The Brain and Behavior: an Introduction to Behavioral

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The Brain and Behavior An Introduction to Behavioral Neuroanatomy

Third Edition

David L. Clark Nash N. Boutros Mario F. Mendez CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Dubai, Tokyo

Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK

Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521142298 © D. Clark, N. Boutros, M. Mendez 2010

This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2010

ISBN-13 978-0-511-77469-0 eBook (EBL) ISBN-13 978-0-521-14229-8 Paperback

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to- date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use. Contents

Preface to the second edition page vii Preface to the third edition ix

1. Introduction 1 10. Brainstem 167 2. Gross anatomy of the brain 4 11. Limbic system: Temporal lobe 176 3. Histology 14 12. Limbic system: Cingulate cortex 197 4. Occipital and parietal lobes 33 13. Limbic system: Overview 215 5. Temporal lobe: Neocortical structures 59 14. Interhemispheric connections and laterality 226 6. Frontal lobe 84 7. Basal ganglia 122 8. Diencephalon: Hypothalamus and Index 237 epithalamus 140 !e colour plates are to be found between pages 214 and 215. 9. Diencephalon: Thalamus 156

Preface to the second edition

!e last ten years have witnessed an explosion in the We will have accomplished our mission if we can understanding of the neurochemical and neuro- convince the reader that the brain is an organ worthy physiological processes that underlie behavior. Our of being the seat for the immensely complex function understanding of the pathophysiology of many psychi- of behavior. Each chapter includes a list of suggested atric disorders has increased as well. Clinicians are now texts, as well as selected references for those who #nd faced with the overwhelming challenge of the need to the topic interesting and would like further details. keep up with the "ood of basic neuroscienti#c know- In preparing this volume many sources were ledge that appears monthly in scienti#c journals, as utilized (textbooks and published articles). We well as the need to assimilate it with an ever-increasing encountered some discrepancies, particularly in the number of reports in the clinical journals that identify description of anatomical regions subserving behav- structural and biochemical abnormalities associated ior. We either elected to exclude that particular detail with clinical disorders. !e gap that has always existed or chose the version compatible with the excellent and between the basic science of neuroanatomy and clin- highly recommended Principles of Neural Science, by ical behavioral science seems to be widening at an Kandel, Schwartz and Jessell, and its companion text, increasing rate. Neuroanatomy: Text and Atlas, by John Martin. One Although the current level of knowledge of behav- goal of our book is to provide a summary view of each ior and psychopathology does not necessitate a topic. Every e$ort has been made to make that view as detailed understanding of all neuroanatomy, a basic accurate as possible. Many details have been omitted level of some neuroanatomical knowledge is neces- because of the summary nature of the text. We hope sary. Familiarity with those brain regions that are heav- the accuracy of the text has not been distorted by the ily implicated in both normal and abnormal behavior process of summarization. Please contact us if you #nd will help the clinician assimilate new knowledge as the errors in the material or in its interpretation (clark.32@ #eld evolves. As the clinician becomes more aware of osu.edu, [email protected], mmendez@ucla. the structure and function of the behaviorally sensitive edu). regions of the brain, the concept that brain abnormal- Cross chapter references are provided to help the ities can produce the symptomatology that is seen in the reader link the related parts of the di$erent chapters. clinic becomes progressively more understandable. Simpli#ed diagrams are provided throughout the text. Currently available neuroanatomy books are writ- Selected material from clinical experience (N.N.B. ten with the neurologist in mind. Emphasis is placed on and M.F.M.) is included to help relate the dry science the neuroanatomy that is examined during a standard of neuroanatomy to our everyday clinical encounters. neurological exam. Areas that are known to be heav- Other clinical material is referenced. It is not the pur- ily involved in behavior such as the nucleus accumbens pose of this book to present a complete picture of what and the nucleus locus ceruleus receive only passing is currently known about behavioral/anatomical rela- mention. We wrote this volume with the behavioral tionships. !is is the domain of clinical neuropsych- clinician in mind. It is meant to be an introduction iatry, for which many excellent textbooks are now rather than a comprehensive neuroanatomy text. We available. Much ongoing research is aimed at de#ning hope to be able to convey the immense complexity of the neuroanatomical bases of the various psychopatho- the neuronal circuitry that subserves our cognitive and logical states. A complete discussion of this research is emotional lives. At the same time we hope to present beyond the scope of this introductory volume. Selected the reader with a simpli#ed view of the complexity of references regarding this fascinating research are vii the neuroanatomy that underlies certain behaviors. included and may be used as starting points for readers Preface to the second edition

who would like to obtain a more complete understand- consists of anatomy and behavioral considerations. In ing of one speci#c area. some chapters further behavioral considerations are Two introductory chapters covering an overall included before the select bibliography and references. view of the brain are included. Neuroanatomy has its We have allowed ourselves to speculate on the possible own language. Such language tends to make reading function of some of the CNS circuits for the purpose of neuroanatomy literature even more di%cult. Chapter stimulating the reader’s interest. !e speculative nature 1 includes de#nitions of the more commonly used of such statements is clearly stated. neuroanatomy terms. Chapter 2 reviews some critical We suggest that the reader reads through the entire gross brain structures. book at least once to develop an overview of the brain. Many of the central nervous system (CNS) Be sure to examine the orientation and terminology regions that are thought not to be central to behav- displayed in Figure 1.1. !e reader can then return to ior are mentioned only in passing in the two introduc- individual chapters to develop a further understanding tory chapters. It should be noted that as knowledge of a particular region. about brain and behavior increases such areas may attain more central positions. A chapter on histology References includes an introduction to synaptic structure and to Kandel, E.R., Schwartz, J.H., and Jessell, T.M. 2000. neurotransmission. Principles of Neural Science. New York: Appleton and !e book targets brain areas that are known to Lange. be heavily involved in behavior. Each chapter begins Martin, J. 1996. Neuroanatomy: Text and Atlas. New with a brief introduction. !e majority of each chapter York: Appleton and Lange.

viii Preface to the third edition

Our intent in this as well as earlier editions has been as well. Our knowledge of the anatomy of the parietal to provide the psychiatrist, psychologist, and others lobe has been advanced by studies revealing the func- in the mental health #eld with a simple, easy-to-read tion of its medial aspect and the intraparietal sulcus. introduction to clinically relevant brain anatomy from !ese two areas have been infrequently explored until a functional perspective. !e story of brain function now and still receive little attention in basic neuroanat- continues to unfold, told through the continued publi- omy texts. Evaluation of the prefrontal lobes is now cation of an impressive number of functional imaging more complete with a somewhat better understanding studies. We have attempted to put the published results of the function of the medial aspect of that portion of in simpli#ed language while minimizing the distortion the cortex. inherent in such an approach. !e line drawings also A number of networks have been introduced in re"ect this perspective. !e goal is to help the reader Chapters 4, 5, and 6. A network may span several lobes remember the basics. More cited references have been and include subcortical structures with interconnect- included in this edition to allow readers access to the ing white matter. !e networks operate in support of original studies so that they may peruse the original various functions including attention, spatial orien- publications at their leisure. tation, threat recognition, and theory-of-mind, as !e results of published studies have dictated well as mind-wandering. Several of the networks are extensive revision of the chapters of the book dealing related to clinical disorders such as schizophrenia and with the cortex. Updates are included in other chapters depression.

Chapter 1Introduction

Human behavior is a direct re"ection of the anatomy Physiologically, the nervous system can be divided and physiology of the central nervous system. !e goal into somatic and autonomic (visceral) divisions: of the behavioral neuroscientist is to uncover the neuro- t !e somatic nervous system deals with the anatomical substrates of behavior. Complex mental contraction of striated muscle and the sensations processes are represented in the brain by their elemen- of the skin (pain, touch, temperature), the tary components. Elaborate mental functions consist innervation of muscles and joint capsules of subfunctions and are constructed from both serial (proprioception), and the reception of sensations and parallel interconnections of several brain regions. remote to the body by way of special senses. !e Introduction to the nervous system covers general ter- somatic nervous system senses and controls our minology and the ventricular system. interaction with the environment external to the body. Major subdivisions t !e autonomic nervous system controls the tone !e nervous system is divided anatomically into the of the smooth muscles and the secretion of glands. central nervous system (CNS) and the peripheral ner- It senses and controls the condition of the internal vous system (PNS). environment. t !e CNS is made up of the brain and spinal cord. t !e PNS consists of the cranial nerves and spinal Common terms nerves. !e neuraxis is the long axis of the brain and spinal cord (Figure 1.1). A cross section (transverse section)

Cerebrum orientation Figure 1.1. The neuraxis is the long axis Dorsal Plane of of the spinal cord and brain. The neuraxis superior coronal section of the human brain changes at the junction of the midbrain and diencephalon. Caudal Rostral Caudal to this junction, orientation is as posterior anterior shown on the lower right (brainstem Ventral orientation). Rostral to this junction, inferior orientation is as shown on the upper left (cerebrum orientation).

Occipital Frontal pole pole Horizontal neuraxis Plane of horizontal section Plane of cross section Rostral Dorsal superior posterior

Ventral Caudal anterior Neuraxis inferior 1 Brainstem orientation Introduction

is a section taken at right angles to the neuraxis. !e t E$erent means away from and is sometimes used neuraxis in the human runs as an imaginary straight to mean motor. line through the center of the spinal cord and brainstem t Ipsilateral refers to the same side; contralateral (Figure 1.1). At the level of the junction of the midbrain refers to the opposite side. and diencephalon, however, the neuraxis changes ori- !e CNS di$erentiates embryologically as a series entation and extends from the occipital pole to the of subdivisions called encephalons. Each encephalon frontal pole (Figure 1.1). !e neuraxis located above can be identi#ed in the adult brain. In many regions of the midbrain is the neuraxis of the cerebrum and is the brain, the embryological terminology is applied to sometimes called the horizontal neuraxis. A cross sec- adult brain subdivisions: tion taken perpendicular to the horizontal neuraxis is called a coronal (frontal) section. t !e prosencephalon is the most anterior of With regard to the neuraxis of the spinal cord and the embryonic subdivisions and consists of brainstem: the telencephalon and diencephalon. !e cerebrum of the adult corresponds with the t Dorsal (posterior) means toward the back. prosencephalon. t Ventral (anterior) means toward the abdomen. ‡ !e telencephalon consists of the two cerebral t Rostral means toward the nose. hemispheres. !ese include the super#cial gray t Caudal means toward the tail. matter of the cerebral cortex, the white matter t !e sagittal (midsagittal) plane is the vertical plane beneath it, and the corpus striatum of the basal that passes through the neuraxis. Figure 1.1 is cut ganglia. in the sagittal plane. ‡ !e diencephalon is made up of the thalamus, t !e parasagittal plane is parallel to the sagittal the hypothalamus below it, and the epithalamus plane but to one side or the other of the midline. located above it (pineal and habenula; Figure t A horizontal section is a cut of tissue taken parallel 13.5). to the neuraxis (Figure 9.1). t !e brainstem lies caudal to the prosencephalon. It t A cross section (transverse section) is a cut taken consists of the following: perpendicular to the neuraxis (Figures 10.1, 10.2, ‡ !e mesencephalon (midbrain). 10.3, and 10.4). ‡ !e rhombencephalon, which is made up of: With regard to the neuraxis of the cerebrum (horizon- t !e metencephalon, which contains the pons tal neuraxis): and cerebellum. t Dorsal (superior) means toward the top (crown) of t !e myelencephalon (medulla oblongata). the skull. t Ventral (inferior) means toward the base of the Ventricular system skull. !e central canal of the embryo di$erentiates into the t Rostral (anterior) means toward the nose. ventricular system of the adult brain. !e ventricular t Caudal (posterior) means toward the occipital cavities are #lled with cerebrospinal "uid (CSF), which bone of the skull. is produced by vascular tu&s called the choroid plex- t !e sagittal (midsagittal) plane is the vertical plane uses. !e ventricular cavity of the telencephalon is rep- that passes through the neuraxis. resented by the lateral ventricles (Figure 1.2). !e lateral t !e parasagittal plane is parallel to the sagittal ventricles are the #rst and second ventricles. !ey con- plane but to one side or the other of the midline. nect to the third ventricle of the diencephalon by the t A horizontal section is a cut of tissue taken parallel interventricular foramina (of Monro). Continuing to the horizon. caudally, the cerebral aqueduct of the midbrain opens t A coronal section (transverse section) is a cut into the fourth ventricle. !e fourth ventricle occupies taken perpendicular to the neuraxis. the space dorsal to the pons and medulla and ventral to Other terms that relate to the CNS: the cerebellum. CSF "ows from the fourth ventricle into the subarachnoid space through the median aperture t A$erent means to or toward and is sometimes (of Magendie) and the lateral apertures (of Luschka). used to mean sensory. 2 Most of the CSF is produced by the choroid plexus of References

Arachnoid villi Superior sagittal sinus the lateral ventricles, although tu&s of choroid plexus are found in the third and fourth ventricles as well. !e lateral as well as the third ventricles have been Lateral Subarachnoid noted to be enlarged in a number of psychiatric dis- space ventricles orders, particularly schizophrenia (Daniel et al., 1991;

1 Elkis et al., 1995). Enlargement of the ventricles usually re"ects atrophy of the surrounding brain tissue. Choroid plexus !e term hydrocephalus is used to describe abnormal enlargement of the ventricles. In the condition known as III normal-pressure hydrocephalus, the ventricles enlarge in the absence of brain atrophy or obvious obstruction Cerebral to the "ow of the CSF. Normal pressure hydrocephalus aqueduct is classically characterized by progressive dementia, 2 ataxia, and incontinence (Friedland, 1989). However, IV symptoms may range from apathy and anhedonia to aggressive or obsessive-compulsive behavior or both 3 (Abbruzzese et al., 1994).

Spinal References cord Abbruzzese, M., Scarone, S., and Colombo, C. 1994. Subarachnoid Obsessive-compulsive symptomatology in normal space pressure hydrocephalus: A case report. J. Psychiatr. Neurosci. 19:378–380. Daniel, D.G., Goldberg., T.E., Gibbons, R.D., and Weinberger, D.R. 1991. Lack of a bimodal distribution of ventricular size in schizophrenia: A Gaussian Lumbar cistern mixture analysis of 1056 cases and controls. Biol. Psychiatry 30:886–903. Figure 1.2. Cerebrospinal !uid (CSF) is produced by tufts of chor- Elkis, H., Friedman, L., Wise, A., and Meltzer, H.Y. 1995. oid plexus found in all four ventricles. CSF exits the lateral ventricles Meta-analyses of studies of ventricular enlargement and through the interventricular foramina (of Monro) (1). CSF exits the ventricular system through the lateral apertures (of Luschka) (2) and cortical sulcal prominence in mood disorders. Arch. the median aperture (of Magendie) (3). CSF is reabsorbed into the Gen. Psychiatry 52:735–746. blood by way of the arachnoid villi that project into the superior Friedland, R.P. 1989. Normal-pressure hydrocephalus and sagittal sinus. the saga of the treatable dementias. J.A.M.A. 262:2577– 2593.

Clinical vignette A 61-year-old man reported that his work performance was slipping. He was forgetting names and dates more than usual. Because of recent losses in his family, he assumed he was depressed. He saw a psychiatrist (his wife had a history of depression), who prescribed an antidepressant. Soon after this, the patient had an episode of urinary incontinence. A neurology consult- ation was obtained, which revealed gait problems. A computed tomographic scan showed enlarged ventricles without enlarged sulci (which would have indicated generalized brain atrophy). The diagnosis of normal pressure hydrocephalus was made. Progressive improvement in the patient’s clinical condition was seen following the installation of a ventricular shunt. 3

Chapter 2 Gross anatomy of the brain

Introduction caudal pair consists of the inferior colliculi (Figure 10.3; auditory system), and the cranial pair consists !e brain is that portion of the central nervous system of the superior colliculi (Figure 10.4; visual system). that lies within the skull. !ree major subdivisions are !e ventricular cavity of the midbrain is the cerebral recognized: the brainstem, the cerebellum, and the aqueduct. Most nuclei and tracts found in the mid- cerebrum. !e cerebrum includes both the cerebral brain lie ventral to the cerebral aqueduct and together hemispheres and the diencephalon. make up the midbrain tegmentum (Figure 2.1). !e basilar midbrain contains the crus cerebri (“motor Brainstem pathway” in Figures 10.3 and 10.4) and the substan- !e brainstem is the rostral continuation of the spi- tia nigra, one of the basal ganglia. !e cranial nerves nal cord. !e foramen magnum, the hole at the base associated with the midbrain are the trochlear and of the skull, marks the junction of the spinal cord and oculomotor. the brainstem. !e brainstem consists of three sub- Ischemia (particularly transient ischemia) of the divisions: the medulla, the pons, and the midbrain midbrain tectum can result in visual hallucinations (Figure 2.1). (peduncular hallucinosis). Auditory hallucinations have also been reported with lesions of the tegmentum Medulla of the pons and lower midbrain (Cascino and Adams, !e caudal limit of the medulla lies at the foramen 1986). !e sounds have the character of noise: buzzing magnum. !e central canal of the spinal cord expands and clanging. To one patient, the sounds reportedly in the region of the medulla to form the fourth ven- had a musical character like chiming bells. tricle (IV in Figure 1.2). !e cranial nerves associated with the medulla are the hypoglossal, spinal accessory, Cerebellum vagus, and the glossopharyngeal. !e cerebellum arises embryologically from the dorsal pons. In the mature brain the cerebellum overlies the Pons pons and medulla (Figure 2.2) and is connected with !e pons lies above (rostral to) the medulla (Figure them by the three paired cerebellar peduncles (Figures 2.1). !e bulk of the medulla is continuous with the 10.1 and 10.2). !e cerebellum is separated from the pontine tegmentum. !e tegmentum consists of nuclei pons and medulla by the cavity of the fourth ventricle. and tracts that lie between the basilar pons and the "oor Like the cerebrum, it displays a highly convoluted sur- of the fourth ventricle (IV in Figures 1.2 and 10.2). !e face. !e cortex of the cerebellum is gray and a layer of basilar pons consists of tracts along with nuclei that white matter lies deep to it. Although it represents only are associated with the cerebellum. !e fourth ven- about 10% of the brain, the cerebellum contains more tricle narrows at the rostral end of the pons to connect than four times the number of neurons in the cerebral with the cerebral aqueduct of the midbrain (Figures cortex (Andersen et al., 1992). 1.2, 10.2, 10.3, and 10.4). !e cranial nerves associated Traditionally the cerebellum is thought to be with the pons are the vestibulocochlear (statoacoustic), involved in the control and integration of motor func- facial, abducens, and trigeminal. tions that subserve coordination, balance, and gait. It is usually divided into three functional/structural com- Midbrain ponents: the "occulonodular lobe (archicerebellum), 4 !e dorsal surface of the midbrain is marked by four which is closely connected with the vestibular system hillocks, the corpora quadrigemina (tectum). !e and is involved in eye movements; the vermis and Cerebellum

Dorsal Figure 2.1. The brainstem consists of (posterior) the medulla, the pons, and the midbrain. A lateral view of the brainstem (left) is Tectum marked to indicate the level from which each of the cross sections (right) is taken. See Chapter 10 for signi"cant structures Basilar portion found in each cross section. Cranial refers Tegmentum to the top of the head, and caudal refers to the spinal cord.

Midbrain

Midbrain Tegmentum Cerebellar peduncle Pons

Basilar portion Medulla Pons

Cranial Cerebellar peduncle Ventral Dorsal

Caudal

Olive Medulla Motor tract (pyramid) Ventral (anterior)

Clinical vignette which are linked with the neocortex and function in the coordination of hand/arm movements and speech. A 71-year-old man had no prior history of psychiatric !e vermis is further divided into the classic lobules or neurological problems. While at home with his two sons, daughter and wife, he suddenly experienced numbered from I to X, with I being most anterior/ weakness in all four extremities and started seeing superior. Technical limits of imaging have produced a policemen entering the front door of his house. He modi#ed classi#cation. !e vermis is o&en reported to became irritable and fearful that the police would take be subdivided into vermal regions V1–V4 (V1, lobules him away. He was brought to the emergency room I–V; V2, lobules VI and VII; V3, lobule VIII; V4, lob- (ER). A neurological examination was normal, and the ules IX and X) (Sullivan et al., 2000). hallucinations ceased. The patient was discharged !e cerebellum is generally credited with detect- with follow-up at the psychiatry clinic. Three days ing and correcting errors in ongoing muscular activ- later he was brought to the ER completely comatose ity (i.e., motor coordination). Accumulating evidence owing to a brainstem stroke. In retrospect, the patient suggests that the cerebellum also plays a role in a$ective was found to have had a brainstem transient ischemic and higher cognitive functions. For example, stimula- attack (TIA), which caused him to experience peduncular hallucinosis. tion of the fastigial nucleus, which relays signals from the "occulonodular lobe, has been shown to result in changes in blood pressure as well as changes in the paravermal area (spinocerebellum), which are related to nucleus accumbens and the hippocampus of the lim- the axial and paraxial musculature involved with walk- bic system (Heath et al., 1978; Andrezik et al., 1984). 5 ing; and the cerebellar hemispheres (neocerebellum), !e vermis has connections with limbic structures Gross anatomy of the brain

Superior Central sulcus parietal lobule Inferior Lateral fissure parietal lobule

Frontal pole

Occipital pole

Temporal pole Cerebellum Superior temporal gyrus Middle Inferior temporal gyrus temporal gyrus

Thalamus Paracentral lobule Cingulate gyrus Precuneus Corpus callosum Parieto-occipital fissure Frontal pole Calcarine fissure

Occipital Anterior pole commissure

Optic chiasm

Hypothalamus Cerebellum Midbrain Pons Medulla

Figure 2.2. Lateral (above) and medial (below) views of the gross brain. Compare with Brodmann’s areas, Figure 2.3.

