, 289 Foramen of Magendie, 92 Edinger–Westphal nucleus, 246, 342 Foramina of Luschka, 92 468 Index

Foramina of Monro, 81 Growth cone, 109 Fornix, 391, 409 Growth hormone-releasing hormone (GHRH), 377 G GTO, see Golgi tendon organ GABA, see L-Aminobutyric acid Guidepost cell, 109 Gag reflex, 257, 258 Gustation, Gamma motoneuron, 134, 141, 144, 149, central taste pathway, 264, 265 151, 152, 194 gustatory cortex, 447 Gamma reflex loop, 149, 150 gustatory nucleus, 264 Gastric inhibitory peptide (GIP), 358 pathways, 262–265 Gated ion channels, 45 taste buds, 262 General somatic afferent fibers, 132 taste modalities, 262, 264 General somatic efferent fibers, 133 General visceral afferent fibers, 132 H General visceral efferent fibers, 133 Hair cells, Generator potential, 45–47, 49, 52 auditory, 290–292 GHRH, see Growth hormone-releasing overview, 32 hormone vestibular, 296, 298 Gigantocellular reticular nucleus, 233, 234 Helicotrema, 286 GIP, see Gastric inhibitory peptide Hemianopsia, 346, 347 Glial cell, Hemiplegia, 212 astrocytes, 28–30 Heteronymous muscle, 149 classification, 28 Hippocampal formation, 391–393 differentiation, 106, 107 Hippocampus, ependyma, 31, 32 Korsakoff’s syndrome, 403 functions, 27, 28 learning and memory, 459 microglia, 30, 31 overview, 2 oligodendrocytes, 30 Hirschsprung’s disease, 368 Schwann cells, 32 Histamine, 415 Global aphasia, 451 Homonymous muscle, 149 Glomerulus, 317 Horizontal cell of Cajal, 442 Glossopharyngeal nerve, 234, 254 Horner’s syndrome, 210 Glucagon, 280 Huntington’s disease, 271, 419, 434, 436 Glucostat hypothesis, 380 Hydrocephalus, types, 98 Glutamate, 271, 272, 414, 415 Hyperalgesia, 210 Glycine, 271 Hyperpolarization, 45 GnRH, see Gonadotropin-releasing Hyperreflexia, 208, 212 hormone Hypertonia, 151, 212 Golgi cell, 317 Hypesthesia, 210 Golgi tendon organ (GTO), 143, 146, Hypoglossal nerve, 246, 258 150, 153 Hypoglossal nucleus, 231 Golgi tendon reflexes, 143 Hypothalamus, Gonadotropin-releasing hormone autonomic control, 363, 364, 378, 379 (GnRH), 377 behavioral regulation, 380, 381 G-proteins, 63, 267 circadian rhythm control, Graded potential, 45–47 melatonin, 383 Granule cell, 317 overview, 381 Great vein of Galen, 81 sleep–wake cycle, 382, 383 Index 469

suprachiasmatic nucleus, 382 Korsakoff’s syndrome, 403 circuitry, inputs, 376 L outputs, 376 Labyrinths, food intake and energy balance membranous labyrinth, 285, 287 regulation, 380 osseus labyrinth, 285, 286 functional overview, 371–373, 375 sensory receptor areas, 288 intrinsic receptors, 375 Laminin, 109 neurohumoral reflexes, 375–378 Language, releasing and inhibiting hormones, 375, aphasias, 450–452 377, 378 circuitry, 450, 451 temperature regulation, 379 Large aspiny neuron, 431 water balance regulation, 379, 380 Lateral dorsal nucleus, 413 Hypotonia, 151, 208, 326 Lateral geniculate body (LGB), 412, 413 Lateral geniculate nucleus (LGN), 337 I Lateral inhibition, 268 Incus, 289 Lateral lemniscus, 237 Inferior colliculus, 220, 238, 239 Lateral posterior nucleus, 413 Inferior olivary complex, 232–234 Lateral reticular nucleus, 232 Inferior salivatory nucleus, 246 Lateral reticular zone, 234 Inferotemporal cortex, 448 Lateral spinothalamic tract pain and Inhibitory postsynaptic potential (IPSP), 47, temperature system (LSTT), 165, 50–52, 63 166, 174 Initial segment, 49, 50, 52 Lateral tegmental receptor field (LTF), Integrated potential, 52 364–367 Internal arcuate fibers, 230, 231 Learning, 456–460 Internal capsule, 415, 415 Lenticular fasciculus, 25 Internal carotid artery, 79 Leptomeninges, 89 Internal jugular veins, 81 LGB, see Lateral geniculate body Interneurons, LGN, see Lateral geniculate nucleus integration of spinal reflexes, 152, 153 Limbic system, lateral inhibition, 268 amygdala, 395–399 Internuclear ophthalmoplegia, 310, 311 basal nucleus of Meynert, 390 Interoceptor, 157 circuitry, 395–397 Interpeduncular nucleus, 241 electrical stimulation studies, 401, 402 Intersegmental interneuron, 152, 196 extended amygdala, 390, 391 Intersegmental reflex, 143 functional overview, 387, 390 Interstitial nucleus of Cajal, 241 hippocampal formation, 391–393 IPSP, see Inhibitory postsynaptic potential Klüver–Bucy syndrome, 402, 403 Itching, 171 Korsakoff’s syndrome, 403 limbic lobe, 439 J Papez circuit, 393 Jaw jerk reflex, 187, 188 processing triangle, 397 Juxtarestiform body, 234 reinforcement and reward centers, 402 schizophrenia defects, 400, 401 K subdivisions, Kinesthetic sense, 177 amygdala pathway, 394, 395 Klüver–Bucy syndrome, 402, 403 caudal limbic system, 395 470 Index

mesocorticolimbic system, 395, Meissner corpuscle, 178 399, 400 Melanocyte-stimulating hormone release- mesolimbic system, 395, 399, 400 inhibiting factor (MIF), 377 overview, 393, 394 Melanocyte-stimulating hormone-releasing rostral limbic system, 395 factor (MRF), 377 septal pathway, 394 Melatonin, 383 substantia innominata, 390 Memory, 456–460 Locus ceruleus, Meniere’s disease, 300 norepinephrine projections, 275 Meninges, 89, 90, 129 overview, 238 Merkel cell, 32 spinal pathway, 202, 203 Merkel disk, 178 Long circumferential arteries, 79 Mesencephalic nucleus of the trigeminal Lower motor neurons, nerve, 187, 188 alpha motoneurons, 134, 141, 144, 151, Mesencephalon, 1 152, 194 Mesocortex, 439 cell bodies, 194–196 Metencephalon, 1 functions, 193, 194 N-Methyl-D-aspartate (NMDA), 272 gamma motoneurons, 134, 141, 144, 149, MGB, see Medial geniculate body 151, 152, 194 Microglia, 30, 31 LSTT, see Lateral spinothalamic tract pain Middle cerebral artery, 79, 83 and temperature system Middle-ear reflex, 295 LTF, see Lateral tegmental receptor field MIF, see Melanocyte-stimulating hormone Lumbar puncture, 98 release-inhibiting factor MLF, see Medial longitudinal fasciculus M Monosynaptic reflex, 143 Macula, 331 Mossy fiber, 320 Magnocellular pathway, 341, 342 Motion sickness, 302 Malleus, 289 Motor neurons, see Lower motor neurons; Mamilothalamic tract, 408 Upper motor neurons Martinotti cell, 442 Motor pathways, Mechanoreceptor, 157, 160, 177, 178, 180 corticobulbar tract, 200 Medial geniculate body (MGB), 412 corticoreticulospinal pathway, 201 Medial lemniscus decussation, 230–232 corticorubrospinal pathway, 201 Medial longitudinal fasciculus (MLF), 202, corticospinal tract, 199, 200 225, 310, 311 corticotectal tract, 202 Medium spiny neuron, 429, 431 extrapyramidal system, 200, 201 Medulla, functional groups of descending autonomic control, pathways, 203, 204 cardiovascular function, 366, 367 locus ceruleus–spinal pathway, 202, 203 functional neuroanatomy, 365, 366 medial longitudinal fasciculus, 202 lateral tegmental receptor field, raphe–spinal pathway, 202, 203 364–367 tectobulbar tract, 202 lesions, tectospinal tract, 202 medial zone, 307 vestibulospinal tract, 202 posterolateral region, 307–309 Movement, sensation pathways, 185, 187 overview, 1, 9 MRF, see Melanocyte-stimulating hormone- pyramids, 219 releasing factor Index 471