(amygdala and hippocampus) as well as with the red 1991; Roskies et al., 2001). Activation of the cerebellar nucleus (a motor nucleus). It is hypothesized that the nuclear structures has been demonstrated during cog- vermis may a$ect emotional behavior through con- nitive processing (Kim et al., 1994). Abnormalities in nections with the ventral tegmental area (Nestler and cerebellar activity and size do not follow a particular Carlezon, 2006). !e lateral cerebellar lobes (includ- pattern but relationships to neuropsychiatric disor- ing the dentate and emboliform nuclei) may be more ders, including schizophrenia, have been summarized involved with cognitive functions such as strategic plan- by Hoppenbrouwers et al. (2008) and Andreasen and 6 ning, learning, memory, and language (Schmahmann, Pierson (2008). Cerebrum

!e cerebellar cognitive a$ective syndrome in 12% (Courchesne et al., 1994b). It is hypothesized (CCAS) was described based on patients with cerebel- that cerebellar abnormalities in autism may be respon- lar lesions. Symptoms may be motor and nonmotor. sible for de#cits in shi&ing attention (Akshoomo$ and Among the nonmotor symptoms are anxiety, per- Courchesne, 1992). severation, anhedonia and aggression. In addition, Higher blood "ow to the cerebellum has been visuospatial, linguistic dysfunction and impairments reported in patients with posttraumatic stress disorder in working memory and planning have been reported (Bonne et al., 2003) and reduced cerebellar size was (Schmahmann and Sherman, 1998). Other symptoms described in attention-de#cit hyperactivity disorder reported include lethargy, depression, and lack of (Castellanos et al., 2002; Valera et al., 2007). A model empathy (Schmahmann et al., 2007). has been proposed suggesting that abnormalities in Abnormalities of the vermis are more frequently connectivity within the cerebellum or between the reported in behavioral disorders than in other por- cerebellum and other brain structures may be respon- tions of the cerebellum. Although observations in sible for the “cognitive dysmetria” seen in schizophre- di$erent studies vary, the vermis is generally smaller nia (Andreasen et al., 1998). in autism spectrum disorders (vermal area V2) (Courchesne et al., 1988, 1994a, 2001; Murakami Cerebrum et al., 1989; Hashimoto et al., 1995). In fact, V2 has !e diencephalic portion of the cerebrum consists of been linked speci#cally with stereotyped behavior the thalamus (Chapter 9), the hypothalamus, and the and reduced exploration (Pierce and Courchesne, epithalamus (Chapter 8). !e thalamus is an integra- 2001). Several studies have found a smaller vermis tive center through which most sensory information in several patients with schizophrenia (Sandyk et al., must pass in order to reach the cerebral cortex (i.e., the 1991; Nopoulos et al., 1999; Ichimiya et al., 2001; level of consciousness). !e hypothalamus serves as Varnas et al., 2007). A decrease in vermal volume has an integrative center for control of the body’s internal been reported in patients with bipolar disorder (V2 environment by way of the autonomic nervous sys- and V3), depression (Shah et al., 1992; DelBello et al., tem (Figure 8.1). !e pituitary gland (hypophysis) 1999; Mills et al., 2005), and schizophrenia (Sandyk extends ventrally from the base of the hypothalamus. et al., 1991; Nopoulos et al., 1999; Ichimiya et al., !e epithalamus consists of the habenula and the 2001; Varnas et al., 2007). An increase in blood "ow pineal gland. !e ventricular cavity of the dienceph- in the vermis has been observed in depression (Dolan alon is the third ventricle (III in Figure 1.2). !e optic et al., 1992). nerve is associated with the diencephalon (dotted Courchesne et al. (2001), using head circumfer- lines, Figure 8.3). ence, found that the total brain size in children with !e cerebral hemispheres include the cerebral autism was normal at birth. However, 90% of 2–4-year- cortex and the underlying white matter, as well as a old autistic children had signi#cantly larger (18%) number of nuclei that lie deep to the white matter. brains compared with controls. Comparison of both Traditionally, these nuclei are referred to as the basal groups as 5–15 year olds showed no di$erence. !e ganglia (Chapter 7). One of these forebrain nuclei, the authors hypothesized that the overgrowth is restricted amygdala (Figure 11.1), is now included as part of the to childhood followed by a period of slowed growth limbic system (Chapters 11, 12, and 13).!e surface (Courchesne et al., 2001; Sparks et al., 2002). of the cortex is marked by ridges (gyri) and grooves Decreased cerebellar hemisphere size has been (sulci). Several of the sulci are quite deep, earning reported in autism (Murakami et al., 1989) and schizo- them the status of #ssure. !e most prominent #ssure phrenia (Bottmer et al., 2005). A loss of cerebellar cor- is the longitudinal cerebral #ssure (sagittal or inter- tex granular cells has been reported in autism, and the hemispheric #ssure), which is located in the midline same studies showed loss of Purkinje cells in both the and separates the two hemispheres. Each hemisphere vermis and the cerebellar hemispheres (Ritvo et al., is divided into four lobes: frontal, parietal, occipital, 1986; Kemper and Bauman, 1998). It was argued that and temporal. these losses occurred before 30 weeks of gestation !e frontal lobe lies rostral to the central sulcus and (Bauman and Kemper, 1985). An analysis of mag- dorsal to the lateral #ssure (Figures 2.2 and 2.3). An netic resonance imaging (MRI) of 50 subjects showed imaginary line drawn from the parieto-occipital sul- decreased vermal size in 86% but increased vermal size cus to the preoccipital notch separates the occipital 7 Gross anatomy of the brain

Anterior cerebral a. Anterior communicating a. Middle Posterior cerebral a. communicating a. Internal carotid a. Posterior Basilar a. cerebral a.

Vertebral a. Right subclavian a. Left subclavian a.

Brachiocephalic a.

Figure 2.4. Principal arteries serving the brain. The shaded vessels make up the cerebral arterial circle (of Willis).

Figure 2.3. The cytoarchitectonic regions of the cortex as t !e paleostriatum consists of the globus pallidus. described by Brodmann. Compare with the surface of the brain, t Two additional nuclei that are included as basal Figure 2.2. ganglia are the subthalamic nucleus (subthalamus) and the substantia nigra. lobe from the rest of the brain (Figure 5.1). A second !e internal capsule is made up of #bers that inter- imaginary line, perpendicular to the #rst and continu- connect the cerebral cortex with other subdivisions ing rostrally with the lateral #ssure, divides the parietal of the brain and spinal cord. !e anterior and poster- lobe above from the temporal lobe below. Spreading ior commissures as well as the massive corpus callo- the lips of the lateral #ssure reveals the smaller insular sum interconnect the le& side with the right side of the region deep to the surface of the cortex. cerebrum. !e limbic system (limbic lobe) is made up of contributions from several areas. !e parahippocampal Vasculature gyrus and uncus can be seen on the ventromedial aspect Two major systems supply blood to the brain of the temporal lobe (Figure 5.4). !e hippocampus and (Figure 2.4). !e vertebral arteries represent the pos- amygdala lie deep to the ventral surface of the medial terior supply; they course along the ventral surface of temporal lobe (Figure 11.1), and the cingulate gyrus lies the spinal cord, pass through the foramen magnum, along the deep medial aspect of the cortex (Figure 12.1). and then merge medially to form the basilar artery on !ese structures are joined together by #ber bundles the ventral aspect of the medulla.!e basilar artery and form a crescent or limbus (Figure 13.1). splits at its rostral terminus to form the paired poster- !e basal ganglia represent an important motor ior cerebral arteries. control center. !e internal carotid system represents the anter- t !e neostriatum is made up of the caudate nucleus 8 ior supply and arises at the carotid bifurcation. Major and putamen (Figure 7.1). branches of the internal carotid include the anterior Electroencephalogram

Central sulcus arteries Figure 2.5. The stippled area repre- Posterior parietal artery sents the cortex served by the middle cerebral artery. The vessels emerging Operculofrontal artery from the longitudinal cerebral "ssure are the terminal branches of the anterior cerebral artery (after Waddington, 1974; compare with Figure 2.6).

Orbitofrontal artery Temporal arteries

t !e large middle cerebral artery serves the remainder of the cortex, including the majority of the lateral aspect of the frontal, parietal, and temporal cortices. !e blood–brain barrier is a physiological concept based on the observation that many substances, including many drugs, which may be in high concentrations in the blood, are not simultaneously found in the brain tissue. !e location of the barrier coincides with the endothelial cells of the capillaries found in the brain. !ese endothelial cells, unlike those found in capillaries elsewhere in the body, are joined together by tight junctions. !ese tight junctions are recognized as the Anterior cerebral artery Posterior cerebral artery anatomical basis of the blood–brain barrier. Sackeim et al. (1990) reported that blood "ow to Figure 2.6. The distribution of the anterior cerebral artery (right) the brain was reduced in elderly patients diagnosed and the posterior cerebral artery (left) on the medial aspect of the with major depressive disorder when compared with brain. age-matched control subjects. Overall blood "ow was reduced by 12%. !e distribution of the e$ect was uneven, and there were brain regions in which the cerebral and the middle cerebral arteries. !e verte- reduction was even greater. bral-basilar and the internal carotid systems join at the base of the brain to form the cerebral arterial circle (of Electroencephalogram Willis). Electroencephalography uses large recording elec- !e cerebral cortex is served by the three major trodes placed on the scalp (Figure 2.7). !e activity cerebral arteries (Figures 2.5 and 2.6): seen on the electroencephalogram (EEG) represents t !e anterior cerebral artery supplies the medial the summated activity of large ensembles of neurons. aspect of the frontal and parietal cortices, with More speci#cally, it is a re"ection of the extracellular terminal branches extending a short distance out current "ow associated with the summed activity of of the sagittal #ssure onto the lateral surface of the many individual neurons. Most EEG activity re"ects brain. activity in the cortex, but some (e.g., sleep spindles) t !e posterior cerebral artery serves the medial represents activity in various subcortical structures. and most of the lateral aspect of the occipital lobe, !e record generated re"ects spontaneous voltage as well as portions of the ventral aspect of the "uctuations. Abnormalities in the brain can produce 9 temporal lobe. pathological synchronization of neural elements that Gross anatomy of the brain

Figure 2.7. An example of a normal electroencephalogram (EEG). Metal sensors (electrodes) placed on various scalp locations are used to record the electrical activity of the brain. The actual brain electrical signal is ampli"ed 10 000 times before it can be recorded for visual inspection. The various electrodes are electronically connected to form mon- tages. The particular montage used for the example shown is listed on the left of the "gure. Note that the rhythmic sinus- oidal alpha activity is most developed on the occipital regions (electrodes 4, 8, 12, and 16).

can be seen, for example, as spike discharges represent- dura mater. !e subarachnoid space is #lled with cere- ing seizure activity. !e detection of seizure activity is brospinal "uid. one of the most valuable assets of the EEG. Sexual dimorphism and aging Meninges It has been found that men have signi#cantly larger vol- !e brain and spinal cord are surrounded by three umes of gray and white matter than women (7–10%) meninges: the dura mater, the arachnoid, and the pia when controlling for weight (Allen et al., 2003). !is mater. Blood vessels as well as cranial and spinal nerves di$erence is also present in neonates (Gilmore et al., all pierce the meninges. !e pia mater is intimate to 2007). In another study, women showed a higher pro- the surface of the brain and spinal cord and envelops portion of gray matter than men (0.46 vs 0.45, respect- the blood vessels that course along its surface. !e ively) and smaller ratio of white matter (0.29 vs 0.30, dura mater is a thick, heavy membrane that forms the respectively), but the di$erences were not signi#cant internal periosteum of the skull. !e dura is made up (Chen et al., 2007). Regionally, men have been reported of two layers, and these layers separate at several loca- to have larger gray matter volume in the le& parietal tions to form the venous sinuses, such as the superior lobe and bilaterally in the frontal and temporal lobes sagittal sinus (Figure 1.2). !e epidural space and the (Carne et al., 2006). Women have been shown to have subdural space are only potential spaces. !e arach- larger gray matter volumes in the cingulate gyrus, infer- 10 noid lies between the pia mater and the dura mater and ior parietal lobe, and right dorsolateral temporal cor- forms a very thin layer along the inner surface of the tex (Van Laere and Dierckx, 2001). Women also have References greater gyri#cation and #ssuration of the brain surface Shalev, A. 2003. Resting regional cerebral perfusion in than men (Luders et al., 2004, 2006). recent posttraumatic stress disorder. Biol. Psychiatry Gray matter volume begins to decrease at the 54:1077–1086. end of the #rst decade whereas white matter volume Bottmer, C., Bachmann, S., Pantel, J., Essig, M., Amann, M., begins to decrease at the end of the fourth decade Schad, LR, Magnotta, V., and Schröder, J. 2005. Reduced cerebellar volume and neurological so& signs in #rst- (Courchesne et al., 2000). A group of 662 individ- episode schizophrenia. Psychiatry Res. 140:239–250. uals, controlled for age (63–75 years), were studied Carne, R.P., Vogrin, S., Litewka, L., and Cook., M.J. 2006. over four years. Brain tissue loss was observed to be Cerebral cortex: an MRI-based study of volume and 3 3.9 cm /year. !e largest rates of atrophy were seen variance with age and sex. J. Clin. Neurosci. 13: in the primary auditory, somatosensory, visual, and 60–72. motor cortices. !e orbital prefrontal cortex and Cascino, G.D., and Adams, R.D. 1986. Brainstem auditory hippocampus also showed age-related reduction in hallucinosis. Neurology 36:1042–1047. volume (Salat et al., 2004). !e hippocampus loss Castellanos, F.X., Lee, P.P., Sharp, W., Je$ries, N.O., appears to accelerate in the sixth decade (Raz et al., Greenstein, D.K., Clasen, L.S., Blumenthal, J.D., and 2004). Loss of white matter was much less than that of James, R.S. 2002. 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Chapter 3 Histology

Introduction Nissl substance !e adult brain weighs between 1100 and 2000 g. It contains an estimated 100 billion neurons. !e average neuron has up to 10 000 synapses. At least a third Soma Mitochondrion of this immensely complex system is dedicated to the Axon hillock Nucleus function of behavior. Initial segment Golgi apparatus Two types of cells make up the nervous sys- Myelin tem: neurons and neuroglial cells (glia). Neurons are specialized to conduct bioelectrical messages, whereas Axon the glial cells play an interactive and supportive role. Polysome Both are involved in the production and management Dendrite of neurotransmitters. Figure 3.1. Major components of a typical neuron cell body. The The neuron cytoskeleton and lysosomes have been omitted. !e neuron is the structural and functional unit of the nervous system. It is made up of four distinctive regions: the soma (nerve cell body), the dendrites, Nerve cell body the axon, and the synapse (Figures 3.1 and 3.4). !e soma is the metabolic center of the cell and contains the cell nucleus. !e nucleus is centrally located in the Myelinated axon soma, and the cytoplasm immediately surrounding the nucleus is called the perikaryon. Most neurons have several dendrites, but each neuron has a single axon (Figure 3.2). !e cytoplasm of the axon is called the axoplasm. !e axon arises from a specialized region of the cell body called the axon hillock Axon terminal (Figure 3.1) that is specialized to facilitate the propaga- tion of the all-or-none action potential. Dendrites Nissl substance (rough endoplasmic reticulum) and Golgi apparatus are restricted to the perikaryon and to Direction of impulse the base of the dendrites. !ey synthesize proteins for use throughout the neuron. !ree classes of proteins Figure 3.2. Signals pass from the dendrite to the cell body to the are produced. One of the classes produced in the peri- axon of the neuron. karyon includes the neurotransmitters. Substances to be used in the axon for growth, for membrane repair, and for the neurotransmitters must be packaged into Neuron cell membrane vesicles and transported along the axon to the pre- !ere is a di$erence in electrical potential across the synaptic axon terminal. !erefore the axon and its syn- resting neuron cell membrane of about 70 millivolts 14 aptic terminal are dependent on the cell body for their (mV). !is di$erence is due to an excess of negatively normal function and survival. charged ions on the inside of the membrane relative The neuron to the outside. !ree processes are responsible for this Dendrites di$erence: an ion pump, simple di$usion, and electro- Dendrites are extensions of the cell body and expand static charge. Ion pumps move selected ions from one the receptive surface of the cell. !ey branch repeatedly side of the cell membrane to the other. !e sodium/ and, beginning a short distance from the cell body, are potassium pump moves sodium ions to the outside covered by cytoplasmic extensions called gemmules or and potassium ions to the inside. It is largely respon- dendritic spines. !e spines further increase the recep- sible for the membrane potential. !e membrane is not tive surface area of the dendrites. freely permeable to ions, and ions can cross the membrane only through the transmembrane channels. !e channels are controlled by transmembrane proteins. Axon Di$erent channels are specialized to allow only speci#c !e axon may be short but is typically depicted as ions to pass. !ere are ion channels for potassium (K+), being many times longer than the dendrites and, sodium (Na+) and chloride (Cl–). Nongated channels are in fact, may extend up to a meter from the cell body. always open whereas gated channels only open or close Microtubules and neuro#laments (micro#laments) are in response to speci#c stimuli. !e nongated channels found throughout the cytoplasm of neurons and are of restrict the rate of ion transfer and the pump normally particular interest in the axon. Microtubules measure is able to maintain the resting potential against the approximately 20–25 nm in diameter (a nanometer incoming tide of ions through the nongated channels. is one millionth of a millimeter), are hollow cylin- Gated channels may be voltage-gated or ligand-gated. ders, and are made of the protein tubulin. !ey are the Voltage-gated channels open in response to a change in highways of the axon, that is, they are involved in the membrane electrical potential. Ligand-gated channels transport of macromolecules up and down the axon. open in response to the binding of a signal molecule Neuro#laments are approximately 10 nm in diameter (ligand), such as a neurotransmitter. and provide skeletal support for the neuron. !ere are four specialized regions of the neuron cell Substances produced in the soma must be transmembrane: ported along the axon to reach the cell membrane t !e receptive region is represented by the of the axon as well as the axon terminal (Figure 3.3). dendrites and, to a lesser extent, the neuron Substances are normally thought of as being trans- cell body. When the dendrite membrane is ported from the soma to the axon terminal; however, depolarized, a wave of negativity passes down transport from the axon terminal back to the soma also the dendrite toward the cell body cell membrane occurs. and the axon hillock. As the wave continues along t Anterograde (orthograde) axon transport carries the membrane of the dendrite and cell body, the substances from the soma to the axon terminal. amplitude of the voltage decreases due to the Anterograde transport may be fast (3–4 cm/ resistance inherent in the membrane. day) or slow (1–4 mm/day). Fast axon transport t !e trigger region for the generation of the all-or- moves synaptic vesicles or their precursors via none action potential is represented by the axon motor molecules along the external surface of the hillock. If the wave of negativity from the dendrite microtubules. Organelles, vesicles, and membrane is of su%cient magnitude when it arrives at the glycoproteins are carried by fast axon transport. axon hillock, an all-or-none action potential is Slow axon transport re"ects the movement of the produced in the initial segment of the axon. entire axoplasm of the axon. Neuro#laments and t !e conductance region of the neuron cell components of microtubules are two elements that membrane is represented by the axon. Where move by slow axon transport. the axon is myelinated, there are no sodium t Retrograde axon transport carries substances ion channels and the electrical signal must pass back from the axon terminal to the nerve cell through the cytoplasm to the next node of Ranvier. body. Microtubules are involved in retrograde !e neuron cell membrane at the node contains axon transport. !e speed of retrograde transport many ion channels where the action potential is is about half that of fast anterograde transport. renewed. Metabolic by-products and information about the t !e output region of the neuron is represented by condition of the axon terminal are sent back to the 15 the axon terminal. cell body by retrograde transport. Viruses (e.g., Histology

Anterograde transport Action potential V 1 Mm

Synaptic vesicle Ca2+ Retrograde transport 2

6 Reuptake Endocytosis

Figure 3.3. Microtubules are important in fast axon transport. Enzyme 3 Presynaptic Motor molecules (Mm) attach the vesicles (V) to the microtubules degradation Neurotransmitter 5 receptor site (Mt). Vesicles and mitochondria move at rates of up to 4 cm per day. 6 Postsynaptic Microtubules do not extend the entire length of the axon, and the receptor site vesicles can transfer across overlapping microtubules. Anterograde 4 and retrograde transport can take place at the same time over a single microtubule. Postsynaptic cell Figure 3.4. A chemical synapse. The arrival of the action potential at the synapse terminal (1) opens the calcium channels (2). The rise herpes, rabies, polio) as well as toxic substances in intracellular Ca2+ releases neurotransmitter into the synaptic cleft (e.g., tetanus toxin, cholera toxin) taken up by the (3). The neurotransmitter depolarizes the postsynaptic membrane (4) and sends an inhibitory feedback signal to the presynaptic cell (5). nerve terminal may be transported back to the cell The neurotransmitter is metabolized or returns to the presynaptic body by this same mechanism. terminal, or both (6). All the axon terminals of the same neuron contain the same neurotransmitters. However, there may A basic chemical synapse consists of a presynaptic be more than one transmitter found in a single neu- element and a postsynaptic element separated by a syn- ron. When two or more neurotransmitters coexist aptic cle& of 10–20 nm. Within the central nervous sys- within a single neuron, one is usually a small-molecule tem (CNS), the postsynaptic tissue is usually another transmitter, whereas the second (or more) is usually a neuron. !e presynaptic element is usually an axon ter- peptide. minal, although dendrites and even cell bodies can be a presynaptic element. !e postsynaptic element is usu- Synapse ally a receptor located on a dendrite or dendritic spine !e synapse is the junctional complex between the but also may be a receptor found on the cell body, or on presynaptic axon terminal and the postsynaptic tissue the initial segment or terminal of an axon. (Figure 3.4). !ere are two types of synapse: the elec- !e chemical synapse can be identi#ed in an electrical synapse and the chemical synapse. Electrical tron micrograph by the large number of synaptic vesi- synapses provide for electrotonic coupling between cles clustered in the axon terminal on the presynaptic neurons and are found at gap junctions between neu- side of the synaptic cle& (Figure 3.4). Each synaptic ves- rons. !ey permit bidirectional passage of ions directly icle is #lled with several thousand molecules of a chem- from one cell to another. Electrical synapses are found ical neurotransmitter. !e arrival at the axon terminal in situations in which rapid stereotyped behavior is of the action potential triggers an in"ux of calcium ions needed and are uncommon in the human nervous across the axon membrane into the axon terminal [(2) system. in Figure 3.4]. !e in"ux of calcium ions causes synap- One example of electrotonic coupling is found tic vesicles located near the presynaptic membrane to between axons of the neurons of the locus ceruleus fuse with the membrane and release the neurotrans- (Chapter 10). It is proposed that these junctions help mitter into the synaptic cle& – a process called exocyt- synchronize the discharge of a small grouping of osis [(3) in Figure 3.4]. closely related locus ceruleus neurons to optimize the Axon terminals can terminate on a dendrite (axo- regulation of tonic and phasic activity of the locus cer- dendritic), on the spine of a dendrite (axospinous), on uleus and release of norepinephrine (Aston-Jones and the neuron cell body (axosomatic), or on another axon 16 Cohen, 2005). terminal producing an axoaxonic synapse. Axoaxonic The neuron arrangements allow for regulation of speci#c termi- facilitate the entry of Ca2+. !is triggers depolariza- nals of a neuron and not the whole neuron, as would, tion of the postsynaptic membrane. Axon terminals for example, the actions of an axodendritic synapse. located on the axon terminal of another axon are usu- Many axon terminals have receptor sites imbedded ally inhibitory. !ey inhibit the entry of Ca2+ into the in their membrane sensitive to the neurotransmitter presynaptic terminal and in this way can produce pre- that they release. !ese are referred to as autorecep- synaptic inhibition. Neurotransmitters are potent and tors. Activation of an autoreceptor functions as part of typically only two molecules of a neurotransmitter are a negative feedback loop to inhibit continued release of required to open one postsynaptic ion channel. !e transmitter. Autoreceptors may also be located on the response seen in the postsynaptic cell is dependent on proximal axon or cell body. Most of these neurons have the properties of the receptor rather than on the neuro- feedback axon collaterals or very short axons. transmitter, that is, the same neurotransmitter may Synapses are associated with a number of special- excite one neuron and inhibit another. ized proteins that are asymmetrically distributed. For Synapses located on distal dendrites and dendritic example, the presynaptic site contains specializations spines tend to be excitatory. For example, synapses of for transmitter release and the postsynaptic site con- cortical neurons located on the distal dendrites and tains receptors and ion channels for depolarization. dendritic spines are glutamate-sensitive. Glutamate Adhesion molecules are anchored in the membranes receptors are excitatory and the constant presence on both sides of the cle& and function to maintain a of glutamate tends to drive neurons continuously. proper distance between the presynaptic and post- Synapses located more proximally on the dendrites are synaptic membranes. !ey are important in target γ-aminobutyric acid (GABA)-sensitive and are inhibi- recognition when new synapses are formed. Once tory. !e GABA receptors function as “GABA-guards” the synapse is formed adhesion molecules promote to prevent overstimulation of the neuron by blocking mechanical security and help regulate proper func- discharges coming down the dendrite. Both excitation of the synapse (Yamagata et al., 2003). Neurexins tory and inhibitory synapses are found on the nerve and neuroligins are proteins that represent a class of cell body. Synapses found on axon terminals tend to be adhesion molecules, and like other adhesion molecules inhibitory in function. are important in forming and maintaining synapses. Synapses change in response to stimuli. It is thought Genetic alterations that a$ect neurexins and neuroli- that some of these changes re"ect a structural basis of gins may play a role in autism (Sebat et al., 2007). learning. Within the cortex, the number of synapses Small (40 nm) vesicles are found in all presynaptic appears to be stable within a given region, however, terminals. Large (100 nm) vesicles are found along with elements of individual synapses are subject to change. small vesicles in some terminals. Some of the small ves- !e number of vesicles physically docked to the pre- icles viewed with the electron microscope appear "at- synaptic membrane (the readily releasable pool) may tened and some appear dark. Some of the large vesicles change as well as the number of vesicles held in reserve have a dense core. !e di$erences re"ect the di$erent away from the membrane (the reserve pool). !e pre- neurotransmitter found in each. For example, clear synaptic membrane may change in size and as a result and "attened vesicles are found in inhibitory axon ter- be capable of releasing more neurotransmitter (Zucker, minals. Small molecule transmitters are found in small 1999). !e presynaptic element may also change shape, vesicles whereas neuropeptides are found in large vesi- including the size of the neck of the synaptic spine cles. Some large vesicles contain both a neuropeptide (Marrone et al., 2005), the curvature of the cle&, and and a small molecule transmitter. perforations in the presynaptic membrane (Marrone, Chemical transmission consists of two steps: the 2007). #rst is the transmitting step, in which the neurotransmitter is released into the synaptic cle& by the presynap- Receptors and receptor mechanisms tic cell, and the second is the receptive step in which Receptors represent specialized regions of the neuron the neurotransmitter becomes bound to the receptor cell membrane. Channels through the membrane in site in the postsynaptic cell. Receptor sites located in these regions can be triggered to open (or close) and the membrane of the postsynaptic cell are sensitive change the transmembrane electrical potential. to and respond to the presence of a neurotransmitter. !e fast-acting, ionotropic receptor consists of !e action of an excitatory presynaptic terminal is to an ion channel that spans the neuron cell membrane. 17 Histology