Muscle spindles, 143–146, 149 apoptosis, 117–119 Muscle tone, 151 differentiation, 106, 107 Myasthenia gravis, 208, 210 navigation and docking, 108, 109, Myelencephalon, 1 111–113 Myotome, 134 electrophysiology, action potential, 45–48, 52, 53 N coding and processing in nervous NCAMs, see Neural cell adhesion system, 71, 72, 74 molecules dendrite function, 68, 70, 71 Negative feedback loop, 65 excitability, 44, 45 Neocerebellum, 317, 326 functional organization, 48–50 Neocortex, see Cerebral cortex graded potential, 45–47 Nernst equation, 43, 44 integrated potential, 52 Nerve growth factor (NGF), 25, 109 messenger systems, 61–64 Netrins, 111 Nernst equation, 43, 44 Neural cell adhesion molecules receptor potentials, 50–52 (NCAMs), 112 resting potential, 41–43 Neural crest, 105 stimuli integration, 65–67 Neural fold, 103 neurotransmission, 58–61 Neural plate, 103 neurotrophic factors, 24, 25 Neural stem cell (NSC), peripheral nerves, 26 development, 107, 108 plasticity, see Plasticity, neurons therapeutic prospects, 108 protein synthesis, 14, 15 Neural tube, 103, 105 regeneration, Neurofibrillary tangles, 460 axon reaction, 33, 34 Neurogenic hyperthermia, 379 central nervous system, 36 Neuromodulators, 64 collateral sprouting, 35 Neuromuscular junction (NMJ), peripheral nervous system, 34, 35 structure, 67 spinal cord, 36, 37 synapse, 54, 56, 58 synapse, Neuron, chemical, 53, 54, 56, 58 axonal transport, 21, 23 electric, 64, 65 components, structure, 24 cytoskeleton, 21 Neuropeptides, 278–281 dendrites, 23, 24 Neuropeptide Y (NPY), 281, 363 endoplasmic reticulum, 19, 20 Neurotensin, 281 Golgi apparatus, 20, 21 Neurotransmitters, see also specific lysosomes, 20 transmitters, mitochondria, 20 receptor interactions, 59, 60 Nissl bodies, 19 storage and release, 59 nucleus, 11, 14, 15, 17 synapse activity, 61 peroxisomes, 20 synaptic vesicle removal and recycling, 60 plasma membrane, 17–19 synthesis, 58, 59 ribosomes, 19 types, 58, 268 development, Neurotrophins, 25 activity-dependent and experience- NGF, see Nerve growth factor dependent stage, 113 Nitric oxide (NO), 281, 282 472 Index

NMDA, see N-Methyl-D-aspartate Organum vasculosum of the lamina NMJ, see Neuromuscular junction terminalis (OVLT), 385 NO, see Nitric oxide Oval window, 289 Nociception, see Pain OVLT, see Organum vasculosum of the Node of Ranvier, 26 lamina terminalis Nodulus, 316, 327 Oxytocin, 281 Norepinephrine, extrathalamic modulatory pathways, 415 P metabolism, 272, 273 Pacinian corpuscle, 178 projections, 273–275 PAG, see Periaqueductal gray reticular formation neurotransmission, Pain, 227 afferent first-order neurons, 159, 160 sympathetic nervous system, 353, 354 central pain syndrome, 173 NPY, see Neuropeptide Y central perception, 170, 171 NSC, see Neural stem cell dermatomes, 160 Nucleus accumbens, 397, 399 modulation, Nucleus ambiguus, 231, 246 descending control mechanisms, Nucleus gracilis, 229, 230 171, 172 Nucleus interpositus, 234 endogenous pain control, 172 Nucleus of Darkschewitsch, 241 gate control theory, 171 Nucleus of the inferior colliculus, 238 nociceptors, 158, 159 Nucleus reticularis pontis oralis, 238 pathways from anterior head, 169, 170 Nucleus ruber, 241 pathways from body, limbs, and back of Nucleus solitarius, 231, 246, 264 head, 160, 162–165 Nystagmus, 300 phantom limb sensation, 173, 174 referred pain, 172, 173 O spinal cord neurons and ascending Oculomotor nerve, 246, 248–250 projections, Oculomotor nuclear complex, 240 functional considerations, 165 Olfaction, spinothalamic and trigeminothalamic accessory olfactory system, 261, 262 pain pathways, 165, 166 olfactory receptor