!e neurotransmitter receptor site is located on the Primary messenger extracellular surface of the wall of the ion channel Primary effector itself. Some ion channels have an additional binding Receptor Ion channel site for a regulator molecule. Anesthetics, alcohol, etc., are believed to have their e$ect on ionotropic Extracellular side receptors. !e slow-acting, metabotropic receptor has a dif-

ferent con#guration. !e receptor spans the neuron Intracellular side cell membrane just as does the ion channel of the iono- Transducer tropic receptor, but it cannot open to allow the passage protein of ions (Figure 3.5). !e slow receptor is linked by an Secondary intracellular protein to the ion channel that the recep- messenger tor controls in an indirect manner. !e linking pro- Figure 3.5. The opening of an indirect ion channel is a multistep tein is called a G-protein (guanine nucleotide-binding process. The receptor, primary e#ector and ion channel span the cell membrane. The primary messenger is the neurotransmitter. protein), and the receptors are called G-protein– The receptor activates a transducer protein, which excites primary linked receptors. G-protein receptors include α- and e#ector enzymes to produce a secondary messenger. Secondary β-adrenergic, serotonin, dopamine, and muscarinic messengers may act directly on the ion channel or through several steps. acetylcholine (ACh) receptors as well as receptors for neuropeptides. !e G-protein is loosely associated with the inner layer of the neuron cell membrane and Neurotransmitter removal consists of three subunits. !e subunits vary depend- Timely removal of neurotransmitters from the synap- ing on the receptor with which they are a%liated and tic cle& prepares the synapse for continued usage. Four the e$ector enzyme with which they communicate and mechanisms are involved in transmitter removal: they also vary as to whether they excite or inhibit the t Active reuptake returns the transmitter substance e$ector enzyme. into the presynaptic nerve terminal. !is is When activated by a receptor, the subunit of the the most common inactivation mechanism. G-protein binds with a second messenger. Four major Reuptake mechanisms have been described for second messengers are recognized [calcium, cyc- norepinephrine, dopamine, serotonin, glutamate, lic nucleotides (cAMP and cGMP), inositol triphos- GABA, and glycine. phate, and diacylglycerol]. !e second-messenger t All neurotransmitters are passively removed molecule may directly open (or close) an ion chan- to some degree by di$usion into the adjacent nel but more o&en initiates a cascade of enzymatic extracellular space. activity within the neuron cytoplasm. More than one t Enzyme systems break down neurotransmitters. second- messenger system may exist within a neuron, For example, ACh is removed by the action of the and cross talk can occur during the operation of two or enzyme acetylcholinesterase (AChE). more second-messenger systems. Ampli#cation of the signal can occur with second messengers. More than t Glial cells and astrocytes, in particular, play a role one G-protein may be activated by a single receptor, in transmitter removal. and second messengers can di$use to a$ect a distant Many drugs take advantage of neurotransmitter part of the neuron. Second-messenger systems also can removal mechanisms: for example, monoamine oxi- induce the synthesis of new proteins by altering gene dase inhibitors block the degradation of amine trans- expression, thus altering the long-term function of mitters; cocaine blocks the reuptake of monoamines the neuron, including cell growth. Second-messenger, (norepinephrine, dopamine, and serotonin); tricyclic metabotropic systems operate relatively slowly, can antidepressants block the reuptake of epinephrine and interact with other transmitter systems within the serotonin; and selective serotonin reuptake inhibitors neuron, and operate at some distance from the recep- (SSRIs) selectively block the reuptake of serotonin. tor site. !e resulting action, which is relatively slow, is o&en described as one that modulates neuron activ- Neurotransmitters ity. !e neurotransmitter activating such a receptor is 18 To qualify as a neurotransmitter, a chemical must be rec- sometimes termed as neuromodulator. ognized to be synthesized in the neuron, to be present Neurotransmitters in the presynaptic terminal, to depolarize the postsyn- in subcortical regions. Although ACh does not have a aptic membrane and #nally, must be removed from the primary excitatory role, it increases excitability though synaptic cle& in a timely fashion. More than 100 sub- the activation of muscarinic receptors. stances have been recognized as neurotransmitters. Acetylcholine is associated with the control of !ere are two general classes of neurotransmit- cerebral blood "ow (Sato et al., 2004), cortical activ- ters based on size: small-molecule neurotransmitters ity (Lucas-Meunier et al., 2003), sleep–wake cycle (Lee and neuropeptides. Small-molecule neurotransmitter et al., 2005), and cognitive function and cortical plasti- precursors are synthesized in the soma. !e precursors city (McKinney, 2005). ACh is important in cognitive are transported to the axon terminal by way of rapid processes and damage to the basal forebrain cholin- anterograde axon transport where they are assembled ergic system produces cognitive de#cits (McKinney, into neurotransmitters, which are stored in synaptic 2005). It plays a role in the formation of new synaptic vesicles. Degraded (used) small-molecule neurotrans- contacts in the forebrain related to cognition (Berger- mitters can be remanufactured within the axon ter- Sweeney, 2003). minal. Neuropeptide neurotransmitters are less well Basal forebrain cholinergic neurons undergo understood. !ey are short-chain amino acids con- moderate degenerative changes during normal aging sisting of three to 36 amino acids. !ey are supplied to and are related to the progressive memory decline of the axon terminal in #nal form. !ey are also stored in aging. Greater cell loss accompanies disorders such as vesicles in the synaptic terminal. Following exocytosis, Parkinson disease, Down syndrome, and Korsako$ however, neuropeptide neurotransmitters must be syndrome, and Alzheimer disease, as well as follow- returned to the neuron cell body for remanufacture. ing excessive chronic alcohol intake and head trauma Four common small-molecule neurotransmitters (Bartus et al., 1982; Bohnen et al., 2003; Terry and are the amino acid neurotransmitters glutamate (GLU), Buccafusco, 2003; Toledano and Alvarez, 2004; Garcia- aspartate (ASP), GABA, and glycine (GLY). Another Alloza et al., 2005; Salmond et al., 2005; Schliebs and group of small-molecule neurotransmitters consists of Arendt, 2006). the biogenic amines including ACh, serotonin (5-HT), Postmortem studies of patients with schizophrenia histamine, and the catecholamines dopamine (DA), have reported decreased muscarinic receptor dens- epinephrine (EPI), and norepinephrine (NE). ity. !e results are region-speci#c and include regions known to be a$ected in schizophrenia (e.g., frontal Acetylcholine cortex, basal ganglia, and hippocampus). Whether the Although better known as the neurotransmitter of spi- e$ects are primary or secondary is not known (Tandon, nal cord motor neurons, ACh is also a neurotransmitter 1999; Raedler et al., 2007). within the CNS. Short-axon cholinergic interneurons are found in the striatum. Long axon cholinergic pro- Glutamate jection neurons are found primarily in the nucleus Glutamate is the workhorse excitatory neurotransmit- basalis (of Meynert), which is located in the substan- ter of the CNS. Nearly all CNS neurons are glutama- tia innominata of the basal forebrain. Fibers from the tergic. GLU is regulated within the synaptic cle& by nucleus basalis project preferentially to the frontal and the rate of release and reuptake. Glial cells take up the parietal lobes. A smaller number of cholinergic projec- majority of GLU, with neurons responsible for some tion neurons are located in the nearby diagonal band reuptake (Shigeri et al., 2004). Reuptake is particularly (of Broca) and in the magnocellular preoptic nucleus important in preventing excitotoxicity resulting from of the hypothalamus. Brainstem cholinergic nuclei high levels of GLU in the synaptic cle&. Reduced levels include the paramedian pontine tegmental nucleus and of glial cells in brain regions identi#ed as abnormal in the laterodorsal (lateral and dorsal) tegmental nuclei. patients with mood disorders raises the question of the !ere are two main classes of ACh receptor: nico- ability of glial cells in these areas to maintain normal tinic and muscarinic. Nicotinic receptors are fast-acting GLU levels (Ullian et al., 2001). Indirect evidence links ionotropic receptors whereas muscarinic receptors are GLU and anxiety disorders and posttraumatic stress slow-acting metabotropic receptors. Nicotinic receptor disorder (PTSD) (Cortese and Phan, 2005). N-methyl- subtypes include α and β. Muscarinic subtypes are M1 *-aspartate (NMDA) receptor overactivity resulting in and M . M receptors are more common in the cortex neuronal death is involved in neurodegenerative disor- 2 1 19 and striatum whereas M2 receptors are more common ders, including Alzheimer disease, Huntington disease, Histology

and human immunode#ciency virus (HIV)-associated depression (Nudmamud-!anoi and Reynolds, 2004). dementia (Lancelot and Beal, 1998; Kaul et al., 2001). Karolewicz et al. (2004) reported that nitric oxide Glutamate is synthesized in astrocytes and con- synthetase, which is activated by NMDA stimulation, verted to glutamine that can be transferred to neurons, was reduced in patients with depression. Patients where it can be converted to glutamate. !is forms with unipolar major depression have been shown to the “glutamate–glutamine cycle.” Disruption of the have increased glutamate levels coupled with reduced glutamate–glutamine cycle may play a role in schizo- GABA levels, suggesting a disruption in the normal phrenia. It has been shown that astrocytes in brains glutamate:GABA ratio (Sanacora et al., 2008). !is dis- with schizophrenia are more vulnerable to mechan- ruption is speculated to be due to glial cell dysfunction ical damage than healthy brains (Niizato et al., 2001). (Kugaya and Sanacora, 2005). Healthy persons exhibit- Evidence suggests that in schizophrenia, GLU is trans- ing anxiety as well as persons diagnosed with anxiety ferred normally from neurons to astrocytes but that it disorders have been reported to show increased levels accumulates in abnormal amounts in the astrocytes, of GLU in the frontal cortex and anterior cingulate cor- implying a disturbance of the glutamate–glutamine tex (Grachev and Apkarian, 2000; Phan et al., 2005). cycle. A decrease in GLU synthetase found in the brains GLU levels have also been found to be abnormal in the of patients with schizophrenia lends further credence anterior cingulate cortex in adult patients with atten- to this hypothesis (Burbaeva et al., 2003). tion de#cit/hyperactivity disorder (Perlov et al., 2007). !ere are a number of GLU receptor sites, many of Many genes associated with schizophrenia are which work in conjunction with other substances. !e known to play a role in synaptogenesis (Stephan et al., best known receptor is the NMDA ionotropic recep- 2006; Straub and Weinberger, 2006). Several of these tor. !is receptor is critical for maintaining prolonged target the NMDA receptor and control proteins that act excitatory responses such as those seen in the wind-up to strengthen the synapse. Dysfunction of NMDA con- of pain signals in the spinal cord substantia gelatinosa, trol proteins can result in hypofunction of the NMDA long-term potentiation in the hippocampus, and epilep- synapse: the NMDA receptor hypofunction hypothesis tiform activity. !ere are at least #ve NMDA subtypes. of schizophrenia (Stahl, 2007a). Weak synapses with Most glutamatergic synapses contain both NMDA and AMPA receptors may be pruned, but this process takes α-amino-5-hydroxy-3-methyl-4-isoxazole propionic time. In addition, synaptic pruning is very active dur- acid (AMPA) receptors (see below). ing adolescence. !is may explain why schizophrenia Non-NMDA GLU receptors include AMPA, kain- onset is associated with the adolescent period of life ite, and metabotropic receptors. !ere are a number of (Stahl, 2007b). subtypes of each. Synaptic currents produced by AMPA Evidence indicates a decreased production or receptors are faster and shorter acting than those pro- release, or both, of GLU in the brains of patients with duced by NMDA receptors. Metabotropic receptors schizophrenia, especially in the hippocampal and are least understood and several act in an inhibitory dorsolateral prefrontal cortex. Reduced GLU is accom- fashion. panied by an increase in GLU receptors and in receptor Aspartate activates NMDA receptors weakly. sensitivity (Tsai et al., 1995). !is, along with reports Glycine and *-serine act on many NMDA receptors as of alterations in dopamine in schizophrenia, has pro- co-agonists. Zinc (Zn2+) is reported to co-localize with duced the “glutamate hypothesis of schizophrenia.” GLU in many cortical neurons, and zinc accumulation !is hypothesis describes a balance between dopamine may play a role in excitotoxicity (Jeng and Sensi, 2005; and GLU in the cortex. !ese two neurotransmitters Sekier et al., 2007). Nitric oxide is a gas neurotrans- normally produce a balanced signal in the basal ganglia mitter that is activated by the calcium in"ux induced (striatum) that results in an optimal feedback from the by activation of the GLU receptors. It is involved basal ganglia and thalamus to the cortex. An increase in excitotoxicity, synaptic plasticity, and long-term in dopamine or a decrease in GLU would upset this bal- potentiation. Some anesthetics and recreational hallu- ance and could result in psychosis (Tamminga, 1998; cinogenic drugs are NMDA receptor antagonists. Carlsson et al., 1999). !e NMDA receptor is important in memory and Glutamate may be involved in both the establish- neuroprotection (Quiroz et al., 2004). A reduction in ment and maintenance of addictive behavior. A greater density re"ecting the glycine site of NMDA receptors number of GLU receptors are established in sensi- 20 has been reported in patients with bipolar disorder and tive regions as cocaine addiction is established. It is Neurotransmitters proposed that increased levels of GLU in the amygdala Neural networks in the cortex consist of two gen- mediate the craving experienced by cocaine addicts eral types of neuron. Excitatory projection neurons are (Kalivas et al., 1998). glutamatergic. !e remainder consists of local circuit AMPA receptors may be involved in depression. interneurons, which make up 20%–30% of all cortical AMPA activation has been shown to increase levels neurons, most of which are GABAergic (Di Cristo, of brain-derived neurotropic factor (BDNF) (Zafra 2007). GABAergic neurons in the amygdala and pos- et al., 1990). BDNF promotes neuron proliferation sibly elsewhere have kainite glutamatergic endings and survival within the CNS as well as synapse for- located on their somatodendritic regions as well as mation. Levels of BDNF have been shown to increase axon terminals where they regulate GABA release. in response to antidepressant drugs (Duman, 2004)). Norepinephrinergic endings on GABAergic neurons in !e time required to increase BDNF levels may be the amygdala also regulate GABA output (Aroniadou- responsible for the delay in response to antidepres- Anderjaska et al., 2007). sants (O’Neill and Witkin, 2007). In addition, evidence !e GABAA receptor is the target of benzodi- has been found of reduced AMPA receptor pathways in azepines, anesthetics, barbiturates, and alcohol. !ese depressed suicide patients (Dwivedi et al., 2001). drugs operate at di$erent sites but all function to Glutamate NMDA synapses in the hippocampus increase the opening of the channel and increase post- of rats exposed to sensory stimuli (by stimulating only synaptic inhibition. !e GABAA receptor is involved one whisker) have been shown to result in a change in acute actions of alcohol as well as alcohol tolerance in synaptic strength (synaptic plasticity). !e same and dependence (Hanson and Czajkowski, 2008). stimulation continued over time resulted in further Variations in the GABAA receptor genes may contrib- synaptic strengthening accompanied by the insertion ute to the vulnerability to alcoholism (Krystal, et al., of new GLU AMPA receptors into the synaptic mem- 2006). brane (Clem et al., 2008). !e di$erent stages of syn- Low GABA activity or low levels of GABA have been aptic strengthening may correspond with stages of associated with anxiety (Nutt, 2006). !erapies e$ect- memory formation. ive in enhancing relaxation also result in increased levels of GABA (Streeter et al., 2007). Studies suggest that γ-Aminobutyric acid GABA levels are decreased in individuals with depres- γ-Aminobutyric acid is the major inhibitory neuro- sion (Krystal et al., 2002; Brambilla et al., 2003). GABA transmitter in the brain, and it acts to hyperpolar- in physiological situations regulates cortical circuits ize the postsynaptic membrane. GABA may activate and the plasticity of those circuits (Hensch and Stryker, receptors on the presynaptic or postsynaptic side of 2004). GABAergic downregulation has been reported the synaptic cle&. It is found primarily in small, local in the prefrontal cortex in psychosis and it is believed circuit interneurons, and it is removed from the cle& this is through regulatory action of glutamatergic neu- by astrocytes and by reuptake into the GABAergic rons (Guidotti et al., 2005). presynaptic neuron. !ere are three classes of GABA GABA in the developing brain plays an excitatory receptors: GABAA, GABAB, and GABAC. GABAA role. !is action appears to be instrumental in sig- receptors are the most common; they are directly naling and controlling proliferation, migration, and linked to an ion channel and operate quickly (iono- maturation of neurons. Once neuronal maturation is tropic). !ree major GABAA receptor types are complete, GABA activity becomes inhibitory (Ben- recognized (α, β, and γ -A). GABAB receptors are Ari, 2002). !is has implications of the e$ects of in metabotropic; they use a second messenger and oper- utero exposure to drugs such as diazepam (Valium). ate more slowly. GABAC receptors have been described It is suggested that alterations in GABA function dur- almost exclusively as receptors on the horizontal cells ing the prenatal period has a role in the formation of of the retina. !ey are ionotropic receptors. More abnormal cortical circuits (Di Cristo, 2007). recent studies indicate they are also found in many areas the brain, where their function is unknown Glycine (Schmidt, 2008). Although GABA is an inhibitory Glycine is an inhibitory neurotransmitter. Serine neurotransmitter, GABAergic neurons may synapse hydroxymethyltransferase (SHMT) is present in mito- on other GABAergic neurons and thus produce exci- chondria of neurons and glial cells; SHMT converts tation through the process of disinhibition. +-serine to glycine. !e GLY cleavage system (GCS), 21 Histology

believed to be localized in astrocytes, is a four-enzyme At the same time these neurons become more sensi- complex that breaks down GLY. !e serine resulting tive to speci#c sensory inputs indicating that NE func- from the GCS is transported to nearby neurons, where tions to increase the signal-to-noise ratio for sensory it serves as the endogenous ligand for the glycine-bind- signals (Segal and Bloom, 1976). NE is associated with ing site or is converted to GLY (Yang et al., 2003). !e arousal, vigilance, and reward dependency (Cloninger, conversion of +-serine to GLY may operate much like 1987; Menza et al., 1993). NE hyperactivity can lead the glutamine–glutamate cycle. to insomnia, weight loss, irritability, agitation, and a Glycine is found as a neurotransmitter primarily in reduction in the pain threshold. Peripheral NE hyper- the ventral spinal cord, where its action is inhibitory. In activity results in symptoms of anxiety (i.e., tachycar- the brain GLY acts as a co-agonist at NMDA-type glu- dia, muscular cramps, and increased blood pressure). tamate receptors and in this situation potentiates the A decrease in NE activity is associated with some forms e$ect of GLU, that is, it facilitates excitation rather than of depression, and an increase of NE is linked with act as an inhibitor. Small levels of GLY added to anti- mania (Schildkraut, 1965). Abnormal regulation of psychotic drugs are reported to improve both negative NE levels in the CNS is implicated in attention-de#cit and positive symptoms in patients with schizophre- hyperactivity disorder (Pliszka, 2005). nia (Heresco-Levy and Javitt, 2004; Shim et al., 2008). Reduced levels of GLU and GLY have been found in Dopamine patients with refractive unipolar and bipolar disorder, Most of the dopaminergic neurons of the brain are most of who were depressed at the time of the study found in the substantia nigra pars compacta (the A9 (Frye et al., 2007). Another study found increased levels nucleus). A smaller concentration of DA neurons is of GLY in the plasma of patients with bipolar disorder found in the nearby ventral tegmental area (A10) and who were in the manic phase. !e authors suggested the retrorubral area (A8). !ere are four major DA sys- that the changes in GLY levels are more critical than tems in the brain: changes in those of GLU (Hoekstra et al., 2006). t One extends from the substantia nigra and Startle disease (hyperexplexia) is due to a mutation retrorubral area to the striatum (nigrostriatal in chromosome 5 that results in a defect in the GLY system) and is associated with motor activity of the receptor (Garg et al., 2008). !is causes an exaggerated basal ganglia (Chapter 7). startle re"ex because of the loss of normal inhibition. t Two arise from cells located in the ventral Norepinephrine tegmental area of the mesencephalon (Figure Norepinephrine is produced primarily by neurons that 10.3). One makes up the mesolimbic system make up the locus ceruleus, and it is also formed in and extends to the nucleus accumbens, which some small nearby nuclei. NE is involved with arousal is involved with reward and reinforcement. !e and alertness, and functions to help focus attention on second is the mesocortical system and projects to salient stimuli. It is released in response to stress and the prefrontal cortex, where it acts in support of has a role in stress-induced reinstatement of drug use as cognitive activity. well as depression (Leri et al., 2002; Dunn et al., 2004). t One extends from the arcuate nucleus of NE receptors make up two groups, α-adrenergic and the hypothalamus to the median eminence β-adrenergic, both of which are metabotropic. Each (tuberoinfundibular pathway), where DA inhibits group contains three subgroups. Fibers from the locus the release of prolactin from the pituitary gland ceruleus descend to the spinal cord. !ere are two spe- (Chapter 8). ci#c ascending pathways. !e dorsal norepinephriner- !ere are #ve DA receptors, which make up two fam- gic system arises from the locus ceruleus and projects ilies; D1-like and D2-like.!e D1-like family consists of to the hippocampus, cerebellum, and forebrain. !e the D1 and D5 receptors, which are excitatory. D2, D3, ventral norepinephrinergic system arises from a num- and D4 receptors make up the D2-like family and are ber of small nuclei in the lateral medulla and pons, and inhibitory. D1 receptors are concentrated in the stri- projects to the hypothalamus, midbrain, and extended atum, nucleus accumbens, and olfactory tubercle. amygdala (Moore and Bloom, 1979). D2 receptors are also found in the striatum, nucleus Norepinephrine released in the cortex inhibits accumbens, and olfactory tubercle, as well as on DA cell 22 the spontaneous, resting activity of cortical neurons. bodies, where they act as autoreceptors. D3 receptors Neurotransmitters are fewer in number, with most found in the nucleus the paranoid psychosis that is o&en seen in amphet- accumbens and olfactory tubercle. D4 receptors are amine and cocaine addicts can be clinically indistin- sparse and located in the frontal cortex, midbrain, and guishable from paranoid schizophrenia and appears amygdala. !ere are up to 18 variants of the D4 receptor to be due to DA activation (Manschreck et al., 1988). type. !e D4.7 variant has been associated with ADHD !e DA hypothesis contends that negative and cog-

(Bobb et al., 2005). !e D4.7 receptor gene may be asso- nitive de#cits of schizophrenia are primary and arise ciated with a milder form of ADHD (Gornick et al., from DA insu%ciency in the frontal lobe (Andreasen

2007). D5 receptors also appear to be fewer in number et al., 1999). Positive symptoms arise from secondary and are found in the hippocampus and hypothalamus. hyperfunction of DA in the striatum (Abi-Dargham

D1, D2, and D3 receptors are related to motivation and Moore, 2003). A dopamine–glutamate theory and reward, whereas D4 and D5 receptors are more of schizophrenia has been proposed (Carlsson and involved with behavioral inhibition. Activation of D1 Carlsson, 1990; Carlsson et al., 1999). It is now believed receptors correlates with stimulus reward (e.g., food, that DA may not be directly related to schizophrenia alcohol, cocaine), reward-related learning, and remod- but may act in connection with glutamate. Abnormal eling of neuron dendrites in the nucleus accumbens in modulation by DA may a$ect the signal-to-noise ratio response to cocaine (Wolf et al., 2004; Lee et al., 2006). in the prefrontal cortex (Rolls et al., 2008).

Enhanced sensitivity of D1 receptors may contribute to Reduced cortical DA function has been reported addiction (Goodman, 2008). in schizophrenia and in Parkinson disease (Brozoski Dopamine in the cortex is described as acting as an et al., 1979). Raising DA levels in these same groups ampli#er, that is, its presence extends periods of quies- improves performance on tests that examine working cence in inactive glutamatergic neurons but increases memory (Daniel et al., 1991; Lange et al., 1992). Low and extends the periods of actively #ring glutamatergic DA levels may be associated with dysfunctional eating neurons (Kondziella et al., 2007). In contrast, the activ- patterns (Ericsson et al., 1997). ity of DA neurons projecting to the cortex from the Evidence suggests that the D1 receptor located in brainstem is regulated by cortical glutamatergic neu- the dorsolateral prefrontal cortex may be particularly rons either directly or via GABAergic interneurons, important in working memory and that an optimal acting as accelerator and brakes, respectively (Carlsson level of DA is critical in facilitating working memory. et al., 2001). It is hypothesized that novel stimuli Novelty-seeking behavior in humans and explora- increase the level of DA production in the midbrain, tory activity in animals are analogous (Cloninger, which in turn increases the degree of synaptic plasticity 1987) and may be related to the level of DA. Patients in the striatum (Redgrave and Gurney, 2006). with Parkinson disease have reduced levels of DA and Dopamine has an important role in the reward exhibit personality characteristics consistent with mechanisms. Amphetamines increase the concentra- reduced novelty seeking that can be described as com- tion of DA in the synaptic cle& by accelerating its release pulsive, industrious, rigidly moral, stoic, serious, and from synaptic vesicles. Cocaine increases levels of DA quiet (Menza et al., 1993). in the synaptic cle& by blocking reuptake transporters. !ese same D1 receptors are found predominantly Prolonged use of cocaine may dysregulate brain dopa- on the dendritic spines of pyramidal neurons, which minergic systems and can result in persistent hypo- place them in a position to directly a$ect corticotha- dopaminergia. !e downregulation of dopaminergic lamic, corticostriatal, and corticocortical projections. pathways due to long-term cocaine abuse may underlie D5 receptors are also associated with pyramidal neu- anhedonia and relapse in cocaine addicts (Majewska, rons but are localized to the sha&s of the dendrites. 1996). Permanent changes are seen in the anterior It is not surprising to #nd that a hyperactive DA sys- cingulate cortex pyramidal cell dendrites in rabbits tem can result in increased motor activity, whereas a exposed prenatally to cocaine (Levitt et al., 1997). hypoactive DA system can result in decreased motoric !e DA theory of schizophrenia proposes an excess activity (hypokinesia or akinesia) and a tendency of dopaminergic stimulation and is based on two to physical weariness. D2 receptors appear to be on observations (Snyder et al., 1974; Stone et al., 2007). GABA-containing interneurons and on some pyram- First, there is a high correlation between the e$ect- idal neurons (Goldman-Rakic and Selemon, 1997). ive dose of traditional neuroleptics and the degree Clinically e$ective antipsychotic drugs are antago- 23 to which they block D2 dopamine receptors. Second, nists of D2 receptors. For this reason, high levels of D2 Histology

receptors or excessive DA-mediated neurotransmis- the 5-HT2 class is excitatory. Many of the e$ects of sero- sion was thought to underlie schizophrenia (Nestler, tonin are through its modulation of DA and GABA 1997). A comparison of drug-free schizophrenia neurons (Yan et al., 2004). patients with a control group showed no di$erence in Selective serotonin reuptake inhibitors (SSRIs)

the density of D2 receptors in the striatum. No signi#- slow the reuptake of serotonin, making it more avail-

cant reduction in D1 receptor density was seen in the able to the postsynaptic cell and prolonging its e$ect prefrontal cortex of the patients with schizophrenia in the synaptic cle&. Low 5-HT levels can trigger high (Zakzanis and Hansen, 1998). carbohydrate consumption and are associated with In another study, patients with schizophrenia bulimia and carbohydrate preference in obese women showed greater amphetamine-induced release of DA (Bjorntorp, 1995; Brewerton, 1995; Steiger et al., 2001). in the striatum accompanied by an increase in posi- In contrast, high levels of 5-HT or 5-HT turnover tive (but not negative) symptoms (Abi-Dargham et al., are associated with harm avoidance and compulsive 1998). !e same increased DA release has been seen in behavior (Weyers et al., 1999). High levels of platelet individuals with schizotypal personality disorder but serotonin is an early and consistent #nding in autism not with major depression or bipolar a$ective disorder (Cook and Leventhal, 1996). (Anand et al., 2000; Parsey et al., 2001; Abi-Dargham Low levels of 5-HT turnover are associated with et al., 2004). Negative symptoms are hypothesized to alcoholism, social isolation, and impaired social func- be a function of low levels of DA in the prefrontal cor- tion and in similar behaviors in nonhuman primates tex. !ere is some evidence to support this hypothesis (Heinz et al., 1998). 5-HT may also be altered in panic (Abi-Dargham and Moore, 2003). disorder (Maron and Shlik, 2006), in schizophrenia Dopamine is found in high concentrations in the (Gurevich and Joyce, 1997), in aggressive behavior retina, where it functions as a neurotransmitter and (Unis et al., 1997), and in borderline personality dis- neuromodulator in conjunction with color vision. order (New and Siever, 2003). It has been hypothe- Patients recently withdrawn from cocaine show abnor- sized that obsessive-compulsive disorder (OCD) may malities in the electroretinogram accompanied by a involve brain regions that are modulated by normally signi#cant loss of blue–yellow color vision (Desai et al., functioning serotonin neurons. Drugs that a$ect 5-HT 1997). Abnormalities in retinal dopaminergic trans- output improve symptoms of OCD by their actions in mission in patients with seasonal a$ective disorder the involved brain regions (El Mansari and Blier, 2006). also have been suggested (Partonen, 1996) and that A signi#cant decline in the number of 5-HT receptors light exposure for treatment may operate through the in some parts of the brain has been reported with age. retinal dopaminergic system (Gagné et al., 2007). !is decline may predispose elderly individuals to

Decreased density of D2 receptors in the ventral major depression (Meltzer et al., 1998). striatum is reported for alcoholics (Guardia et al., 2000) and obese individuals (Volkow and Wise, 2005). Histamine !is indicates that reduced levels of D2 receptors may Histamine-producing neurons are found concentrated predispose individuals to addiction. Individuals with in the mammillary nucleus of the hypothalamus. !eir higher levels of D2 receptors reported a higher feeling axons project to almost all regions of the brain and of intoxication from a low dose of alcohol (Yoder et al., spinal cord. !ere are three histamine receptors, H1, 2005). Most D receptors which are located primar- 3 H2, and H3, all of which are G-coupled. Histamine- ily in limbic regions are less studied but there are data producing neurons are related to the sleep–wake cycle, indicating that D3 receptors may also be involved in appetite control, learning, and memory (Yanai and reward. D3 hyposensitivity may also be associated with Tashiro, 2007). Histamine also plays a role in the trans- addiction (Goodman, 2008). mission of vestibular signals that can produce nausea and vomiting. Antihistamines that cross the blood– Serotonin (5-hydroxytryptamine) brain barrier interfere with histamine’s role in arousal. Serotonin (or 5-HT) is produced in neuron cell bodies that make up the raphe nuclei. Axons of these neurons Adenosine project caudally into the spinal cord as well as rostrally Adenosine triphosphate (ATP) is well known for its 24 to all regions of the brain. At least 14 receptor subtypes role in providing energy within cells. It is found in are recognized. !e 5-HT1 class is inhibitory whereas all synaptic vesicles and is co-released along with the Neuroglia resident neurotransmitter. Adenosine is a breakdown hormone, adrenocorticotropin, and β-endorphin product of ATP. Both ATP and adenosine are known regulate responses to stress. A neuropeptide may coex- to function at the postsynaptic receptor sites located in ist with a small molecule transmitter within the same diverse regions of the CNS. Adenosine is recognized as neuron. an important neuromodulator of synaptic activity. !ree classes of adenosine receptors are recog- Excitotoxicity nized. One is a ligand-gated ionotropic receptor. !e Excitotoxicity is the pathological process by which other two are G-coupled metabotropic receptors. overactivity of a nerve cell produces damage and !ere are four adenosine receptor subtypes: A1, A2A, ultimately death of that neuron. !is can occur when A2B, and A3. receptors for the excitatory neurotransmitter GLU are Adenosine A1 receptors are found throughout the overactivated. Pathologically high levels of GLU in the body. In the brain they are concentrated in the basal synapse allow high levels of calcium ions to enter the forebrain. !e A1 receptor has an inhibitory function. cell accompanied by quantities of water. A cascade of It is believed to be a major contributor to the e$ect of events follows, including activation of enzymes that deep brain stimulation. !e A1 receptor is blocked by result in permanent destruction of the neuron. ca$eine. It is thought that this is the mechanism by Excitotoxicity is an important mechanism of neu- which ca$eine has its e$ect to combat drowsiness and ron loss following hypoxia or ischemia. Ischemia for to exacerbate the tremors seen in essential tremor. A example, is believed to prevent reuptake of GLU, leav- signi#cant reduction in A1 receptor binding has been ing pathological levels of the neurotransmitter in the found in aged mice (26 months) compared with young synaptic cle&. Excitotoxicity has reported in the case of mice (3 months). !e reduction was restricted to a few stroke, traumatic brain injury, and neurodegenerative sites. !ese included the hippocampus, cortex, basal diseases such as multiple sclerosis, Alzheimer disease, ganglia, and, especially, the thalamus (Ekonomou amyotrophic lateral sclerosis, Parkinson disease, and et al., 2000). Huntington disease (Bedlack et al., 2007; Carbonell Adenosine acts as an anti-in"ammatory agent at and Rama, 2007; Olanow, 2007; Gonsette, 2008). the A2A receptor. Following trauma, ischemia, or seiz- Excitotoxicity has been implicated in schizophre- ure activity adenosine levels increase and activation nia. Coyle and Puttfarcken (1993) suggested that GLU- of the A2A evokes anti-in"ammatory responses. A2A stimulated intracellular oxidation in CNS neurons receptors are found in the periphery and in the brain gradually produces neurotoxic damage and #nally cell are concentrated in the basal ganglia (Jacobson and death. Olney and Farber (1995) proposed that acetyl- Gao, 2006; Gao and Jacobson, 2007). choline overactivation secondary to reduced glutamatergic transmission can result in cell damage or Neuroactive peptide neurotransmitters death. GLU may be involved in both establishment and More than 50 short peptides have been described maintenance of addictive behavior. A greater number as being neuroactive. Some of these are particu- of GLU receptors are established in sensitive regions larly important since they have relatively longlasting as cocaine addiction is established. Increased levels of e$ects. Since these e$ects make them di$erent from GLU in the amygdala may mediate the craving experi- neurotransmitters, which by de#nition are short act- enced by cocaine addicts (Kalivas et al., 1998). ing, this class of longlasting peptides is referred to as neuromodulators. !ere are #ve families of neuroac- Neuroglia tive peptides. !e families of opioids, neurohypophy- !ere are four neuroglial cells. Two of these produce seal peptides, and tachykinins are better known. !e myelin, which consists of multiple wrappings of the opioids consist of the opiocortins, enkephalins, dynor- cell membrane of the myelin-producing cell around phin, and FMRFamide. Neurohypophyseal peptides segments of axons. Myelin insulates the axon from the include vasopressin, oxytocin, and the neurophysins. extracellular environment. As the myelin-producing Substance P is a tachykinin. cell wraps around a segment of an axon, the cytoplasm Among the neuropeptides, substance P and the is squeezed out from between the layers of cell mem- enkephalins have been linked to the control of pain. brane of the myelin-producing cell. !e cell membrane Neuropeptide Y is a potent stimulator of food intake in is a lipoprotein sheath and contains large amounts 25 rats (Sarika Arora, 2006). γ – Melanocyte–stimulating of lipid. !e multiple wrappings produce a white, Histology

glistening appearance in the fresh state, accounting for the prime trigger for pathogenesis. Abnormalities of the white matter of the brain and spinal cord. Myelin amyloid-β processing resulting in the overproduction from one myelin-producing cell extends up to approxi- of amyloid-β may be responsible for Alzheimer dis- mately a 1-cm segment along an axon. !e segment ease (Hardy and Selkoe, 2002). !e excess is hypoth- of myelin does not overlap signi#cantly with the next esized to a$ect synaptic structure, disrupt neuronal myelin segment. !e discontinuity between myelin function, and lead to cognitive impairment (Selkoe, sheaths is called the node (of Ranvier). !e myelin- 2002; Schliebs and Arendt, 2006; Haass and Selkoe, covered length is called the internode and insulates the 2007). Amyloid-β may function as a biologically active axon from the extracellular environment. !e insu- peptide that acts on nicotinic acetylcholine receptors lating e$ect of myelin is minimal at the node, where (Gamkrelidze et al., 2005). It is suggested that under depolarization of the axon membrane occurs. Because normal conditions amyloid-β regulates synaptic plas- the internodal distance is insulated, the action poten- ticity, synaptic transmission, neuronal excitability, and tial hops (saltates) along the axon from one node to the neuron viability (Kamenetz, et al., 2003; Plant et al., next. 2003). Astrocytes act to clear and degrade amyloid-β and form a protective barrier between amyloid-β Oligodendroglial cell deposits and neurons (Rossner, et al., 2005). !e oligodendroglial cell produces myelin in the CNS. !e neurilemmal cell (of Schwann) produces myelin Microglia in the peripheral nervous system (PNS). A&er injury, Microglial cells are the immune cells of the CNS and neurilemmal cells (of Schwann) support the regener- are normally found in a resting state along capillaries. ation of PNS axons. However, within the CNS, axonal !e resting state is maintained in part by suppressive regrowth is insigni#cant following injury. !e oligo- action of neurons. A glycoprotein, CD200, expressed dendrocyte does not appear to provide the same support on the surface of neurons reacts with a receptor site on for regenerating CNS axons as does the neurilemmal microglia to maintain their quiescence (Hoek et al., cell for PNS axons. Other factors are also involved in 2000). Astrocytes may also help suppress microglial the failure of a severed CNS axon to regenerate. activation. Microglia are activated by the loss of inhibition and/or direct activation by neurons. If CNS tis- Astrocyte sue is damaged, microglial cells enlarge, migrate to Astrocytes are found only within the CNS and are of the region of damage and become phagocytic. !ey several types. In general, astrocytes provide structural are sensitive and respond to even small changes in ion and physiological support to neurons. Many astrocytes homeostasis that precedes the pathological changes stretch between individual nerve cell bodies and capil- (Gehrmann et al., 1993). !e in"ammatory response laries. !ey have a characteristic perivascular end foot with activation and cytokine activation may be neu- that is found in apposition to the capillary. !e body roprotective in the early stages but may be damaging of the same astrocyte embraces the body of the neu- over time (Nagatsu and Sawada, 2005). Microglia may ron, producing a bridge between the capillary and the aggravate in"ammation by releasing in"ammatory neuron. cytokines as well as neurotoxins that recruit other cells Astrocytes respond to nerve cell activity. !ey and amplify the in"ammatory response (Kim and Joh, remove excess neurotransmitter from the synaptic 2006). When they act as phagocytes, microglial cells cle&. Once inside the astrocyte the neurotransmitter are called glitter cells. is degraded into its precursor and then made avail- Entry of HIV into the CNS is mediated by lym- able to the axon terminal for recycling. !e astrocyte phocytes and monocytes that transfer the virus to peri- may play a role in directing growing axon terminals vascular macrophages and then to microglia (Lane during development. Astrocytes provide a permissive et al., 1996). Microglia are also activated in multiple substrate for developing axons and help direct neurite sclerosis (Raine, 1994) and Alzheimer disease (Kim growth (Deumens et al., 2004). Astrocytes help main- and Joh, 2006). !ey secrete toxins that may result in tain a balanced extracellular ion environment for the neuron death (Liu et al., 2002). !e substantia nigra has neurons. four to #ve times more microglia than other areas of 26 !e amyloid hypothesis of Alzheimer disease the brain (Kim et al., 2000). Activation and an increase holds that amyloid β-peptides formed by neurons are in microglia are seen in the substantia nigra prior to References the loss of dopamine neurons following experimental Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R.M., Seibyl, axotomy in the medial forebrain bundle (Kim et al., J.P., Bowers, M., van Dyck, C.H., Charney, D.S., Innis, 2005). It is hypothesized that in"ammation with the R.B., and Laruelle, M. 1998. 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CChapterhapter 4 Occipital and parietal lobes

Occipital lobe !e entire cortex of the occipital lobe is dedicated to vision and consists of Brodmann’s areas 17, 18, and 19 Functional anatomy (Figures 2.2, 2.3, 4.1, and 4.2). Brodmann’s area (BA) 17 is the primary visual cortex (striate cortex) and occu- !e occipital lobe is clearly demarcated from the par- pies a large portion of the medial aspect of the occipital ietal lobe on the medial surface by the parieto-occipital lobe. Much of the primary visual cortex lies within the sulcus and the anterior limb of the calcarine #ssure calcarine #ssure, which extends approximately 2.5 cm (Figure 4.1). !e short section of parieto-occipital sul- deep into the occipital lobe. A portion of BA 17 curves cus on the dorsolateral surface is used as an anchor for posteriorly around onto the posterolateral surface of an imaginary line that extends ventrally to the preoc- the occipital lobe. Brodmann’s areas 18 and 19 are rec- cipital notch (Figure 5.1). !is imaginary line is the ognized as secondary and tertiary visual areas, respect- border between the occipital and parietal lobes as well ively, and represent the visual association area of the as the temporal lobe on the lateral cortical surface. !e occipital lobe. border between the occipital lobe and temporal lobe Many direct and indirect connections exist between on the ventral surface is less distinct (Figure 5.4). Some the occipital lobe and other cortical regions. !e super- authors include all of the lingual (medial occipitotem- ior occipitofrontal (subcallosal) fasciculus links the poral) gyrus and fusiform (lateral occipitotemporal) occipital, parietal, and temporal cortices with the insu- gyrus with the temporal lobe; others assign the poster- lar and frontal regions. !e superior occipitofrontal fas- ior portions of these gyri to the occipital lobe. ciculus is joined by the arcuate fasciculus in its anterior

Primary somesthetic area (1, 2, and 3) Figure 4.1. The primary visual cortex (BA (postcentral gyrus) 17) is largely buried within the calcarine Central sulcus "ssure. A greater portion of the superior parietal lobule (BA 5 and 7) lies along the Precuneus midline (compare with Figure 4.2).

7 5

e g y r u s a t Parieto-occipital u l fissure g 19 i n C

17 Calcarine fissure 18

33 Occipital and parietal lobes

Primary somesthetic area Figure 4.2. The secondary (BA 18) and (1, 2, & 3) tertiary (BA 19) visual cortex is better appreciated from the lateral view. The Central sulcus 5 Intraparietal sulcus primary somesthetic cortex coincides with Superior parietal BA 1, 2 and 3. The superior parietal lobule lobule coincides with BA 5 and 7 and the inferior parietal lobule coincides with BA 39 (angu- Parieto-occipital fissure lar gyrus) and 40 (supramarginal gyrus). 7 Stippling indicates approximate location of 19 parietal lobe mirror neurons. 40 18 39 Lateral fissure 17

Inferior parietal lobule

Preoccipital notch

"ow at the junction of the parietal and temporal lobes. Clinical vignette !e arcuate fasciculus is important in speech. !e An 84-year-old woman underwent craniotomy 17 inferior occipitofrontal fasciculus interconnects the years previously for the removal of a right occipital occipital cortex with the lateral and ventrolateral parts meningioma (Nagaratnam et al, 1996). She presented of the frontal lobes. Two transverse occipital fasciculi at this time with a three-year history of formed hallu- have been described. Together they interconnect the cinations, the ringing of bells, and the monotonous primary visual cortex on the medial aspect with the lat- repetition of the same Christmas carol. The hallucina- eral occipital cortex and the inferior occipitotemporal tions had increased in frequency and intensity in the cortex. past few months. She reported people standing to her left, and, to her annoyance, some of them stroked her Primary visual cortex (BA 17; V1; striate cortex) face. She had been observed brushing away imaginary objects. A computed tomography scan revealed a Fibers that originate from nerve cell bodies located 5-cm diameter mass superior to the tentorium in the in the lateral geniculate body (thalamus) project to right occipital region. She was treated with steroids for the V1, where they terminate in an orderly fashion an unrelated cardiac condition. The musical hallucina- to produce a retinal map. Macular areas of the retina tions continued unabated until her death from left are represented close to the occipital pole and occupy ventricular failure. a relatively large area of the visual cortex. Peripheral vision is represented more anteriorly. Small spots of light are very e$ective in exciting Secondary and tertiary visual cortex (BA 18 and BA 19) the cells of the retina and the lateral geniculate body. Brodmann’s areas 18 and 19 are o&en referred to as In contrast, cells of the primary visual cortex respond the extrastriate visual cortex. Recent studies show that only to visual images that have linear properties (lines areas of both the temporal and parietal cortices are also and edges). !e neurons of the primary visual cortex involved in visual processing. BA 18 (V2; prestriate cor- interpret contours and boundaries of a visual target in tex) receives binocular input and allows for the appreci- terms of line segments. ation of three dimensions (stereopsis). Target distance A lesion of V1 will produce an area of blindness is coded by some neurons. Some neurons of BA 19 inte- (scotoma) in the contralateral visual #eld. Loss of an grate visual with auditory and tactile signals. area as large as an entire quadrant of vision may go Area V3 is located dorsal and anterior to V2 on 34 unnoticed by the patient. A lesion of the entire primary both the medial and lateral surfaces of the occipi- visual cortex on both sides results in cortical blindness. tal lobe. Area V4 is represented by the cortex of the Occipital lobe lingual and fusiform gyri, located on the inferior sur- midget retinal ganglion cells that serve mainly cones face of the brain, and is important in color perception. associated with the macula of the retina and termin- It also responds to moving visual targets regardless ates on cells in the parvocellular layer of the lateral gen- of the direction of movement. Area MT of the mon- iculate body. !e parvocellular pathway carries signals key is comparable with area V5 of the human and like related to color and form. !ese two continue as sep- V2, it is important in stereopsis. Area V5/MT of the arate parallel pathways to V1 of the occipital cortex. A human is located just posterior to the junction of the third pathway arises from small cells in the lateral gen- ascending limb of the inferior temporal sulcus with iculate body that make up the koniocellular layer. !e the lateral occipital sulcus. It extends over a small koniocellular layer receives color information from part of the posterior BA 37 as well as a small part of the retina as well as input from the superior colliculus the anterior BA 19. Area MT contains neurons that (Hendry and Reid, 2000). !ere is considerable mixing respond selectively to the direction of moving visual of all three pathways in V1. objects and determines target velocity in space. !ere Two cortical visual streams arise from V1. !ey appear to be two regions of MT: one region responds appear to diverge within V3 with the dorsal stream to visual targets in a retinotopic frame of reference represented in dorsal V3 and the ventral stream in and the second appears to use a spatiotopic frame of ventral V3. !e ventral visual stream represents foveal reference (d’Avossa et al., 2006). Area V5/MT in the vision. It leaves V1 and passes through V2, ventral V3, human (sometimes referred to as the MT+ complex) and on to V4. !e ventral stream is sometimes called may correspond to areas MT and MST in the mon- the “What Pathway” and is associated with object rec- key (Becker et al., 2009). !is area is important in ognition (Himmelbach and Karnath, 2005; Karnath planning smooth pursuit eye movements (Ono and and Perenin, 2005). Signals pass to the extrastriate Mustari, 2006; Nuding et al., 2008). body area located bilaterally in the lateral occipitotemporal cortex (Downing et al., 2001). !e extrastriate body area is sensitive to static and dynamic human Clinical vignette and nonhuman bodies, and body parts exclusive of A 47-year-old right-handed woman (DF) had a severe the face. Activation of the extrastriate body area (more form of agnosia as a result of carbon monoxide poi- so on the right) is increased to images of bodies or soning and was incapable of discriminating even the simplest geometric forms. She could not recognize body parts presented from an external (allocentric) objects but was able to use information about loca- perspective (i.e., another person) as opposed to one’s tion, size, shape, and orientation to reach out and grasp self (Saxe et al., 2005). !e extrastriate body area is the object. She could not copy objects but was able to believed to be important in reasoning about others’ draw them from memory. She was better able to rec- actions since activation here is a #rst step in recogniz- ognize objects based on surface information than on ing the presence of another’s body or body part (Saxe, outline. She could correctly identify objects with col- 2006). It is also activated during goal-directed hand ored or gray-scale surfaces but performed poorly with and foot movements of the observer and may function line drawings. Her primary visual cortex appeared to to distinguish between the consequence on one’s own be largely intact. The ventral stream pathway (“what”) and another’s behavior (Asta#ev et al., 2005; David et seemed to be defective (Figure 4.3). The dorsal stream al., 2007). It also receives input from the right poster- pathway (“where”) proved to be intact. ior superior temporal sulcus where body movements are evaluated in terms of their goals (Pelphrey et al., 2004). A lesion of the occipital lobe extrastriate body Parallel visual pathways area results in body form and body action agnosia Two parallel pathways from the retina process visual (Moro et al., 2008). images simultaneously. !e magnocellular (magno) A region of the striate cortex in the inferior occipi- pathway arises from large, parasol retinal ganglion tal gyrus is sensitive to faces (face-responsive occipital cells concentrated near the periphery of the retina and region). !is appears to be an initial screening area for terminates on cells in the magnocellular layer of the face recognition since the signals from this area pro- lateral geniculate body. !e magnocellular pathway ject to the fusiform gyrus on the ventral surface of the carries signals related to object motion and location. brain –the fusiform face area. !e occipital face region !e parvocellular (parvo) pathway arises from small, is bilateral and is sensitive to physical di$erences 35 Occipital and parietal lobes