neurons, 259 types of neurons, 165 overview, 258 stress induced analgesia, 173 pathways, 259, 260 Wall’s concept of pain and target motor refinement and neural processing, 259, responses, 166, 168 261 Paleocerebellum, 316 uncinate fit, 261 Paleospinothalamic pathway, 164 Olfactory nerve, 247, 248 Papez circuit, 393 Olfactory receptor cell, 32 Parabrachial nucleus, 364 Oligodendrocyte, 30 Parafascicular nucleus, 413 Olivary complex, 232–234 Paramedian arteries, 79 Ophthalmic artery, 79 Paramedian reticular nuclei, 233 Opioid peptides, 280 Paraneurons, types, 32, 33 Optic chiasma, 346 Paraplegia, 214 Optic disk, 345, 346 Paresthesia, 210 Optic nerve, 248 Parinaud’s syndrome, 313 Organ of Corti, 290–292 Parkinson’s disease, 419, 433, 434, 436 Index 473

Pars caudalis, 170 Posterior thalamic nucleus, 413 Pars interpolaris, 170 Prefrontal cortex, 452, 453 Pars oralis, 170 Premotor cortex, 199, 443–445 Parvicellular reticular nucleus, 234 Presbycusis, 294, 295 Parvocellular pathway, 341, 342 Presynaptic facilitation, 67 Passive diffusion, 43 Presynaptic inhibition, 67, 68 Pattern code, 72 Pretectum, 221 Pedunculopontine nuclei, 238 Primary motor cortex, 196, 198, 199 Periaqueductal gray (PAG), 171, 172 Prion disease, 327 Peristaltic reflex, 358, 359 Projection fibers, 440 Periventricular tract, 364 Proprioception, see also Vestibular system, PET, see Positron emission tomography cerebellar pathways, 189, 190 Phantom limb sensation, 173, 174 discriminatory general sensory pathway, Phenylketonuria (PKU), 124 overview, 180–183 Pheromones, 262 paths from receptors to cortical Pia mater, 89 columns, 183, 185 Pituitary gland, thalamus and somatosensory cortex, anatomy, 371 183 hypothalamic regulation, 375–378 head pathways, 187, 188 neurohypophysis as circumventricular overview, 142, 155, 156, 180 organ, 384, 385 pathology, 190, 191 PKU, see Phenylketonuria proprioceptors, 157 Placode, 103 trigeminothalamic pathway, 185 Plasticity, neurons, Pseudobulbar palsy, 306, 312 aging brain, 102, 103 Ptosis, 312 chemical, 115 Pulvinar, 413 cortical columns, 449 Purkinje cell, 317–319 developmental, 115 Pyramidal cell, 440 neuronal, 115 Pyramidal decussation, 229, 230 neurotrophic-derived, 115 overview, 11, 37, 114 Q, R synaptic, 115, 116 Quadriplegia, 214, 215 Polysynaptic reflex, 143 Radicular arteries, 130 Pons, Raphe nuclei, 238 lesions, Raphe–spinal pathway, 202, 203 lateral half of midpons, 311, 312 Rebound phenomenon, 326 medial and basal portion of caudal Receptive segment, 49–52 pons, 310 Red nucleus, 239, 240 overview, 1, 9 Referred pain, 172, 173 Pontine micturition center, 368 Reflected excitation, 74 Pontocerebellar tract, 225 Reflected inhibition, 74 Positron emission tomography (PET), 77, Reissner’s membrane, 289 325, 397, 443 Release phenomenon, 207, 325 Posterior cerebral arteries, 78 Renshaw cell, 65, 152 Posterior column–medial lemniscus Resting potential, 41–43 pathway, 224 Reticular formation (RF), Posterior communicating artery, 79 anatomy, 387, 388 474 Index