A. Lesions in Subject DF

B. Location of LOC in Neurologically-Intact Subjects

–5 –20 p <10 p <10

Figure 4.3. A, B. The ventral visual stream lesions in a patient with visual agnosia (subject DF) are compared with the expected region (lateral occipital complex) for object recognition. A. Lesions in subject DF. Her lesions were traced on slices that indicated tissue damage and rendered on the pial surface in pale blue (see color plate). Lateral views of the left and right hemispheres are shown, as is a ventral view of the underside of the brain. B. The expected location of the lateral occipital complex based on functional magnetic resonance imaging date from seven neurologically intact participants. The activation of the slice is shown in orange in panel A in the color plate for comparison with the lesions in patient DF’s brain. (Reproduced with permission from Oxford University Press from James et al., 2003.) See also color plate.

between faces and between faces and objects, but it Clinical vignette does not extract face identity. A 58-year-old right-handed woman (DF) had a three- !e dorsal visual stream deals with location and to four-year history of progressive di!culty “seeing” motion and represents peripheral vision. Dorsal stream objects. Her visual acuity and visual "elds were intact, signals from V1 pass through V2, dorsal V3 and on to but she could not draw simple geometrical "gures, V5/MT. !e dorsal stream terminates in the posterior such as a triangle or a square. Even more distress- parietal cortex. Area V5/MT is retinotopic, and is par- ing to her was the presence of visual agnosia, or the ticularly sensitive to the direction of moving visual tar- inability to recognize objects by sight despite intact gets. !e dorsal stream is sometimes called the “where basic vision. She could not visually recognize common pathway” and is responsible for the registration of loca- objects such as a cork, a thimble, or a pipe, especially tion, movement, and spatial relationships (Figures 4.5 if they appeared in unusual views, angles, or light- ing. When she touched the objects, however, she was and 6.10). immediately able to identify and name them. Her per- !e cortical area in the human representing the formance on photographs and drawings of objects medial superior temporal area (MST) of the mon- was similarly impaired. The patient had a progressive key is not completely clear. Area MST in the human visual agnosia from disease a#ecting her ventromedial is believed to include a portion of the occipitotempo- occipital cortex (see Figure 4.4). Her slowly progressive roparietal cortex just anterior to V5/MT. It includes a history and positron emission tomography scan were portion of the inferior parietal lobule (IPL) as well as consistent with the syndrome of posterior cortical the posterior superior and middle temporal gyri. !e atrophy. At autopsy, this syndrome has usually been a MST is further divided into a dorsal (MSTd) and ven- variant of Alzheimer disease with a shift of the charac- 36 tral region (MSTv). !e ventral region is more involved teristic pathology into visual areas of the brain. Occipital lobe

Figure 4.4. The patient’s 18-!uorodeoxyglucose positron emission tomography image revealed bilateral hypometabolism in the secondary and tertiary visual cortex (posterior, lateral light areas), while sparing the primary visual cortex (posterior, mesial dark area). (Reprinted with permission from Mendez, 2001.)

Figure 4.5. A schematic outline of Cingulate gyrus the projections of the parietal lobe. The Premotor and supplementary superior parietal lobule projects to the motor areas premotor and supplementary motor areas of the frontal lobe. The inferior lobule projects to the multimodal region of the temporal lobe as well as to the Primary Primary Superior ventromedial temporal lobe. Inferior motor area somesthetic area parietal lobule lobule projections include those to the dorsolateral prefrontal area.

Dorsolateral Inferior frontal area parietal lobule

Ventromedial temporal lobe Temporal lobe multimodal sensory convergence area with analysis of visual target direction and velocity, and not statistically signi#cant but was consistent and was the generation of pursuit eye movements. Neurons in accompanied by a 10% increase in neuronal density. MSTd are activated in response to radial motion, rota- It was speculated that the decrease in neuronal dens- tion and translation related to optic "ow (Orban, 2008). ity in the visual cortex is related to poor eye tracking Optic "ow is de#ned as the perceived visual motion of (Selemon et al., 1995). A group of patients with schizo- stationary objects as the observer moves relative to phrenia regardless of medication status exhibited vis- them. Input to MSTd includes V5/MT as well as sig- ual defects when tested for contrast sensitivity and nals re"ecting smooth pursuit commands (Ono and form discrimination (O’Donnell et al., 2006). Patients Mustari, 2006). !e MST works in conjunction with with schizophrenia exhibiting reduced gray matter in the ventral intraparietal area to combine signals from the occipital lobe were found to have a poor outcome visual, vestibular, auditory, and tactile input to plot and compared with patients with reduced gray matter in guide movement through the environment (Britten, more anterior regions (Mitelman and Buchsbaum, 2008). 2007). Behavioral considerations Hallucinations Four general categories of visual hallucinations are Schizophrenia elementary, complex, and illusions and distortions. V1, along with BA 9 in the frontal lobe, has been Elementary hallucinations include static or mov- found to be decreased in thickness in the brains of ing spots, line segments or simple geometric shapes. 37 patients with schizophrenia. !is decrease in V1 was Complex hallucinations include objects, faces and Occipital and parietal lobes

scenes. Illusions and distortions are alternations in Infarction of the le& posterior cerebral artery perception of the external world, commonly altera- involving the medial occipital lobe (Figure 2.6) is suf- tions in shape, color, size, or movement. It has been #cient to produce a confusional state, including diso- suggested that elementary hallucinations re"ect activ- rientation, distractibility, irritability, and paranoia. ity in primary visual areas or even precortical struc- Confusion and agitation may alternate with mutism. tures. Complex hallucinations re"ect activity in the !e acute confusional state presented by the patient ventral visual stream. Distortions re"ect the dorsal may be misdiagnosed as a psychiatric illness (Devinsky visual stream (Santhouse et al., 2000). et al., 1988). Stimulation of V1 produces elementary hallucina- Visual agnosia tions in the contralateral visual #eld. !ese hallucina- Visual agnosia sometimes occurs a&er lesions in the tions include sparks and "ashes of color or bright light. ventromedial occipital lobe. !e objects are seen but Hallucinations of object fragments (e.g., lines, corners, cannot be named, and the patient does not know what patterns) have been reported following a stroke in the the object can be used for (Critchley, 1964). Loss of the occipital cortex (Anderson and Rizzo, 1994). Parekh ability to recognize the faces of known people (proso- et al. (1995) reported an increase in the cerebral blood pagnosia) may follow unilateral or bilateral lesions of "ow to the occipital cortex in patients who experienced the ventromedial occipital lobe that extend into the procaine-induced visual hallucinations. Blood "ow ventral temporal lobe and include the fusiform gyrus. also was increased in limbic structures and in the lat- Color naming may also be impaired, especially with eral frontal lobe. right-sided lesions (DeRenzi and Spinnler, 1967). It is Electrical stimulation of BA 18 and BA 19 can hypothesized that visual agnosia results from discon- produce complex visual hallucinations. Objects may nection of the visual cortex from the temporal lobe become disproportionately large (macropsia) or dis- rather than from destruction of occipital lobe tissue torted in shape. Images of people, animals, and various (Joseph, 1996). Lesions restricted to BA 19 may result geometrical shapes have been reported. Many complex in loss of only color vision (achromatopsia), leaving hallucinations appear real to the patient (Hecaen and shape detection relatively intact. Albert, 1978). Complex hallucinations occur more frequently a&er right-sided lesions. A complete bilat- Blindsight eral lesion of all visual cortices which can result from Activity in V1 is believed to be required for visual stim- occlusion of both posterior cerebral arteries may prod- uli to be perceived. V1 acts as the gatekeeper of visual uce denial of blindness (Anton syndrome; Redlich and awareness (Silvanto, 2008). Loss of the V1 renders the Dorsey, 1945). patient blind according to conventional clinical tests !e migraine visual aura typically consists of sim- (Rees, 2007). However, when confronted with forced- ple positive and/or negative (scotoma) components. choice testing some patients show residual capacity in !ey may occur up to an hour before the onset of a the blind visual #eld. !is residual capacity is called migraine headache. !e positive component o&en blindsight (Rees, 2008). !e patient retains a sense of includes bright, white, silver, or colored line seg- the presence of a nearby object. Some can accurately ments, patterns or geometrical shapes. !e auras usu- guess the location or identity of objects presented in ally last only a few seconds followed by other, more their blind hemi#eld (Weiskrantz, 2004). !e retained severe manifestations of the aura. !e hallucina- vision favors the dorsal visual stream with the retention tions are o&en seen as dots, spots or disks that may of a sense of motion, "icker, and contrast more o&en "icker, pulsate, or move. More complex hallucina- than object recognition. !e probable neuroanatom- tions, including faces, may be seen (Panayiotopoulos, ical basis has been identi#ed with the discovery of dir- 1999). Activity corresponding with the aura usually ect ipsilateral connections from the lateral geniculate begins near the fovea and then spreads across the vis- body of the thalamus to the middle temporal area (MT/ ual #eld. !e blindness that usually follows may per- V5) in the monkey (Sincich et al., 2004). !is path- sist for several minutes. !e aura begins in a restricted way has been con#rmed in the human (Behrens et al., area of the occipital lobe representing the fovea then 2003). Blindsight subject GY, who has been extensively migrates as a form of spreading depression across the studied and has been blind since an auto accident at age cortex representing the peripheral retina (Hadjikhani 8, has been shown to have responses to visual input in 38 et al., 2001; Wilkinson, 2004). area MT/V5 (Morland et al., 2004). Evidence indicates Occipital lobe

Figure 4.6. Subjects (N =14) with phobias (snakes and spiders) were examined during exposure to videotapes of spiders and during exposure to videotapes of a neutral park scene. The positron emission tomographic image data were subtracted. Blood !ow is increased to the visual association area (right panel) and decreased to the orbital prefrontal cortex (left panel) during exposure to phobia-provocative visual stimuli. rCBF, relative cerebral blood !ow. (Reproduced by permission from Fredrickson, M., Fischer, H., and Wik, G. 1997. Cerebral blood !ow during anxiety provocation. J. Clin. Psychiatry 48 (Suppl. 16):16–21.) the presence in GY of a right lateral geniculate to le& to cataracts, glaucoma, or age-related macular degen- MT/V5 pathway as well as strengthened transcallosal eration. !e hallucinations may be simple or complex connections (Bridge et al., 2008). and are experienced as amusing or sometimes disturb- !e emotional valence of facial images can be ing but are not emotionally laden events (Wilkinson, detected by way of a separate subcortical pathway 2004). Hallucinations involving color activate the pos- involving the colliculus, pulvinar, and amygdala terior fusiform area; faces the le& middle fusiform area, (Williams et al., 2006). !is pathway does not pass objects the right middle fusiform area, and textures the through the occipital lobe and allows for the noncon- cortex bordering the collateral sulcus ($ytche et al., scious recognition of fearful as well as happy expres- 1998). sions in sighted individuals. If retained in blind patients Other behavioral considerations it is called a$ective blindsight (Tamietto and de Gelder, Visual objects compete for attention, and it is believed 2007). that emotional aspects can operate in a top-down fash- Anxiety disorder ion to direct attention to a speci#c target while simul- Increased blood "ow has been reported in the occipi- taneously suppressing attention to peripheral targets tal region in patients with generalized anxiety disorder (Kastner and Ungerleider, 2001; Pessoa et al., 2002). (Buchsbaum et al., 1987) and with obsessive-compul- Signals conveying emotional bias from areas such sive disorder (Zohar et al., 1989). Wik et al. (1992) as the prefrontal cortex and amygdala can alert the found that blood "ow to the secondary visual cortex occipital lobe to anticipate speci#c emotion-provoking (BA 18 and BA 19) in subjects with snake phobia was stimuli, such as looking for a familiar face in a crowd. increased over control levels when they viewed images Pourtois et al. (2004) showed that activity in the pri- of snakes. !e relative blood "ow increase seen dur- mary visual cortex was enhanced when viewing fearful ing visually induced anxiety is limited to BA 18 and faces, suggesting the ability of other areas such as the 19 (Fredrikson et al., 1997). !e increase seen in the amygdala to enhance attention to emotional stimuli in visual association area is coupled with a decrease in a top-down manner. blood "ow to the prefrontal areas (Figure 4.6). !e Age a$ects visual processing. Davis et al. (2008) authors propose that the increased activity re"ects an found that compared with 20-year olds, activity in the externally directed vigilance function. !e secondary occipital region was decreased but increased in the visual area may take control of limbic areas during frontal region of 60-year olds, as measured by fMRI. visually elicited defense reactions (Fredrikson et al., !e shi& in activity from occipital to frontal lobe was 1997). independent of task or degree of di%culty. !e authors suggested the shi& is a compensation for age-related Charles Bonnet syndrome declines in occipital processing. Chronic alcohol con- !e Charles Bonnet syndrome is characterized by sumption also has an e$ect. A group of nine detoxi#ed 39 visual hallucinations following loss of vision, o&en due male alcohol-dependent patients showed signi#cantly Occipital and parietal lobes

lower bilateral occipital lobe activation than controls Table 4.1. Simpli"ed summary of some functions of the parietal lobe and lesions seen following formation of lesions to either the (Hermann et al., 2007). dominant or nondominant side. Parietal lobe Side of lesion Since the masterful volume by Macdonald Critchley Dominant Nondominant was published in 1953, the parietal lobe has come to be Superior parietal lobule recognized as being heavily involved in the higher cog- Function nitive functions of the brain. !e parietal lobe receives Spatial-motor Spatial incoming somatosensory signals, but, unlike the orientation occipital lobe, is involved in far more than processing Lesion a single sensory modality. !e parietal lobe is integral Aphasia Spatial agnosia to the perception of external space, body image, and Agnosia Sensory neglect attention. !e complex and fascinating cognitive dis- Astereoagnosia Astereoagnosia turbances that can occur with parietal lobe lesions may Agraphesthesia Agraphesthesia at #rst be mistaken for hysteria. Information perceived Dressing apraxia and elaborated by the parietal lobe is submitted to the frontal association areas. One may speculate that if the Inferior parietal lobule information received by the frontal lobes is inaccurate, Ideomotor/ideational apraxia Aprosodia delusional perception or ideas could develop. Gerstmann syndrome Bilateral Functional anatomy Balint syndrome !e parietal lobe underlies the parietal bone of the Movement agnosia skull. Its anterior border on the lateral aspect is marked by the central sulcus and its posterior border by the parieto-occipital #ssure (Figures 2.2, 4.1, 4.2 and 5.1). somatotopic map on the postcentral gyrus and has On the medial aspect it extends inferiorly to the cingu- access to the retinotopic map of the occipital cortex. late gyrus, anteriorly to the central sulcus, and poster- In order to navigate through space we use maps and iorly to the parieto-occipital sulcus. !e parietal lobe landmarks. An allocentric map uses an external frame consists of the primary somatosensory (somesthetic) of reference and as with a road map, we identify direc- cortex (BA 1, BA 2, and BA 3), the superior parietal tion in terms of north, east, south, and west. An ego- lobule (SPL; BA 5 and BA 7), and the inferior parietal centric map is one de#ned by our current location as lobule (IPL ; BA 39 and BA 40). It makes up about a #&h seen on an automobile global-positioning (GPS) dis- of the total neocortex. play. We de#ne directions in the case of an egocentric !e anterior parietal lobe, made up of the postcen- map as ahead, behind, le& and right. !e allocentric tral gyrus (lateral aspect) and posterior paracentral map belongs to the hippocampus (page 177). !e ego- lobule (medial aspect), is concerned with somatosen- centric map appears to be located in the lateral parietal sory sensations –touch, pain, temperature, and limb area, more strongly on the right side. position (proprioception).!e posterior parietal lobe !e parietal lobe attends to attractive (salient) consisting of BA 7, BA 39, and BA 40 (Mesulam, 1998), environmental targets and locates these targets in integrates somatosensory signals with signals from the terms of map coordinates. Input from the temporal visual, auditory, and vestibular systems (sensorimotor lobe gives it information about a target’s identity and integration). from past experience, its anticipated weight, texture, !e parietal lobe is important in interacting with and possible value. !e parietal lobe formulates motor the world around us (Table 4.1). It operates on a plans in cooperation with the frontal lobe and subcor- moment-to-moment basis evaluating and respond- tical structures to generate eye, head, arm, and hand ing to environmental stimuli in a bottom-up manner. movements (and presumably leg movements) to inter- Movements are scripted here and may be executed in cept these targets. !e motor plans are submitted to the cooperation with the motor cortex with the permis- frontal lobes including those areas that act as a reposi- 40 sion of the prefrontal cortex. !e parietal lobe contains tory for socially acceptable behavior. !e motor plans and/or has access to one or more maps. It has its own will be executed unless deemed socially inappropriate Parietal lobe or inhibited by voluntary movements generated inde- timing of small groups of synergistic muscles during pendently in the motor areas of the frontal lobe. !e adjustments to sensory input (Drew et al., 2008). motor plan formulated by the parietal lobe may range Association #bers from the primary somatosen- from eye movements used to read text when sitting sory cortex pass through the white matter of the pari- quietly, to catching a ball in "ight while running. In etal lobe and connect the postcentral gyrus with the response to visual and auditory cues, the parietal lobe somatosensory association areas behind it. !ese high- selects and generates speech appropriate to the current er-order association areas, including the superior and social situation, thus contributing to personality. inferior parietal lobules, integrate touch and conscious !e parietal lobe responds in an almost automatic proprioception with other sensory modalities. mode to sensory signals and attends to the most salient Rauch et al. (1995) reported that cerebral blood target (e.g., a red balloon in a sea of blue balloons). !is "ow increased in the somatosensory cortex, as well as is described as bottom-up processing. In contrast, it can in the frontal, cingulate, insular, and temporal cortices, be governed by the frontal lobe to search out for a par- in subjects with simple phobia when they were pro- ticular target (e.g., trying to spot your mother-in-law as voked (snake, rodent, spider, bees). Subjects reported passengers disembark a plane). !is is top-down pro- that tactile imagery was the most prominent sensory cessing, is not as automatic as bottom-up processing, aspect of the phobic experience. and can require considerable mental e$ort (Buschman and Miller, 2007; Womelsdorf et al., 2007). Secondary somatosensory cortex (SII) and the parietal operculum Primary somatosensory cortex (SI) !e portion of the parietal lobe that makes up the upper !e primary somatosensory cortex (SI) occupies the bank of the lateral #ssure is the parietal operculum. !e postcentral gyrus (BA 3, BA 1, and BA 2). Projections parietal operculum immediately inferior to SI contains to the postcentral gyrus include thalamocortical #b- a secondary somatosensory cortex (SII). SII receives ers from the ventral posteromedial (VPM) and ventral input from SI as well as from VPL and VPM of the thal- posterolateral (VPL) nuclei of the thalamus (Table 9.1). amus. It occupies much of the parietal operculum and !ese nuclei relay somatosensory signals from both extends deep into the lateral #ssure. It may overlap and sides of the face and from the contralateral body, include part of the insula. SII is somatotopically organ- respectively. Touch and proprioceptive signals project ized but receives input from both sides of the body. predominantly to BA 1. Pain signals project to BA 3. Four areas of the parietal operculum have been A somatotopic map of the contralateral body called a described: OP (OPercular) 1–4. OP 1 and OP 2 lie pos- sensory homunculus exists along the postcentral gyrus teriorly and occupy the inferior part of BA 40. OP 3 and laterally and extends onto the paracentral lobule medi- OP 4 correspond roughly with BA 43, which lies at the ally. !e leg and genitalia are represented on the medial base of BA 1, BA 2, and BA 3 (SI), and extend anteriorly aspect of the cortex, with the remainder of the body and to border on the insular cortex. Areas OP 1, OP 3, and head on the lateral aspect. Corticothalamic projections OP 4 appear to be a part of SII (Eickho$ et al., 2006a). from the primary somatosensory cortex project back to OP 2 lies deep inside the lateral #ssure just posterior to the VPM and VPL thalamic nuclei. Sereno and Huang the insula. OP 2 is recognized as the primary vestibular (2006) showed that the superior part of the postcentral area (Eickho$ et al., 2006b). gyrus was activated in response to pu$s of air directed !e anatomy of the parietal lobe varies from indi- to various parts of the face. !is appears to be an area vidual to individual, including that of the parietal that codes for the location of objects near to, or in con- operculum. One variation describes an accessory post- tact with, the face that might be used in feeding. central gyrus accompanied by a parietal operculum of A lesion of the primary somatosensory cortex pro- reduced length (Steinmetz et al., 1990). !is variation is duces a temporary loss of sensation over the contralat- suggested to be related to impaired receptive language eral body. Recovery may be almost complete with time. processing and dyslexia (Kibby et al., 2004). Another Some loss in muscle control may remain. !e parietal variation (Steinmetz type IV) in which the lateral #s- lobe supplies #bers to the corticospinal tract that pro- sure transitions into the postcentral sulcus appears to ject to the ventral region of the dorsal horn of the spinal correlate with dyslexia and superior nonverbal processing (Steinmetz et al., 1990; Chiarello et al., 2006; cord. Here they are believed to regulate incoming sen- 41 sory signals. !ey may also be involved in the level and Craggs et al., 2006). Occipital and parietal lobes

Superior parietal lobule the hand. !e anterior SPL (BA 5 and anterior BA 7) Brodmann’s areas 5 and 7 on the lateral aspect make is involved in evaluating the shape and size of objects up the superior parietal lobule (Figures 4.1 and 4.2). based on touch (Naito et al., 2008). BA 7 on the medial aspect is more commonly referred !e SPL is concerned with “where” a target is to as the precuneus and is discussed separately below located (dorsal visual stream) (Figure 6.10). It provides (Figure 2.2). information about the location of the target including !e SPL receives heavy input from the primary the direction and velocity of movement of that target. somatosensory cortex. Cortical association #bers con- It can program a plan designed to intercept the tar- nect it with adjacent cortex, including the occipital get using saccadic eye movements or hand and body lobe, temporal lobe, and insular lobe, thus providing movements. Long association #ber bundles from the direct access to touch, vision, audition and vestibu- SPL to the frontal cortex allow for the accurate execu- lar signals. Reciprocal #bers connect the SPL with the tion of the developed plan. !e anterior SPL is import- pulvinar, the anterior cingulate gyrus, and the lateral ant in the perception of object shape based on feedback thalamic nuclei (Chapter 9). Pyramidal cells found in of #ne #nger movements. !e right anterior SPL attends the SPL contribute heavily to #bers that project to the to the object being explored while the le& anterior SPL brainstem and to the spinal cord. E$erent #bers from maintains information about object shape in working the SPL also project to motor control centers such as memory (Stoeckel et al., 2004). the red nucleus, basal ganglia, superior colliculus, and !e SPL is part of a dorsal network that functions pontine tegmentum. Long association bundles connect in spatial attention and includes the frontal lobe. !e the SPL with the frontal lobe (Figure 4.5). Commissural right SPL appears to be an especially important com- connections through the corpus callosum intercon- ponent of this network (Abdullaev and Posner, 2005; nect the le& and right SPLs. Corbetta et al., 2005). Neurons representing various !e right (nondominant) SPL is part of the poster- objects compete for representation and it appears that ior attention system. It is critical in selecting one stimu- a top-down mechanism exists to bias the #nal selection lus location among many. It also disengages and shi&s (Bisley and Goldberg, 2003). !at is, other areas such attention to a new target when appropriate (Posner and as the prefrontal cortex, can alert the SPL to narrow Dahaene, 1994; Chapter 12). !e right side attends to its search to attend to a particular target. Both sides stimuli in both visual #elds and accounts for the fact play a role in shi&s in attention during this process that neglect is more severe following right parietal (Behrmann et al., 2004). damage (Posner and Petersen, 1990). Norepinephrine Lesions in the le& (dominant) SPL can produce input to the right parietal region is greater than to the dysphasia and agnosias. !e dysphasic patient speaks le&, and norepinephrine primes the cortical neurons slowly, makes many grammatical errors, and may be during times of heightened arousal to react to novel mistakenly labeled uncooperative or confused. A stimuli (Tucker and Williamson, 1984). lesion bordering the postcentral gyrus can produce !e SPL integrates the sensation of touch and pro- tactile agnosia, in which the patient cannot recall the prioception with vision as well as with audition, mark- name of an object by touch alone. With eyes closed a ing it as a multimodal integrative area. It is especially patient with astereoagnosia is unable to name a famil- important in planning and executing visually guided iar object held in his or her hand based on the weight reaching. It is activated during tactile exploration of and three-dimensional characteristics of the object. A objects and body part localization (Binkofski et al., number or letter written on the patient’s skin will not 1999, 2001; Felician et al., 2004), and visuomotor track- be recognized by touch following a lesion in the super- ing (Gra&on et al., 1992), as well as when imagining ior parietal lobule (agraphesthesia). rotary hand movements (Wolbers et al., 2003). It is also activated during attentional switching, i.e., when vis- Precuneus ual attention is switched between targets (Rees et al., !e precuneus is the medial aspect of the SPL repre- 2002). !e parietal lobe is concerned with selecting sented by BA 7. It is rarely damaged due to strokes or and attending to a speci#c target located on the skin trauma and its function has been revealed only recently or in the nearby extrapersonal space. Anterior superior by imaging studies. !e neurons are not uniform in 42 parietal association area (BA 5) provides the ability to shape throughout the precuneus. !e anterior por- appreciate the weight and texture of an object held in tion is characterized by larger neurons and the smaller Parietal lobe

Clinical vignette the frontal lobe, including the premotor and supple- A 65-year-old right-handed man had progressive dif- mentary motor areas, as well as the dorsolateral and "culty locating items in space or orienting himself in ventromedial prefrontal areas. Intermediate between familiar surrounding. He behaved as if blind, unable to the precuneus and prefrontal lobe in terms of signal either look at or reach for objects in his environment, processing is the posterior cingulate and the retrosple- such as the buttons on his clothes or utensils for eat- nial cortices (BA 30) (Figure 12.1). !e retrosplenial ing. When presented with complex scenes, he could cortex has reciprocal connections with the precuneus not recognize more than one item at a time (simul- as well as with the medial temporal lobe including the tanagnosia). He could not identify two adjacent but hippocampus. !e precuneus has connections with unlinked drawings, large letters made up of smaller the dorsal thalamus including the pulvinar. Brainstem ones, or fragmented pictures. When commanded to move his eyes to speci"c visual objects in his periph- connections with structures such as the pretectal area, eral "elds, he could not do so (oculomotor apraxia). superior colliculus, and reticular formation as well as When attempting to reach out and touch objects in the frontal eye #elds suggest a role in eye movement his peripheral "elds with either arm, he would entirely control (Leichnetz, 2001; Parvizi et al., 2006). !e pre- miss them (optic ataxia).In addition to the visuospatial cuneus is recognized as being involved in four general de"cits of Balint syndrome, the patient had other functions: consciousness, body movements in space, impairments. Despite the absence of motor weak- self-awareness, episodic memory retrieval, and visuo- ness, he was unable to brush his teeth or wave good- spatial imagery. bye with his left upper extremity on verbal command (ideomotor apraxia). His attempts at performing these Consciousness praxis tasks resulted in grotesque motor movements Along with the IPL and the ventromedial, dorsomedial of his left upper extremity. He also had a slow, rigid prefrontal, and retrosplenial cortices, the precuneus gait (parkinsonism), abnormal posturing of his right hand and neck (dystonia), and spontaneous jerking of is highly metabolically active during the resting state his extremities (myoclonus). Single photon emission (Alkire et al., 2008). !e precuneus and the retros- tomography imaging showed decreased perfusion plenial cortex and posterior cingulate gyrus make up in both parietal regions (Figure 4.7). This patient’s ill- the “posteromedial cortex.” !e precuneus is the most ness was consistent with corticobasal degeneration, active of these areas consuming about 35% more glu- a disorder that includes cortical de"cits such as Balint cose (Gusnard and Raichle, 2001). !e precuneus syndrome and ideomotor apraxia, and basal ganglia is believed to be tonically active during the resting, de"cits, such as parkinsonism and dystonia. waking state. It continuously gathers and processes information about the world within and around us. posterior portion is populated with smaller neurons, It receives visual input from the dorsal visual stream suggesting a regional di$erence in the function of the so is constantly monitoring the peripheral visual #eld. precuneus (Zilles et al., 2003). !e precuneus receives It can choose at any time to shi& attention to a novel multimodal sensory input from the lateral parietal attractive target unless inhibited by the frontal lobe. cortex including the superior and inferior lobules as Joint activation of the precuneus and prefrontal cortex well as from the cortex within the intraparietal sul- may underlie a state of re"ective self-awareness, and cus (IPS). It has strong reciprocal connections with activity correlates with mind-wandering (Kjaer and

Figure 4.7. This scan is a three- dimensional computerized reconstruction of the patient’s single photon emission tomography images. The left hemisphere is on the left side. There are prominent bilateral areas of decreased perfusion in both parietal lobes consistent with his Balint syndrome and ideomotor apraxia. (Reprinted with permission from Mendez, 2000.)

43 Occipital and parietal lobes

Lou, 2000; Kjaer, et al., 2002). Both these areas show the precuneus where they are relived and elaborated. signi#cant deactivation during states of altered con- It is believed to gather and integrate past information sciousness including sleep, hypnosis, dreaming, and regarding the self and external world especially in the persistent vegetative state (Maquet et al., 1997, 1999; realm of spatial tasks (Gündel et al., 2001; Lou et al., Laureys et al., 1999; Rainville et al., 1999; Hobson et 2004). It provides self-representation, alertness, and al., 2000; Maquet, 2000). Along with the posterior cin- “the internal mentation processes of self-conscious- gulate gyrus, the precuneus becomes progressively ness” (Cavanna, 2007). deactivated as anesthetic-induced sedation progresses (Alkire et al., 1999; Fiset et al., 1999). It is also one of Self-awareness the #rst areas to resume activity when consciousness Self-awareness includes the recognition of self-own- is regained (Laureys et al., 2004, 2006). !e precuneus ership and that “I am the initiator of the action and becomes less active during goal-directed cognitive or thus that I am causally involved in production of that perceptual tasks, suggesting it is selectively reducing action” (Gallagher, 2000). Self-awareness allows one awareness of potentially distracting environmental fac- to realize that someone else may be the initiator of tors (Gusnard and Raichle, 2001). Its activity is reduced action in appropriate situations. Action attributed to in normal aging but more so in patients with dementia another produced activity in the right IPL suggesting (Lustig et al., 2003). that it monitors multimodal sensory signals representing movements of both the self and others in an Body movements in space allocentric frame of reference (Farrer and Frith, 2002). !e precuneus is activated when preparing to make a !e precuneus appears to play a role in self-related movement or when executing a movement in space, tasks whether involving spatial orientation, episodic especially movements involving pointing, reach- memory, or social judgments. Along with the posterior ing, and saccades. It is activated when an individual cingulate, the precuneus is activated when processing just imagines making a movement (Hanakawa, et al., intentions related to the self (Vogeley and Fink, 2003; 2003). It also appears to play a key role in attending to a den Ouden et al. 2005). target and shi&ing attention from one target to another, !e precuneus is believed to be part of a network even if no movement is made (Beauchamp et al., 2001; involved in theory-of-mind processing. Activation of Simon et al., 2002). the precuneus and posterior cingulate (BA 31) occurs !e precuneus is part of a network that elaborates in situations involving deception and cooperation. It information about maps to help locate one’s self on these appears to function in a broad sense related to per- maps. It can operate using retinotopic coordinates or spective taking as well as attribution, and the pro- head-centered coordinates. When imagining moving cessing of emotions and intentions in this situation through an environment with obstacles the precuneus is (Lissek et al., 2008). It shows strong activation when activated bilaterally along with the right lateral parietal making judgments that require empathy in social situ- cortex and le& supplementary motor cortex (Malouin ations (Farrow, et al., 2001; Ruby and Decety, 2001). et al., 2003). It has been suggested that the precuneus In studies, the le& precuneus was preferentially acti- acts as the “mind’s eye” in these situations, assessing the vated when attributing emotions and intentions to the environment and choosing a navigable route through actions of others (Ochsner et al., 2004; Abraham et al., it (Burgess et al., 2001). In this role it may activate vis- 2008). ual images associated with remembered words, objects, and speci#c autobiographical events as part of episodic memory recall of the meaning of speci#c environmental Intraparietal sulcus landmarks. !e anterior precuneus appears to be asso- !e IPS (or intraparietal #ssure) lies on the lateral ciated with attention and active recall (visual imagery) aspect, separates the superior from the inferior par- whereas the posterior precuneus is more selectively ietal lobule, and contains the intraparietal cortex. activated during the successful recall of speci#c events !e shape and course of the sulcus are variable but in (Cavanna and Trimble, 2006). general it extends from the postcentral sulcus to the occipital lobe. !e IPS becomes deeper and its cor- Episodic memory retrieval tex more extensive as it approaches the occipital lobe 44 Evidence suggests that memories of personally expe- (Figure 4.8). !e more anterior parts in the human are rienced events (episodic memory) are retrieved to very similar in location to those of the monkey whereas Parietal lobe

Intraparietal sulcus Figure 4.8. The intraparietal sulcus extends from the postcentral sulcus to the occipital lobe. It is the border between the superior and inferior parietal lobules. The sectional views show the depth and complexity of the sulcus as well as the Lateral fissure extent of the medial and lateral banks. Calcarine fissure

Intraparietal sulcus Central sulcus Lateral fissure

those closer to the occipital lobe are more variable. stream alerts the dorsal visual stream to create a motor !e cortex that makes up the medial and lateral banks program in the IPS and surrounding region to look at within the sulcus has been described as the intrapari- and grasp the desired package (“see and seize”). etal area. It has been subdivided into 17 subregions in the monkey (Lewis and Van Essen, 2000a). !e lateral, Lateral intraparietal area (parietal saccade region) medial, anterior, ventral, and posterior intraparietal !e lateral intraparietal area is one of the most stud- subregions are recognized in the human. !e anterior ied subregions in the monkey, in which it makes up IPS is more concerned with somatosensory process- the lateral bank of the sulcus near the occipital lobe. In ing whereas the posterior IPS processes visual signals. the human the lateral intraparietal area lies close to the Neurons in the medial bank are more responsive to occipital lobe but appears to be more medially located arm movements, and lateral bank neurons are more in the IPS (Koyama et al., 2004). !e lateral intrapa- responsive to eye movements. rietal area receives information regarding objects in Each area of the IPS functions in response to more the contralateral hemi#eld. Object location, direction, than one sensory modality making the cortex of the and velocity are registered, using signals from the vis- IPS a multimodal integrative area. !e IPS acts to ual, auditory, and somatosensory systems (Andersen, focus attention in space to salient stimuli and espe- 1997; Andersen and Buneo, 2003). It also monitors cially threat-related stimuli. Fearful faces bias atten- current eye position with respect to the head and head tion toward the threat-related location and increase position and with respect to the body as well as the the gain of face-related signals in the occipital cortex. head’s orientation to gravity (i.e., vestibular sense). !e timing of these events suggests that negative emo- !e lateral intraparietal area determines the relative tional stimuli can focus attention on a speci#c loca- importance of the object (salience) and then programs tion through mechanisms in the IPS (Pourtois and and executes a saccade to that object (Ipata et al., 2006). Vuilleumier, 2006). !is is a bottom-up control of attention as the atten- Information carried by the dorsal visual stream tion is determined by the attractiveness of the target de#nes target location. Information carried by the (Buschman and Miller, 2007). ventral visual stream de#nes target identi#cation. Top- down signals from the frontal lobe can act to preselect Medial intraparietal area (parietal reach region) targets. An individual in a grocery aisle records the A region of the medial bank of the IPS near the location of all items on the nearby shelf using the dorsal occipital lobe and extending laterally onto the sur- visual stream. !e frontal lobe maintains in working face of the superior parietal lobule is described as memory the speci#c brand from the shopping list. !e the “parietal reach region” (Connolly et al., 2003). ventral visual stream matches the shopping list brand It operates in a manner similar to saccade program- 45 with the package label on the shelf. !e ventral visual ming but is responsible for planning and executing Occipital and parietal lobes

visually guided reaching movements of the upper to monitor a personal zone of safety surrounding the limb. Success of the movement is greater if the target body (Graziano and Cooke, 2005). is located on the fovea. If the target is in the periph- Posterior intraparietal area (three-dimensional analysis) ery (e.g., reaching for a cup of co$ee while reading !e posterior intraparietal area in the monkey occupies the paper) a larger region of parieto-occipital cor- the lateral bank of the IPS close to the occipital lobe and tex is activated including the precuneus. Continual posterior to the lateral intraparietal area. It receives adjustments are made while reaching for an object input from visual areas V3 and V4 and is involved in the periphery, suggesting an “automatic pilot” in the analysis of the features of three-dimensional since the individual is unaware of the adjustments (3D) objects including texture features (Tsutsui et al., (Himmelbach et al., 2006). 2002). Results indicate that this area is responsible for Anterior intraparietal area (parietal reach and grasp region) the short-term memory of object surface features that !e anterior intraparietal area is described as the allows the changing view of an object to be remem- grasp region and occupies the anterior lateral bank bered long enough to compare current with past views. of the sulcus (Grol et al., 2007). Neurons of the anter- Binocular and monocular depth cues and other infor- ior area are active during #xation and manipulation mation from both the dorsal and ventral visual streams of objects (Buxbaum et al., 2003). It contains neurons are integrated in this region. Signals from the posterior that are sensitive to size, shape, and orientation of intraparietal region are forwarded to the anterior intra- objects to be grasped. !e objects may be viewed or parietal region to code for #nger shaping and grasping remembered and the area also monitors hand pos- movements (Gre,es and Fink, 2005). ition and movement (Tunik et al., 2005). !e anter- Lesions involving the IPS may cause neglect or extinc- ior intraparietal area projects to the ventral premotor tion a$ecting more than one modality. Since the area is cortex to provide signals for #nger and arm move- head-centered, lesions in this area may account for symp- ments involved in reaching and grasping. Pa and toms seen in visuospatial neglect (Vallar et al., 2003). Hickok (2007) showed that a region of the anterior In comparison with normally developing controls, intraparietal area was activated by pianists making IPS depth in children with Asperger syndrome has covert (imagined) playing movements while listening been reported to be greater. !e depth of the IPS cor- to music, suggesting this is also a region of auditory- relates with age and IQ (Nordahl et al., 2007). !e gray manual integration. matter density is less in the le& IPS in children with dyscalculia (Isaacs et al., 2001). Molko et al. (2004) Ventral intraparietal area (navigation in space) showed that the right IPS was shallower and tended !e ventral intraparietal area lies deep within the IPS to be shorter in girls with Turner syndrome. !is cor- and is believed to contain a crude somatotopic map related with di%culty during calculation tasks and with most of the map devoted to the head. It receives visuospatial processing. input from higher order visual processing areas including the middle temporal area (MT) and the middle Inferior parietal lobule superior temporal area (MST). It also receives input !e inferior parietal lobule (IPL) corresponds with the from motor, somatosensory, auditory, and vestibu- supramarginal gyrus (BA 40) and the angular gyrus lar areas (Lewis and Van Essen, 2000b). It appears to (BA 39; Figure 4.2). Further subdivisions have been code for self and object motion and coordinates eye suggested. Based on its histological and magnetic res- and head movements. Neurons in the ventral intrapa- onance imaging features, the supramarginal gyrus (BA rietal area are sensitive to the direction and velocity of 40) can be divided into #ve areas and the angular gyrus moving visual targets as well as current head position, (BA 39) into two (Zilles et al., 2003; Caspers et al., 2006). velocity, and acceleration. Other neurons in the same Considerable variability has been found between spec- area are active during pursuit eye movements (Schlack imens, as well as le&-right di$erences (asymmetry). et al., 2003). Signals from visual, vestibular, and audi- !e individual variability is believed to be related to tory cortices also contribute to the ventral intrapari- the fact that this is one of the last regions of the cortex etal area, emphasizing its importance as a multimodal to mature. !e #nal con#guration may be in"uenced integrative region (Schlack et al., 2002). It plans motor by experience (Caspers et al., 2006). Like the SPL, the 46 responses to navigate through nearby space while IPL has reciprocal connections with the pulvinar and avoiding obstacles (Bremmer, 2005). It may function the lateral thalamic nuclei. Short association #bers Parietal lobe connect it with nearby occipital and temporal lobes, as the right IPL is larger than the le& (Frederikse et al., well as the SPL and precuneus. Long association #b- 1999; Chen et al., 2007). One subdivision of the supra- ers link the IPL with the frontal cortex, including the marginal gyrus (area PFcm) which makes up part of frontal eye #elds. its inferior aspect, accounts for most of the gender !e IPL receives signals representing the sensation di$erence (Caspers et al., 2008). Weaker le&ward of touch, proprioception, and vision and integrates asymmetry has been reported for patients with bor- these signals in order to determine the identity of a tar- derline personality disorder. Psychotic symptoms and get (Aguirre and D’Esposito, 1997). !e strategic loca- schizoid personality traits of these patients were cor- tion of the angular gyrus between the occipital lobe and related with larger right IPL size suggesting a right- Wernicke’s speech area results in it being “the region sided neurodevelopmental de#cit (Irle et al., 2005, which turns written language into spoken language 2007). In another study, an increase over controls was and vice versa …” (Geschwind, 1965). observed in the gray matter of the right supramarginal !e IPL has been described as where “all the facts gyrus, which was speci#c for de#cits in social commu- can be stored and retrieved” (Bear, 1983). It has also nication and interaction, and repetitive, stereotyped been described as “an association area of association behavior in children with autism spectrum disorder areas” (Geschwind, 1965). Remembering (retrieval (Brieber et al., 2007). of speci#c content) and knowing (perception that !e supramarginal gyrus of the le& IPL works in processed information is from the past) activates the cooperation with the le& dorsolateral prefrontal cortex IPL as well as portions of the intraparietal sulcus. in support of working memory. Collette et al. (2007) Remembering also activates the anterior fusiform found that these two areas became activated dur- gyrus bilaterally, which processes visual information ing working memory in control subjects but failed to related to objects (Wheeler and Buckner, 2004). In one show activation in patients with posttraumatic stress study, the le& IPL, extrastriate body area, premotor disorder. !is failure in activation appears to re"ect a cortex, and supplementary motor were activated when reduction in working memory updating rather than in the viewer saw body movements that were within the working memory maintenance operations. !e reduc- range of motor capability of the viewer (i.e., capable of tion in working memory updating is suggested to relate imitation) (Blakemore and Decety, 2001). !e IPL plays to the di%culty in concentrating and remembering an important role when the self takes the perspective of reported by patients with posttraumatic stress disorder others (Ruby and Decety, 2001) and may be part of a (Moores et al., 2008). “concern mechanism” (Decety and Chaminade, 2003). !e IPL functions to encode and retrieve a motor Behavioral considerations sequence. It is proposed that di$erent areas within the IPL encode di$erent types of sequences. !e angular Schizophrenia gyrus is particularly involved in evaluating visual mes- Attention de#cits are recognized in patients with sages and selecting an appropriate motor sequence in schizophrenia (Laurens et al., 2005). Since the dorsal response (Ruby et al., 2002). visual stream serves areas of the parietal lobe import- !e IPL and the supramarginal gyrus in particu- ant in attention it has been hypothesized that a defect lar are activated in skill learning (right side) and tool in this system may underlie attention de#cits in this use (le& side). It is hypothesized that the supramarginal population (Laycock et al., 2007). However, there gyrus stores information about limb and hand posi- appears to be limited evidence to support this hypoth- tions based on previous experience. Retrieval of a pre- esis (Skottun and Skoyles, 2008). viously formed motor memory may be important in Volume reductions were reported for the IPL in elaborating the skill and adapting it to a new situation patients with schizophrenia (Schlaepfer et al., 1994; (Seidler and Noll, 2008; Vingerhoets, 2008). Goldstein et al., 1999) and in all parietal subregions Although the le& and right IPL are not signi#- in a group of 53 patients with schizophrenia and cantly di$erent in size, asymmetries have been found schizotypal personality disorder (Zhou, et al., 2007). when sex is included in the analysis. Total IPL volume Delusions of passivity in individuals with schizo- is greater in males than females and the le& IPL is lar- phrenia are associated with hyperactivity coupled ger in men than women (i.e., le&ward asymmetry). with reductions in gray matter volume of the infer- !e asymmetry is less marked in women in whom ior parietal lobe (Dankert et al., 2004; Maru$ et al., 47 Occipital and parietal lobes