circuitry, 388–390 Sensory systems, functional overview, 387–390 overview of features, 156, 157 neurotransmission, pathways, dopaminergic system, 227, 228 first-order neurons, 159, 160 noradrenergic system, 227 second-order neurons, 162–164 serotonergic system, 227 third-order neurons, 164, 165 structure, 225, 226 receptors, 156–159 Reticular nuclei, 232, 406, 407 Serotonin, Reticulospinal tract, 201 metabolism, 272, 273 Reticulotegmental nucleus, 238 projections, 277, 278 Retina, Serotonin, adaptation, 333 extrathalamic modulatory pathways, 415 bipolar cells, 336 reticular formation neurotransmission, cell types, 330, 331 227 information flow, 330, 331 Shell neuron, 183 retinal ganglion cells, 333, 335, 336 Short circumferential arteries, 79 rods and cones, 331–333 Signal-line code, 71, 72 Retinogeniculostriate pathway, 337 Sleep–wake cycle, see Circadian rhythm Retrograde transport, 117 Slow-twitch fiber, 134 Retrospinocerebellar tract, 189, 190 Sodium/potassium-ATPase, 42, 43 Rexed’s laminae, 136 Solitary nucleus, 363 RF, see Reticular formation Somatic motor system, organization, Rhombencephalon, 105 142, 143 Rigidity, 151 Somatosensory cortex, 183, 446, 447, 454 Rod, 331–333 Somatostatin, 281, 377 Romberg’s sign, 191 Spastic paralysis, 212 Rostral ventrolateral reticular nucleus, Spina bifida, 126 363, 364 Spinal cord, Rotation test, 302 blood supply, 130, 215 Rubrospinal tract, 201 development, 105, 106, 120 Ruffini corpuscle, 180 dorsal roots, 130, 132, 133 first cervical segment, 229 S laminae, 136, 137 Saccule, 296 lesions, see Spinal cord lesions Scala media, 286, 289, 290 meningeal coverings, 129 Scala tympani, 286 nerve components, 130 Scala vestibuli, 286 pathways and tracts, 137–139 Schizophrenia, regeneration, 36, 37, 217 dopamine hypothesis, 227 spina bifida, 126 limbic system defects, 400, 401 ventral roots, 133–136 Schwann cell, 26, 27, 32, 117 Spinal cord lesions, SCN, see Suprachiasmatic nucleus amyotrophic lateral sclerosis, 216 Scotoma, 345 combined system degeneration, 216 Second messengers, 62, 63 crude touch sensation, 191 Secretin, 280 degeneration, 216, 217 Segmental reflex, 143 dorsal roots, 210, 211 Senile plaque, 460 hemisection, 213, 214 Sensorineural hearing loss, 294 localization, 213 Index 475

release phenomenon, 207 chemical, 53, 54, 56, 58 syringomyelia, 215, 216 electric, 64, 65 tabes dorsalis, 216 structure, 24 transection, types, 66, 67 paraplegia, 214 Synaptic bombardment, 65 quadriplegia, 214, 215 Synaptic potential, 45–47, 49–52 upper motor neurons, 211–213 Synaptic vesicle, removal and recycling, 60 ventral roots, 207, 208, 210 Syringomyelia, 215, 216 Spinal reflex arcs, 143 Spinal reflex responses, 141, 142 T Spinocerebellar tract, 189, 225 Tabes dorsalis, 216 Spinocerebellum, 316, 321 Tactile disorders, 190 Spinocervicocerebellar pathway, 190 Tardive dyskinesia, 434 Spinocervicothalamic pathway, 187 Taste, see Gustation Spinomesencephalic tract, 160, 164 Taste buds, 262 Spinoolivary tract, 190 Taste receptor cell, 32, 262, 263 Spinoreticular tract, 160, 14 Taste–salivary gland reflex, 257 Spinoreticulothalamic pathway, 164 Tectobulbar tract, 202 Spinospinal fasciculi, 138 Tectorial membrane, 291 Spinothalamic tract, 160, 162, 174 Tectospinal tract, 202 Spiny stellate cell, 441 Tectum, 219, 220 Stapedius, 289 Tegmentum, 219, 234 Stapes, 289 Telencephalon, 1 Stellate cells, 317, 440, 441 Temperature, Stereocilia, 291 hypothalamic regulation, 379 Strabismus, 312 perception, Stretch receptors, 144 pathways from anterior head, 169, 170 Stretch reflex, see Deep tendon reflex pathways from body, limbs, and back Striatum, see Basal ganglia of head, 160, 162–165 Stroke, infarct sites, 83 thermoreceptors, 157–159, 170 Subcommissural organ, 385 Temporal lobe, 457, 459 Subfornical organ, 385 Tensor tympani, 289 Substance P, 281 Thalamic syndrome, 173 Substantia innominata, 390 Thalamus, Substantia nigra, 240, 428 drivers and modulators, 405, 406 Subthalamic nucleus, 428, 429 extrathalamic modulatory pathways, 415 Superior central