2005). Male but not female patients with schizophre- Attention nia have been found to show a reversal of the normal !ree attention networks have been described, all of le& greater than right angular gyrus (Frederikse et al., which involve the parietal cortex. !e default network 2000; Niznikiewicz et al., 2000). !ese regions sup- described above is active during resting states (see port language and may help explain the language and page 43). It is believed that the default network sup- thought disorders found in schizophrenia (Shenton ports internally directed, mind-wandering processing et al., 2001). Whalley et al. (2004) found that during that includes spontaneous and introspective thoughts, a verbal task subjects at high risk for schizophrenia remembering one’s role in past events, or planning one’s showed increased activation in the le& IPL compared future (Raichle et al., 2001; Fransson and Marrelec, with controls. It was suggested that the overactivation 2008). When either of the other two attention networks of the IPL is a compensatory action related to attention (dorsal and ventral) is activated, the default network is to task and preparation of a suitable response. Subjects suppressed. at risk for schizophrenia who showed isolated symp- Corbetta et al. (2000) reported that the dorsal atten- toms, reported di%culties in focusing attention and tion network is activated when presented with import- exhibited a state-related overactivation of the intra- ant external stimuli in a bottom-up manner or when parietal sulcus. In another study, gray matter volume the subject is asked to voluntarily direct attention to a was observed to be reduced in the precuneus in men speci#c cue in a top-down manner. !e structures of with schizophrenia accompanied by small regions of the dorsal attention network become activated bilat- increased gray matter in the right IPL (Shapleske et al., erally and include the cortex of the intraparietal sulcus 2002). !e posterior parietal lobe and precuneus have and the junction of the precentral and superior frontal been implicated in distinguishing between self and sulcus (frontal eye #eld). others (Meltzo$ and Decety, 2003). !e ventral attention network consists of the right !e IPL is part of frontal-limbic-temporal-parietal temporoparietal junction and the right ventral frontal network involved in schizophrenia (Torrey, 2007). cortex. When attention is focused, the dorsal network Reduced asymmetry has been reported for individuals is suppressed to prevent attention to distracting stim- with schizophrenia, with smaller le& and larger right uli (Todd et al., 2005). !e ventral attention network is IPLs than controls (Frederikse et al., 2000; Niznikiewicz thought to act in concert with signals from the dorsal et al., 2000; Nierenberg et al., 2005). !e smaller size of attention network to provide an interrupt or reset sig- the le& temporoparietal cortex including the le& supra- nal coincident with shi&ing attention to a new exter- marginal gyrus correlates with the severity of auditory nal target (“Is that my phone ringing?”) or to a new hallucinations in patients with schizophrenia (Gaser thought (“Did I remember to turn o$ the stove?”). It et al., 2004). may be active in reorienting when the individual has A group of men with schizophrenia and antisocial no ongoing task; however in most situations it reacts personality disorder were compared based on a history and supports reorientation in response to important of violent behavior with healthy controls, using fMRI. novel stimuli selected by the dorsal system (Corbetta Men with schizophrenia and a history of violent behav- et al., 2008). ior showed reduced activation in the precuneus, right Spatial neglect IPL, le& frontal gyrus, and anterior cingulate gyrus. Men with antisocial personality disorder also showed Spatial neglect is considered a visual attention dis- reduced activation in the precuneus, le& frontal gyrus, order. Patients do not recognize the opposite side of and anterior cingulate gyrus. !e reduced activation their body and will not dress it (dressing apraxia). of the right IPL in the subjects with schizophrenia Patients are o&en unaware of the de#cit (anosogno- was most strongly associated with ratings of violence. sia). Inability to correctly copy a simple drawn sym- It was hypothesized that the combined involvement metrical #gure (constructional apraxia) is common. of the right IPL and frontal cortex re"ected impaired !e right IPL at the temporoparietal junction trad- executive control (Kumari et al., 2006). Episodic mem- itionally has been implicated (Mort et al., 2003). It has ory, associated with the precuneus, is reported to be been suggested that there is a map of the contralateral one of the most severely impaired neuropsychological body and peripersonal space in the le& IPL, but both an elements in schizophrenia (Reichenberg and Harvey, ipsilateral and contralateral map in the right IPL. Loss 48 2007). of the map found in the le& hemisphere has little or no Parietal lobe e$ect because of a redundant right hemi#eld map in contralesional visual #eld with either hand. !eir the right hemisphere. A lesion in the right hemisphere e$orts are inaccurate when using peripheral vision results in a loss of the map of the le& side. It is theo- (dorsal visual stream), but accuracy is normal when rized that since the brain cannot locate objects on the using foveal vision (ventral visual stream). Pointing opposite side following a nondominant parietal lobe errors improve with time in a way that suggests that lesion, the objects cannot be attended to and therefore recovery involves potential interaction between the are ignored. damaged dorsal visual stream and intact ventral vis- Spatial neglect can occur following damage to ual stream (Himmelbach and Karnath, 2005; Karnath several areas including subcortical sites (caudate and Perenin, 2005). !e dorsal and ventral streams do nucleus, putamen, and pulvinar), the frontal lobe, not work independently since patients with parietal and the superior temporal gyrus. Most frequently, lesions are usually not successful in completing all however, the IPL and temporoparietal junction in visuospatial tasks using intact ventral streams alone particular, are involved, including the white matter (Ellison and Cowey, 2007). deep to this cortex (Mort et al., 2003; !iebaut de Schotten et al., 2005). Neglect of personal space cor- Apraxia relates with lesions of the supramarginal and post- Apraxia is the inability to executed skilled, learned central gyri with some involvement of the posterior motor acts despite preservation of motor and sensory superior temporal gyrus (Committeri et al., 2007). A systems, comprehension, cooperation, and coordin- lesion restricted to the posterior superior temporal ation. Ideomotor apraxia is impaired performance in gyrus may also result in spatial neglect (Karnath et spite of preservation of sensory, motor, and language al., 2001). Lesions involving white matter pathways function (Heilman and Rothi, 2003). !e patient can- between the temporoparietal region and the frontal not perform a meaningful movement of a limb when cortex have been implicated in hemineglect but do not requested. Many authors include the inability to imi- necessarily cause neglect. However, damage to these tate gestures as part of ideomotor apraxia. pathways or to the connections between the dorsal Ideational apraxia is seen as the impaired ability to and ventral attention networks may impair shi&ing carry out the appropriate sequential actions of a multi- from one environment target to another (Doricchi et step, complex task. It is a disruption of the space–time al., 2008). Since the ventral attention network is local- movement plan or of its proper activation. !e patient ized to the right hemisphere, its loss may inhibit an cannot form a plan to carry out movements in a proper attempt to direct attention to the contralesional side sequence. Ideational apraxia is associated with lesions (He et al., 2007). of the le& parietal lobe alone or in combination with Damage to the ventral (temporal) visual stream, temporal and frontal lesions. concerned with detailed object information, leads to !e le& parietal lobe is activated when carrying out allocentric impairment. Damage to the dorsal (pari- meaningful limb movements and ideomotor apraxia is etofrontal) visual stream results in egocentric de#cits seen following a lesion of the le& parietal lobe. Since (Grimsen et al., 2008). Interestingly, caloric vestibular many meaningful movements involve the use of tools, stimulation has been reported to temporarily improve knowledge of the location of tool use is helpful in under- a number of elements of sensory neglect including standing apraxia and patient rehabilitation (Wheaton, anosognosia for le& hemiplegia (Vallar et al., 2005; 2007). Speci#c areas associated with apraxia include Rode et al., 1998; Bottini et al., 2005). It is proposed the cortex of and around the le& IPS and the le& middle that anosognosia of hemiplegia is due to a loss of motor frontal gyrus (Haaland et al., 2000). Right side lesions planning ability (Vallar et al., 2003). can also result in apraxia as well as a lesion of the anterior corpus callosum (Leiguarda and Marsden, 2000; Optic ataxia Petreska et al., 2007). A model of praxis proposes that Optic ataxia can be seen following a lesion on either the le& inferior parietal lobe is an integrative area that side involving the dorsal visual processing stream in brings together information from the dorsal and ven- the posterior superior parietal lobule. It has been seen tral visual streams. It is an area that processes represen- following lesions in or near the medial IPS (Pisella tations of body part positions and generates plans for et al., 2000; Roy et al., 2004). Patients are impaired limb movements (Buxbaum et al., 2007). !e frontal in the ability to reach for and grasp objects in the lobe is responsible for gesture production. 49 Occipital and parietal lobes

Gerstmann syndrome Individuals with borderline personality disorder Pantomime recognition (recognition of common ges- have been shown to have reduced size of the parietal tures) may be lost following damage to the dominant lobes. !e right precuneus has been shown to exhibit IPL. A lesion involving the angular gyrus (BA 39) may reduced resting glucose metabolism and reduced size produce part or all of Gerstmann syndrome: in individuals with borderline personality disorder t Le&–right confusion. (Le&–right confusion (Lange et al., 2005; Irle et al., 2007). !e right postcen- among neurologically intact adults is seen in 9% of tral gyrus was shown to be larger in individuals with men and 18% of women.) a comorbid diagnosis of dissociative amnesia or dis- t Finger agnosia –di%culty in naming #ngers. sociative identity disorder. Individuals with borderline personality disorder have also been reported to have t Dysgraphia –di%culty with writing. elevated pain thresholds coupled with reduced activity t Dyscalculia –di%culty with numbers. in the precuneus in response to pain (Schmahl et al., 2006). Irle et al. (2007) suggested that the smaller pre- Balint syndrome cuneus may relate to symptoms of depersonalization. !e increased postcentral gyrus has been speculated to !e patient with Balint syndrome is unable to view the relate to the dissociative amnesia or dissociative iden- visual #eld as a whole and is #xed on only one part; tity disorder re"ecting severe childhood abuse (Lange a form of tunnel vision (simultanagnosia). Bilateral et al., 2005; Irle et al., 2007). damage to the posterior IPL, o&en including adjacent Parietal lobe seizures can produce bizarre and tran- occipital cortex, may produce Balint syndrome: sient symptoms that can be confusing to both patients t Optic apraxia –eyes tend to remain #xed (stuck) and clinicians. Feelings of paresthesia, numbness, on a visual target, although spontaneous eye heat, or cold have been described. !ese feelings can movements are una$ected. begin locally and spread to other contiguous body t Optic ataxia –a de#cit in using visual guidance to parts. Seizures beginning more posteriorly can cause grasp an object. pronounced distortion of body image. Limbs may feel t Simultanagnosia –seeing only the components heavier or feel as if they disappear. Even more bizarre, of a visual object; unable to see the object as a patients have reported feeling that someone is stand- whole. ing close by or the appearance of a phantom third Bilateral damage to the occipitoparietal area, o&en limb. Patients with newly diagnosed schizophrenia are extending deep enough to involve the precuneus is the reported to show greater sulcal enlargement in the par- most common cause of this disorder (Raichle et al., ietal lobe (Rubin et al., 1993). 2001). !e similarities between hysteria and parietal lobe disease should again be stressed. Patients with parietal lobe lesions may show marked inconsistency Other considerations in task performances, such that he or she may suc- A lesion involving the nondominant IPL may produce ceed in a task that moments before appeared to be a de#cit in processing the nonsyntactic component of impossible. language (aprosodia). In this situation, patients fail to appreciate aspects of a verbal message that are con- Select bibliography veyed by the tone, loudness, and timing of the words (i.e., emotional tone). Critchley, M.!e Parietal Lobes. (London: Edward Arnold, 1953.) Van Essen et al. (2006) found that subjects with Hecanen, H., and Albert, M.L. Human Neuropsychology. William syndrome showed reduced asymmetry of (New York: Wiley, 1978.) the lateral #ssure and no asymmetry in the superior Hyvarinen, J. !e Parietal Cortex of Monkey and Man. (New temporal sulcus compared with controls. !e authors York: Springer-Verlag, 1982.) suggested that in light of the relatively intact language Lishman, W.A. Organic Psychiatry (2nd ed.). (Boston: skills and heightened emotional responses to music Blackwell Scienti#c, 1987.) in William syndrome subjects, the abnormalities in Milner, A.D., and Goodale, M.A. !e Visual Brain in Action cortical folding might re"ect altered cortical circuitry (2nd ed.). Oxford Psychology Series. (New York: Oxford 50 rather than a simple size reduction. University Press, 2006.) References

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CChapterhapter Temporal lobe: Neocortical 5 structures

Functional anatomy major portions of the limbic system and thus contrib- Emil Kraepelin (1919) suggested that abnormalities utes signi#cantly to emotional tone. !e ventromedial, in the frontal lobe were responsible for problems limbic temporal lobe is discussed in Chapter 11. in reasoning and that damage to the temporal lobe !e temporal lobe lies ventral to the lateral #ssure resulted in delusions and hallucinations in patients (of Sylvius) and anterior to the parietal lobe. It also with dementia praecox (schizophrenia). !e classical forms part of the anterior border of the occipital lobe #ndings of Klüver and Bucy in the 1930s clearly and (Figure 5.1). !e superior temporal gyrus is bordered strongly linked the temporal lobes to behavior (Klüver by the lateral #ssure above and the superior temporal and Bucy, 1939). !eir work provided the basis from sulcus below. Both sulci are particularly deep. !e mid- which the concept of the limbic system has developed. dle and inferior temporal gyri make up the lateral sur- !e temporal lobe can be divided into two face below the superior temporal sulcus. regions: dorsolateral and ventromedial. !e dorsolat- !e dorsolateral temporal lobe is recognized as eral region supports cognitive functions associated with important in auditory processing and speech analysis. several sensory systems, especially language. It is now Language is an important means of social communi- accepted that dysfunction of the dorsolateral region of cation. Other methods of communication such as ges- the temporal lobe may be associated with several psy- tures have been found to be analyzed by the temporal chopathological states. Temporal lobe lesions due to a lobe as well. variety of neurological insults can lead a patient to present with signs and symptoms that are more consist- Auditory areas ent with a psychiatric diagnosis than with a traditional !e transverse gyrus of Heschl [Brodmann’s area (BA) neurological one. !e dorsolateral temporal cortex is 41] is located on the superior surface of the superior recognized as neocortex and is the focus of this chapter. temporal gyrus (Figure 2.3). Heschl’s gyrus is recog- !e ventromedial region of the temporal lobe contains nized as the primary auditory area and corresponds

Central sulcus Figure 5.1. The dashed lines indicate the imaginary boundaries between the parietal, occipital, and temporal lobes. The temporal lobe lies below the lateral "ssure Parietal lobe and below the parietal lobe, and to the front of the occipital lobe. The dashed line demarcating the occipital from the parietal and temporal lobes is an imaginary line that runs from the parieto-occipital sulcus above to the preoccipital notch below.

Lateral fissure s yru al g por tem or eri s up yru S ral g mpo te s ddle yru Mi al g por Frontal pole tem rior Infe 59 Temporal pole Occipital lobe Temporal lobe: Neocortical structures

Clinical vignette Clinical vignette A 68-year-old left-handed man had di!culty under- A 71-year-old language teacher complained of a standing speech after a stroke sustained during cor- progressive loss of the ability to use and understand onary artery bypass surgery. When he awoke from Spanish and German. The patient had di!culty under- anesthesia, he could not understand what people standing even common nouns in Spanish, and he were saying, as if they were “speaking too fast or in was no longer able to understand any German words. Chinese.” His own speech was not a#ected, and he His English was impaired as well. The patient had lost could read and write perfectly. In addition, envir- the meaning of many words such as cu#, lapel, and onmental sounds became indistinct and di!cult to eyelashes and, on an aphasia battery, his word com- understand. On examination, he was very talkative, prehension was moderately impaired. Moreover, the but, when spoken to, he appeared confused and per- patient was losing the ability to identify many of the plexed. His audiometry testing was adequate, and he objects that he could not name. This patient’s presen- could discriminate pure tones based on frequency, tation was compatible with the syndrome of seman- intensity, or duration. In contrast, he had di!culty tic dementia characterized by early loss of word understanding spoken commands, and he could not comprehension followed by more pervasive inability understand simple sounds, such as a birdcall or a train in the identi"cation of objects. His magnetic reson- whistle. This patient had auditory agnosia for spoken ance imaging (MRI) studies showed anterior inferior words (word deafness) and environmental sounds. temporal atrophy in the left hemisphere (Figure 5.3) These problems were consequent to a stroke involv- (Mendez et al., 2004). ing the right temporal auditory cortex (Figure 5.2). Whereas right temporal lesions can produce auditory agnosia for environmental sounds, the presence of portion of the middle and inferior temporal gyri which the additional word deafness was probably due to a lie inferior to the parietal lobe constitutes BA 37. !ese greater right hemisphere role in auditory-language areas may be described as the auditory association cor- pathways in this left-handed person. tex. If the lips of the lateral #ssure are pulled apart, the insular cortex is seen to lie deep within the lateral #ssure. Gyri and sulci are more variable on the inferior sur- with the core area described in the monkey. BA 42 is face of the temporal lobe (Figure 5.4). !ree parallel the secondary auditory cortex and surrounds Heschl’s gyri can be recognized. !e most lateral is the infer- gyrus on all but the medial side. It corresponds with ior temporal gyrus. !e fusiform (lateral occipitotem- the belt and parabelt areas described in the monkey poral) gyrus lies next to it and is separated from it by (Saleem et al., 2008; Shapleske et al., 1999). the occipitotemporal sulcus. !e lingual gyrus (medial !e superior, middle, and inferior temporal gyri cor- occipitotemporal gyrus) is separated from the fusiform respond roughly with BA 22, 21, and 20, respectively. gyrus by the collateral sulcus. !e lingual gyrus is con- !e cortex of the temporal pole is BA 38. !e posterior tinuous anteriorly with the parahippocampal gyrus.

Figure 5.2. The patient’s 18-!uorodeoxyglucose positron emission tomography showed focal right temporal lobe hypometabolism a#ecting his auditory cortex. (Reprinted with permission from Mendez, 2001.)

60 Functional anatomy

Figure 5.3. A, B. T2-weighted magnetic resonance image showed bilateral anterior inferior temporal atrophy disproportionately a#ecting the left temporal lobe. (Reprinted with permission from Mendez and Cummings, 2003.)

A B

Parahippocampal gyrus Figure 5.4. The boundary between Collateral sulcus the temporal lobes and the occipital lobe is indistinct on the ventral surface gyrus oral mp of the brain. The isthmus of the cingulate te ior oral gyr gyrus is continuous with the parahip- er temp us nf ito s) I cip gyru pocampal gyrus. APS, anterior perforated c rm l o fo Uncus Occipital a si substance. r u Olfactory bulb pole te (f a s and tract L gyru ual ng Li Brain- Frontal stem pole

APS

Calcarine sulcus Temporal pole

!e collateral sulcus and its anterior extension, the that re"ects the distribution of frequency-dependent rhinal #ssure, mark the lateral extent of the parahip- cells along the organ of Corti. !e auditory cortex con- pocampal (hippocampal) gyrus. !e parahippocam- sists of cell columns in an arrangement similar to that pal gyrus expands at its anterior pole to form the uncus of other sensory cortical areas. (Chapter 11). All incoming sound signals are #rst processed bilaterally in BA 41. Neurons in Heschl’s gyrus of the mon- Heschl’s gyrus (primary auditory area; BA 41) key respond maximally to pure tones. It is not until Heschl’s gyrus receives projections from the med- signals reach the auditory association area that indi- ial geniculate body of the thalamus. !ere are o&en vidual neurons respond maximally to complex sounds two Heschl’s gyri on the right but only one on the le& including species-speci#c vocalizations (Rauschecker (Leonard et al., 1998). !e size of Heschl’s gyrus is vari- et al., 1995; Kosaki et al., 1997). able between individuals and may be asymmetrical in !e gray matter volume of BA 41 has been reported the same individual. It is generally larger on the le& to be signi#cantly greater and to show greater activity (Dorsaint-Pierre, et al., 2006), and it is consistently lar- in professional musicians than in nonmusicians. !e ger bilaterally in females than in males (Rademacher size of the gyrus correlates with the degree of musical 61 et al., 2001). Heschl’s gyrus contains a tonotopic map aptitude (Schneider et al., 2002; Pa and Hickok, 2008). Temporal lobe: Neocortical structures

Electrical stimulation of the primary auditory dorsal “where” stream is important in verbal working region produces elementary hallucinations, including memory and acts to keep auditory-based representa- ringing, buzzing, or whispering. On the rare occasion tions available. It directs motor responses that are use- when tumors involve this area, there is o&en a repetitive ful in repeating back vocalizations or mimicking words quality that makes the experience more disagreeable. and phrases, and nonspeech sounds (Wise et al., 2001). Word deafness may result if the pathway from the pri- !e posterior/dorsal auditory stream projects dor- mary auditory cortex to the auditory association cortex soposteriorly to the parietal lobe and then to frontal is interrupted. Occasionally, in patients with complex regions (Hickok and Poeppel, 2004). partial seizures, more meaningful sounds such as foot- steps or music can be experienced. Planum temporale !e planum temporale makes up the superior surface of Auditory association area (BA 42) the superior temporal gyrus from BA 41 to the parietal !e auditory association area (BA 42) extends anter- lobe. !e planum temporale includes portions of BA ior and posterior to BA 41 along the superior temporal 42 and BA 22. !e posterior extent of the planum tem- gyrus (Figure 2.3). Sounds received by BA 41 are next porale is variably de#ned (Zetzsche et al., 2001). !is handled by the auditory association cortex. Sound pro- has led to variability in estimates of the size and degree cessing in the human appears to proceed from BA 41 in of asymmetry of the planum temporale (Westbury et two directions resulting in two auditory streams. !e al., 1999). !e planum temporale is reported to exhibit two auditory streams are believed to be analogous to asymmetry in many individuals with the le& side lar- the “what” and “where” visual streams. !e auditory ger than the right. !e le&ward asymmetry, however, stream proceeding anteriorly from BA 41 is designated does not directly relate to asymmetry of language pro- the anterior/ventral stream and is believed to be more cessing in all individuals (Dorsaint-Pierre et al., 2006). involved in identi#cation of an object or person based More detailed analysis of planum temporale asym- on sounds or speech. For example, voice gender recog- metry has indicated that the anterior planum tempo- nition takes place in an area rostral to the BA 41 on the rale is responsible for the greater part of the asymmetry right (Lattner et al., 2005). !e stream proceeding pos- (Zetzsche et al., 2001). teriorly is designated the posterior/dorsal stream and is !e anterior planum temporale (BA 42) is auditory more involved in speech content and identi#cation of unimodal association cortex. !e posterior planum location of the source of the sound. Signals proceeding temporale (BA 22) is a multimodal auditory associ- posteriorly move from BA 42 to the posterior planum ation area and the heart of Wernicke’s receptive lan- temporale and then laterally onto the exposed surface guage area. !e exact borders of Wernicke’s area are of the superior temporal gyrus. vague although the area is usually described as the pos- Mummery et al. (1999) demonstrated bilateral terior portion of BA 22. Inferior parts of the parietal activation in the superior temporal gyrus anterior to lobe are sometimes included. Reciprocal transcortical Heschl’s gyrus in response to speech and complex non- projections interconnect BA 41 and the anterior pla- speech sounds. At the same time, a similar response num temporale. A second set of #bers interconnects was observed from the posterior superior temporal the anterior with the posterior planum temporale in gyrus/superior temporal sulcus on the le&. In another a stepwise fashion (Galuske et al., 2000; Brugge et al., study, the anterior/ventral stream was activated only by 2003). !ere are strong connections via the corpus intelligible sounds whereas the posterior le& superior callosum with homologous areas in the contralateral temporal gyrus/superior temporal sulcus responded to hemisphere (Hackett et al., 1999). phonic cues whether or not they were intelligible (Scott !e planum temporale is concerned with analysis et al., 2000). Fibers from the anterior superior temporal of complex sounds including sounds that change fre- gyrus/superior temporal sulcus project to anterior and quency over time such as found in language. !e le& lateral prefrontal cortex (BA 9, BA 10, BA 46). !e planum temporale is related to speech perception posterior superior temporal gyrus/superior temporal (Gri%ths and Warren, 2002; Jäncke et al., 2002). !e sulcus has reciprocal connections via the arcuate fas- right planum temporale plays a role in spatial attention ciculus with the dorsolateral prefrontal cortex (Jones (Karnath et al., 2001). !e planum temporale on the le& and Powell, 1970; Gloor, 1997). !e posterior/dorsal responds to moving sounds presented to the right ear. 62 stream provides auditory spatial information to aid in However, the planum temporale on the right responds directing attention. It is speculated that the posterior/ to moving sounds from both sides (Krumbholz et al., Functional anatomy