nucleus, 238 functional overview, 405, 416 Superior cerebellar peduncle, 237, 238 internal capsule, 415, 416 Superior colliculus, 220, 239–241, 313 lesions, 417 Superior olivary complex, 237, 292, 293 limbic thalamus, 414 Superior salivatory nucleus, 246 morphology, 407, 408 Superior vestibular nucleus, 236 neuron types, 408 Supplementary motor area, 199, 445, 446 neurotransmitters, 414, 415 Suprachiasmatic nucleus (SCN), 382 nuclei, Supramarginal gyrus, 449, 452 anterior nuclear group, 408, 409 Supranuclear facial palsy, 253, 254 classification, 408 Supraopticohypophyseal tract, 375, 378 intralaminar nuclear group, 413, 414 Synapse, lateral nuclear group, 413 476 Index

medial nuclear group, 409, 410 Ventral lateral nucleus, 412 midline nuclear group, 414 Ventral medial nucleus, 413 organization, 407, 408 Ventral pallidum, 422, 423, 446 posterior nuclear group, 413 Ventral pons, 234 ventral nuclear group, 410–413 Ventral posterior nucleus, 412 reticular nucleus, 406, 407 Ventral posterolateral nucleus of the Thermoreceptor, 157–159 thalamus, 182, 183 Thermostat hypothesis, 380 Ventral posteromedial nucleus, 264 Thyrotropin-releasing hormone, 281, 377 Ventral root, lesions, 207, 208, 210 Tinnitus, 294 Ventral striatum, 421, 422, 446 Titubation, 327 Ventricles, 1, 2, 90–92 Tract of Lissauer, 160 Vermis, 315 Transmissive segment, 50, 53, 54, 56, 58 Vertebral arteries, 78 Tremor, 325, 326 Vertigo, 300, 302 Trigeminal nerve, Vestibular cortex, 447 lesion, 252 Vestibular system, midpontine level, 237, 238 hair cells, 296, 298 motor root, 251, 252 labyrinths, nuclei, 231, 237, 241, 245 membranous labyrinth, 285, 287 pathways, 225 osseus labyrinth, 285, 286 sensory root, 250, 251 sensory receptor areas, 288 Trigeminoreticulothalamic pathway, 170 postural pathways, 299, 300 Trigeminothalamic pathway, 185, 231, 238 saccule, 296 Trochlear nerve, 246, 248, 250 tests and disorders, 300, 302 Trophic segment, 50 utricle, 296 Tuber cinereum, median eminence, 384 vestibular nuclei, Tuberohypophyseal tract, 377 inputs, 298, 299 Tympanic membrane, 288 outputs, 299 vestibuloocular pathways, 300 U Vestibulocerebellum, 316, 321, 324, 325 Uncinate fit, 261 Vestibulocochlear nerve, 234, 254 Unipolar brush cell, 317, 318, 320 Vestibuloocular reflex (VOR), 345 Upper motor neuron, Vestibulospinal tract, 202 function, 196 VIP, see Vasoactive intestinal polypeptide lesions, 211–213 Visual agnosia, 452 Utricle, 296 Visual cortex, 447, 448 Visual system, V eye, Vagus nerve, anatomy, 329 dorsal motor nucleus, 247 movement, function, 254, 255 retinotectal pathways, 344, 345 lesion, 255, 256 types, 345 Vasoactive intestinal polypeptide (VIP), retina, 330, 331, 333, 335, 336 279–281, 363 lesions, 345–347 Vasopressin, 281, 380 magnocellular pathway, 341, 342 Ventral anterior nucleus, 410, 411 parvocellular pathway, 341, 342 Index 477

reflex pathways, Vitreous humor, 330 accommodation–convergence reaction VNO, see Vomeronasal organ circuit, 344 Voluntary movement, control, 204, 205 accommodation reflex circuit, 344 Vomeronasal organ (VNO), 261, 262 Argyll–Robertson pupil, 344 VOR, see Vestibuloocular reflex pupillary dilatation circuit, 344 pupillary light reflex pathway, 342, 344 W retinogeniculostriate pathway, 337 Wallenberg’s syndrome, 307 retinotopic representation of visual Water balance, hypothalamic regulation, fields, 337 379, 380 visual cortex, Weber’s syndrome, 312 primary visual cortex, 337, 339, 340 Wernicke’s aphasia, 450, 451 visual association areas, 340, 341 Wernicke’s area, 449–451