2005). !e size of the right planum temporale has been sulcus bilaterally (Lewis et al., 2005). !e rhythm of found to correlate inversely with the degree of absolute music is processed on the le& involving temporal lobe pitch discrimination (Keenan et al., 2001). language areas as well as Broca’s speech area of the Auditory processing beyond Heschl’s gyrus exhibits frontal lobe (Limb, 2006). Some other sounds includ- some degree of asymmetry. Tonal pitch perception ing those involved in spatial location are processed and melody are processed in the right superior tem- on the le& (Zatorre et al., 2002). Meaningful sounds poral gyrus (Peretz and Zatorre, 2005; Limb, 2006). (speech, laughter, sounds from animals, tools, running Activation patterns indicate that voice pitch is proc- water, etc.) are le& lateralized (Belin et al., 2000, 2004; essed close to the right Heschl’s gyrus and a “pitch cen- Engelien et al., 2006). Exposure to rapidly changing ter” is proposed lateral to Heschl’s gyrus (Schonwiesner sounds such as those in speech result in activation of and Zatorre, 2008). Voice spectral information is proc- the le& superior and middle temporal gyri (Zaehle et essed in posterior parts of the right superior temporal al., 2008). More complex sounds such as single words, gyrus and areas surrounding the planum temporale tone and patterns result in the spread of activity to bilaterally. BA 22, in addition to contributing to the involve the entire superior surface as well as the lat- planum temporale, forms part of the lateral surface of eral aspect of the superior temporal gyrus. Intelligible the superior temporal gyrus and even curves anteriorly speech (easy sentences) produced signi#cantly more to make up part of the superior temporal gyrus anter- activation than pseudo-word sentences in the anterior ior to Heschl’s gyrus. BA 22 anterior to Heschl’s gyrus le& superior temporal gyrus/superior temporal sulcus is part of the anterior/ventral auditory system. Imaging (Roder et al., 2002). Activation is greater in response studies have shown that speech processing also acti- to stories than to individual sentences (Xu et al., 2005). vates the cortex within the superior temporal sulcus. It is hypothesized that voice-selective regions of the superior temporal sulcus are the counterpart of the Superior temporal gyrus and superior temporal sulcus face-selective regions of the visual cortex (Belin et al., !e superior temporal gyrus includes all of BA 41 and 2000). BA 42 as well as parts of BA 22 posteriorly and BA !e superior temporal gyrus/superior temporal 38 of the temporal pole anteriorly. It extends beyond sulcus is activated during exposure to auditory stimuli the planum temporale to include cortex on the lateral and when imagining tone when no acoustical stimu- aspect. Much of the cortex of the superior temporal lus is present (Halpern et al., 2004). !e response may gyrus lies within the lateral #ssure where it forms the be modi#ed as a function of learning or early envir- "oor. It extends inferiorly on the lateral aspect to the onmental exposure. Signals from other sensory areas superior temporal sulcus. !e superior temporal sul- converge on the posterior superior temporal gyrus cus refers to the cortex that forms the roof, "oor, and and act to modify the interpretation of language. For fundus (depth) of the sulcus. !e cortex of the super- example, the image of a dog opening its mouth antici- ior temporal sulcus also includes cortex of the superior pates the sound of a bark, not a meow (Zatorre, 2007). and middle temporal gyri located on the lateral surface !e McGurk e$ect demonstrates that speech ana- immediately above and below the superior temporal lysis uses input from more than one sensory modality sulcus. (McGurk and MacDonald, 1976). !e McGurk e$ect Speech sounds including cadence and word mean- occurs when a subject hears a syllable (or word) and ing are processed in the le& hemisphere involving the simultaneously sees a print version that di$ers slightly. superior temporal gyrus/superior temporal sulcus !e subject’s interpretation, processed in the superior and planum temporale, even in infants (Dehaene- temporal gyrus/superior temporal sulcus, is modi#ed Lambertz et al., 2002). Simple auditory tasks such as by the visual input. passive listening to tones, white noise, or constant Speech analysis extends beyond the temporal lobe. vowel sounds result in activation of restricted areas of It is proposed that a sequence of areas is activated during the surface of the superior temporal gyrus (Rimol et al., speech analysis. !e #rst area activated is the superior 2005). Activity can spread anteriorly and posteriorly temporal area, followed by the inferior parietal area and from the area of Heschl’s gyrus but the degree of spread #nally inferior frontal areas (Campbell, 2008). Wise et varies from individual to individual. Pure tones and al., (2001) showed that sound processing may be further simple vowel sounds cause activation to spread more specialized. Two regions of the posterior superior tem- than white noise (Binder et al., 2000). Meaningful and poral sulcus process single words. One area in the pos- 63 nonmeaningful sounds activate the superior temporal terior superior temporal sulcus is involved in response Temporal lobe: Neocortical structures

to the sound of single words and retrieval of words from can result in auditory agnosia. !ree forms have been memory, but not our own utterances. !e second is at described: for words (word deafness), music (amusia), the junction of the posterior superior temporal gyrus and environmental sounds (environmental-sound with the posterior inferior temporal cortex. !is second agnosia) (Gri%ths, 2002). !e patient can hear sounds area is activated by the motor act of speech, independ- and can locate them in the environment apparently ent of the speaker’s own utterances. Wise et al. also using lower level structures, but the meaning of the showed that the le& planum temporale was activated sounds is lost. by the speaker’s own voice and complex nonspeech sounds. !e authors proposed that the le& posterior Temporal association areas superior temporal sulcus acts as an interface between !e cortex in the ascending limb of the superior tem- hearing words (perception) and matching them with poral sulcus close to the occipital lobe is recognized words held in long-term memory (Wise et al., 2001). as visual area V5/MT. !is area is associated with the Sign language and communicative gestures also dorsal visual stream and is important in eye movement result in activation of the superior temporal sulcus control. See Chapter 4 for a detailed description. (MacSweeney et al., 2004). Activation is greater for Posterior portions of the middle and inferior tem- sign language than gestures and the degree of activa- poral gyri adjacent to the occipital lobe are heavily tion appears to be proportional to the meaningfulness involved with visual processing. Visual signals that of the information signed (Gallagher and Frith, 2004). enter the posterior temporal lobe are matched with Pauses used in word retrieval and speech planning that embedded constructs for object recognition (e.g., box, relate to speech cadence are associated with activation sphere, face; Figure 5.6). Lesions in this area in rhesus of the le& superior temporal sulcus (BA 22 and BA 39) monkeys render them unable to distinguish one com- (Kircher et al., 2004). plex visual image from another (as a human would dis- !e posterior superior temporal gyrus/superior tinguish one object from another) (Ungerleider and temporal sulcus is involved in more than just auditory Mishkin, 1982). Reciprocal connections with the anter- processing since it becomes activated when individ- ior inferior temporal gyrus and temporal pole provide uals view biological movements including gaze shi&s recognition of the object (e.g., edible, predator). !ese and mouth movements. Auditory language, visualized same posterior gyri also have extensive reciprocal con- gestures and gaze are all used in combination as social nections with the ventromedial temporal cortex. It is communication signals and can a$ect social attention through these connections that emotional values are (Puce et al., 1998; Allison et al., 2000; Ho$man and assigned to visual objects (Figure 5.6). Haxby, 2000; Puce and Perrett, 2003; Redcay, 2008). !e superior temporal sulcus and inferior temporal Biologically important social signals (head, arm, and gyrus function to detect meaningful movement pat- hand gestures) result in stronger activation of the pos- terns. !e areas did not show the same response when terior superior temporal gyrus/superior temporal sul- only portions of the walker were shown in motion cus on the right (Blakemore and Decety, 2001). Body (!ompson et al., 2005). !e le& posterior inferior movements, gestures, and gaze that are clearly goal temporal area (BA 37) functions to process letters and directed have a greater in"uence than those that are words and is an association area that integrates input not goal directed. !e source of the sound can also from several areas (Scott et al., 2006). !is area is acti- modify interpretation. Integration of face and voice, vated in blind as well as in sighted individuals process- helpful in the identi#cation of a person in social situ- ing a variety of word forms (Büchel et al., 1998). Stevens ations, results in activation of the posterior superior and Weaver (2009) found that subjects blind since early temporal sulcus (Campanella and Belin, 2007; Redcay life showed similar areas of activation compared with 2008). Young adults of both genders listening to voices sighted subjects but were more sensitive to low signal exhibit a stronger response in this region to the sound volume. !ere is reduced activation of the same area in of a female voice (Lattner et al., 2005). individuals with dyslexia (Brunswick et al., 1999). A bilateral lesion of the temporal lobe including the auditory radiations can result in central deafness. Fusiform gyrus and fusiform face area Many patients show initial profound hearing loss fol- !e posterior fusiform gyrus (BA 37), described as the lowed by some degree of recovery. A smaller lesion fusiform face area (Figure 5.4), is an extrastriate vis- 64 that includes the superior temporal gyrus bilaterally ual area that becomes activated when viewing faces Functional anatomy

Clinical vignette A 27-year-old man with a ten-year history of partial complex seizures developed progressive interpersonal di!culties and became socially withdrawn. After having a complex partial seizure with secondary generalization, he behaved in a suspicious manner towards his wife, stating that he knew that she was not whom she claimed to be but rather was an impostor who had abducted and replaced his wife. He had many similar subsequent episodes. Electroencephalography showed intermittent, irregular right anterior temporal theta slowing and right anterior and anteromedial temporal spikes and sharp waves. A computed tomo- Figure 5.5. This functional magnetic resonance image shows graphic scan revealed a mild enlargement of the right activation of the “fusiform face area” responsive to human faces. lateral "ssure, suggesting right temporal atrophy. The The right hemisphere appears on the left. The brain images at the patient responded well to carbamazepine therapy left show (in color in the color plate) the voxels that produced a (Drake, 1987). signi"cantly higher magnetic resonance signal intensity during the epochs containing faces than during those containing objects. These signi"cance images are overlaid on a T1-weighted anatomical image of the same slice. In each image, the region of interest #eld (Vuilleumier et al., 2001). !e fusiform face area is shown outlined in green. (Reproduced with permission from also distinguishes between consciously remembered Kanwisher et al., 1997.) See also color plate. and forgotten faces (Lehmann et al., 2004). It responds to objects other than faces and appears to be sensitive to complex attributes common to both faces and familiar objects (Haxby et al., 2001; Hasson et al., 2004). For Somatosensory cortex Auditory cortex Visual cortex example, it is sensitive to image classes with which an individual may have particular experience, e.g., birds to an ornithologist or old cars to an antique automobile enthusiast (Gauthier et al., 2000). Auditory association cortex Visual signals from the fusiform face area are (identification of object) relayed to the amygdala to evaluate emotional content. Activation of the amygdala can potentiate responses of the fusiform gyrus in a top-down fashion. !e amygdala in turn, feeds back to the occipital cortex probably Anterior inferior temporal Ventromedial temporal through the parietal cortex to attend to and amplify sig- gyrus cortex nals from emotionally salient faces (Tabert et al., 2001). (recognition of object) (emotional meaning of object)

Figure 5.6. The predominant !ow of information is from the Clinical vignette auditory association cortex to the anteroinferior temporal gyrus (recognition of object) and to the ventromedial temporal cortex A 58-year-old man had a right hemisphere stroke (emotional meaning of object). that produced a left-sided weakness. The weakness improved progressively over a few days, and the patient was discharged. Over a number of weeks, the (Figure 5.5) (Narumoto et al., 2001), even in 2-month- patient’s wife noticed that he was di#erent but could old infants (Tzourio-Mazoyer et al., 2002; Gathers et al., not tell how. She complained that he was no longer 2004). It is hypothesized to detect motion related to paying attention to her. They started having repeated facial expression (Cipolotti et al., 1999; Blair et al., 2002). "ghts. The marital discord brought them to a family !e fusiform face area is activated whether the face is counselor, who referred them to a neuropsychiatry clearly de#ned or is implied by surrounding, contextual clinic. On examination it was found that the patient had receptive aprosodia with a complete inability to cues (Cox et al., 2004). !e right side is more sensitive to perceive any emotions displayed either by voice or by emotional than to neutral expressions and face recogni- facial expression. 65 tion is better if the image is presented in the le& visual Temporal lobe: Neocortical structures

Temporal pole and theory-of-mind 2004; Levesque et al., 2003; Mobbs et al., 2003). For !e temporal pole corresponds with BA 38 and covers example, in one study, young men exposed to sexually the anterior aspect of the temporal lobe (Figure 5.4). It arousing, erotic #lm excerpts showed activation of the is sometimes included as part of the perirhinal cortex, right anterior temporal pole along with activation of which is usually de#ned as medial temporal lobe (BA the hypothalamus and right amygdala (Beauregard 35 and BA 36). !e temporal pole has strong connec- et al., 2001). tions with the amygdala and orbital prefrontal cortex Frontal temporal dementia results from a degen- and is sometimes recognized as a component of the eration of the frontal and anterior temporal lobes. paralimbic region. It also has connections with the Patients with right, but not le&, temporal pole atrophy basal forebrain and hypothalamus. It receives input exhibit changes in personality and socially appropri- from auditory association cortex, extrastriate visual ate behavior. !e patient with primarily temporal pole cortex of the inferior temporal lobe, insula, and piri- involvement (temporal variant) o&en becomes intro- form olfactory cortex. !e temporal pole is recognized verted, cold, and lacks empathy (Mycack et al., 2001; as association cortex involved with multimodal ana- Rankin et al., 2006). Personal hygiene may decline and lysis, and is believed to be particularly important in indiscriminate eating behavior can result in weight social and emotional processing. It is hypothesized to gain (Gorno-Tempini et al., 2004). act to match sensory stimuli from sensory or multi- !e temporal pole is believed to be a critical compo- modal association areas with emotional sensations nent of the theory-of-mind network. !eory of mind is (Olson et al., 2007). For example, in one study the right the ability to understand and predict the mental state temporal pole, along with the le& frontal lobe, was of another, to infer their emotions, desires, intentions, activated during the correct identi#cation of a familiar and to recognize that the view point of another may voice (Nakamura et al., 2001). be di$erent from our own. It is believed that the areas !e le& temporal pole is associated with seman- in our brain that become active when viewing another tic memory, i.e., memory for meanings, names, and person experiencing and expressing an emotion are general impersonal facts. Damage to the le& tem- the same as those that are activated in that other per- poral pole o&en results in semantic memory impair- son. !e process by which we read the mental state of ments (Snowden et al., 2004). !e right temporal pole another person is called mentalizing. (For more detail is believed to store personal, episodic memories and is on theory-of-mind see Premack and Woodru$, 1978; more closely associated with emotion and socially rele- Frith and Frith, 2003, 2007; Frith, 2007; George and vant memory (Nakamura et al., 2000). Conty, 2008; Hein and Knight, 2008.) !e temporal Patients with damage to the right temporal pole pole acts as a convergence zone where features of situ- may present with apathy, irritability, depression, emo- ations, persons, and objects are brought together. !e tional blunting, and an expression of being ill at ease identity and/or disposition of the situation, person, or with social company (!ompson et al., 2003). !ese object may be determined by the context in which it individuals exhibit a reduced ability to recognize or appears (Ganis and Kutas, 2003). Based on the evalu- recall information about famous or family faces and ation of the situation, speci#c thoughts and/or feelings memories related to these faces (Tsukiura et al., 2003). are appreciated. In studies, the temporal pole was acti- !ere is some evidence to indicate there are special- vated when subjects were asked to think about other’s ized regions within the temporal pole. !e dorsal por- thoughts and emotions, and to make moral decisions tion of the temporal pole receives input from auditory (Moll et al., 2002; Heekeren et al., 2003; Vollm et al., association areas and is believed to link auditory stim- 2006). uli with emotional reactions. Activation of this area was reported in response to emotionally evocative sounds Temporoparietal junction and the social brain including a baby crying (Lorberbaum et al., 2002) and Portions of the temporal lobe, prefrontal cortex, cin- a woman screaming (Royet et al., 2000). gulate cortex, and amygdala make up the social brain !e ventral portion of the temporal pole is acti- (Frith and Frith, 2007). More speci#cally the neuro- vated in response to complex visual stimuli including anatomical components include the orbital prefrontal faces, cartoons, and photographs of houses that evoke cortex, medial prefrontal cortex and adjacent cingulate 66 both positive (humor) and negative (sadness, anger, cortex, temporal pole, anterior insula, posterior super- disgust, and anxiety) emotions (Damasio et al., 2000, ior temporal sulcus, and temporoparietal junction Functional anatomy

Clinical vignette the outcome of a social situation (Decety and Lamm, A 28-year-old right-handed stockbroker with no prior 2007). During social processing it can direct attention psychiatric history had traumatic brain injury to the to speci#c salient sensory signals in order to focus on right temporoparietal and, to a lesser extent, the right critical events and suppress distracting stimuli (Asta#ev frontal lobe. On recovery, he had the delusion that he et al., 2006; Shulman et al., 2007). It provides the ability was dead. None of his surroundings looked familiar. to adopt the perspective of another and to empathize This delusion of unfamiliarity is called Cotard delusion (Ruby and Decety, 2003). It also functions to adopt a (Young et al., 1992). sense of agency, i.e., recognizing that I am the source of my own actions, desires, and thoughts (Farrer et al., (Brothers, 1990; Amodio and Frith, 2006). !e social 2003), and allows us to distinguish self from nonself brain is involved with social cognition (Adolphs, 2009). (Uddin et al., 2006). Multisensory body-related pro- (See also social brain in Chapter 6.) cessing, along with processing vestibular input in the Signals are routed into the social brain by way of temporoparietal junction, supports the sensation of self the intraparietal sulcus, superior temporal sulcus, fusi- and embodiment (Lenggenhager et al., 2006). !e right form face area as well as associative sensory regions of temporoparietal junction is activated when the person the parietal and occipital cortex (Nelson et al., 2005). must distinguish between self and other (i.e., agency) !is network functions to decipher the social proper- indicating the right temporoparietal junction is more ties of incoming sensory stimuli (Blakemore, 2008). involved with higher level social processing than the le& !e temporoparietal junction is a major player in temporoparietal junction (Farrer et al., 2003). the social brain. It consists of the posterior superior !e right temporal/parietal region plays a role in temporal sulcus, parts of the supramarginal gyrus, and comprehending nonliteral language, understanding dorsal anterior parts of the occipital gyri. It represents jokes, and many aspects of general discourse (Bartolo et a posterior multimodal sensory convergence area and al., 2006; Van Lancker Sidtis, 2006; Virtue et al., 2006). integrates information that arrives from the thalamus, Patients with lesions involving the right (nondomi- visual, auditory, and somatosensory areas, as well as nant) temporal/parietal region may lose their capacity limbic system (Figure 5.7). !e temporoparietal junc- to discern the emotional content of speech (receptive tion has reciprocal connections with the prefrontal and aprosodia). !ese patients misperceive paralinguis- temporal cortices. tic social-emotional messages. A&er the onset of the !e temporoparietal junction is involved in mul- lesion they may notice that the voices of friends and tisensory, body-related processing including self- relatives sound di$erent. Patients then may become awareness and theory-of-mind (Saxe and Wexler, 2005; progressively paranoid and delusional. Lawrence et al., 2006). Functions associated with the Damage to the temporoparietal junction has temporoparietal junction include attention to salient, resulted in anosognosia (denial of illness), asomatog- socially important environmental stimuli (Asta#ev nosia (lack of awareness of all or parts of one’s own et al., 2006). !e temporoparietal junction compares body), and somatoparaphrenia (delusional beliefs ongoing events based on previous experience to predict about the body) (Decety and Lamm, 2007).

Auditory association Somatosensory Visual association Figure 5.7. The temporoparietal junc- cortex association cortex cortex tion is a multimodal sensory convergence area that receives input from all sensory association areas and projects to the frontal and parietal association areas as well as to the basal ganglia and ventromedial temporal cortex. Temporoparietal junction Frontal association multimodal sensory Parietal association cortex convergence area cortex

Ventromedial Basal ganglia 67 temporal lobe Temporal lobe: Neocortical structures

Insula et al., 2008). !e same areas of the insula were hyper- activated in subjects with posttraumatic stress disorder !e insular cortex lies deep within the lateral #ssure, (Simmons et al., 2008a). !e insula and amygdala were centrally located between the posterior sensory cortex activated in young anxiety-prone individuals during an and anterior motor cortex (Figure 9.1). It consists of emotion-processing task. !e degree of activation cor- several long gyri located more posteriorly that paral- responded with measures of anxiety sensitivity (Stein lel the lateral #ssure, and #ve short gyri located more et al., 2007). anteriorly. !e anterior and posterior regions are !e anterior insula is considered part of the social divided by the middle cerebral artery, which passes brain (Frith and Frith, 2007). Game theory has revealed across the surface of the insular cortex. !e insular cor- that the anterior insula plays an important role in sus- tex consists of a core area surrounded by several belt taining and/or repairing cooperation during social areas. !e insula receives input from the somatosen- exchange, especially when shared expectations about sory cortex, auditory cortex, and sensory relay nuclei fairness are violated. It is activated when the individual of the thalamus. E$erent projections go to the motor is faced with a choice that has both positive and nega- cortex and temporal lobe including the temporal pole. tive social outcomes. Activation precedes the rejec- !e insula has reciprocal connections with the parietal tion of low-risk gambles (Knutson and Greer, 2008). operculum, basal ganglia, and many limbic structures, Control subjects showed activation levels of the anter- including the cingulate gyrus, and the orbital and med- ior insula proportional to monetary rewards received ial prefrontal cortices. and repaid to their partner. Subjects with borderline Anterior insula personality disorder showed activation only propor- !e anterior insula is particularly involved with moni- tional to the amount of money repaid to their partner, toring signals generated in the viscera (Critchley et not to the amount o$ered to the subject. !e dimin- al., 2004). It is important in the detection and inter- ished response to the amount o$ered re"ects atypical pretation of certain internal bodily states, “interocep- social norms and correlates with low levels of trust tive awareness,” and has been described as an “alarm (King-Casas et al., 2008). center” for internal, visceral sensations (Critchley !e anterior insula has been called cardiac con- et al., 2004). Many of the sensory signals conveyed trol cortex. It provides the basis of conscious aware- by the vagus nerve terminate here. It is thought that ness of visceral activity (e.g., heart beat) and subjective emotional responses to visceral signals are proc- feelings of visceral awareness (Critchley et al., 2004; essed in the anterior insula. Connections between the Kringelbach et al., 2004). It, along with its close ties anterior insula and amygdala are particularly strong with the amygdala, may be responsible for the unex- (Augustine, 1996). plained anxiety that is reported to sometimes accom- !e insula along with the amygdala plays a role in pany coronary thrombosis. anxiety (Etkin and Wager, 2007). Increased activity !e anterior insula is involved with appetite. Taste in the anterior insula (more so on the right) was seen signals from the ipsilateral solitary nucleus that relay in in response to images of emotional faces in a group the ventral posteromedial nucleus of the thalamus ter- of anxiety-prone compared with anxiety-normative minate in the anterior insula. !e anterior insula along undergraduate students. Bilateral increased amygdala with the adjoining frontal operculum is recognized as activity was also reported (Stein et al., 2007). In other the primary taste cortex (Rolls, 2006). !e le& anterior studies, both the anterior insula and amygdala showed insula is activated in response to all odors whereas the increased activation over controls in subjects with right insula is activated speci#cally by disgusting odors posttraumatic stress disorder, social anxiety disorder, (Heining et al., 2003). !e anterior insula is one of sev- and generalized and speci#c phobia (Lorberbaum, eral areas that are activated during sexual arousal in et al., 2004; Etkin and Wager, 2007; Lindauer et al., both men and women (Stoléru et al., 1999; Yang et al., 2007). !e right insula was reported to be more highly 2008). activated in subjects with posttraumatic stress disorder !e insula is involved with pain. Visceral a$erent than controls when viewing images of faces expressing signals conveying pain information including that fear (Felmingham et al., 2008). !e anterior/middle relayed from the vagus nerve terminate in the insula insula is activated in control subjects in anticipation bilaterally (Brooks et al., 2005). Bladder #lling sen- 68 of negative compared with positive stimuli (Schunck sations produce activation in the insula. !e area of Behavioral considerations activation shi&s anteriorly as the sensation becomes et al., 2000). When an individual speaks the brain is stronger and more unpleasant (Gri%ths and Tadic, aware that it is the self that is speaking by way of connec- 2008). Pain sensitivity is reportedly reduced follow- tions between the temporal and frontal lobes (e$erence ing strokes involving the insula (Schön et al., 2008). copy and forward model) (Miall and Wolpert, 1996). A decrease in gray matter of the insula is common to Activity in the auditory cortex is reduced in response to many pain syndromes (May, 2008), and patients with the sound of one’s own voice when one is speaking. !is migraine headaches and chronic head pain showed suppression is not seen in patients with schizophrenia, decreased insula gray matter (Rocca et al., 2006). !e especially those with auditory hallucinations (Ford decrease correlates positively with headache duration et al., 2001). !e connectivity (coherence) between the in years (Schmidt-Wilcke et al., 2007). In contrast, frontal and temporal areas as measured by electroen- an increase in insular gray matter volume has been cephalography is increased in control subjects when reported in patients with panic disorder (Grae$ and they are speaking. !e increase in connectivity is not Del-Ben, 2008). seen in patients with schizophrenia (Ford et al., 2002). !e right anterior insula is involved in sympa- It is hypothesized that a dysfunction in the neuro- thetic arousal to pain. !e insula in cooperation with anatomical basis of the forward model plays a role in the basal ganglia may function to match pain signals hallucinations and delusions in schizophrenia (Frith, with the appropriate autonomic response (Leone et al., 2005). 2006). Two regions are described as key regions of the Abnormalities of temporal cortex are well docu- “shared circuit” for self and other pain (Danziger et al., mented in patients with schizophrenia (Wright et al., 2009). Both the anterior insula and anterior cingulate 2000; Shenton et al., 2001). !e le& lateral #ssure is lar- are activated during the experience of pain in self and ger in this population, evidently the result of reduction perception of pain in others (Singer et al., 2004, 2006). in gray mater volume of the underlying le& superior It is suggested that both areas function to recruit sys- temporal gyrus (Meisenzahl et al., 2008). A reduction tems that determine the emotional and/or a$ective in volume of the superior temporal gyrus in schizo- level of pain experienced by the self or by another per- phrenia has been suspected for some time and has been son (Saarela et al., 2007; Zaki et al., 2007). In contrast con#rmed more recently (Southard, 1910; Barta et al., to negative aspects, the anterior insula is activated dur- 1990; Hirayasu et al., 2000). !e e$ect appears to be ing feelings of maternal attachment and reward (Elliott lateralized to the dominant cortex, especially in males et al., 2003; Bartels and Zeki, 2004). (Reite et al., 1997; O’Donnell et al., 2005). Subregions such as the le& Heschl’s gyrus and le& planum tem- Posterior insula porale show consistent abnormalities in schizophre- !e posterior insula processes information related to nia (Honea et al., 2005). Kasai et al. (2003) found that somatic and auditory sensation and control of som- gray matter volume of the le& planum temporale and atic musculature. !e posterior insula on the le& is Heschl’s gyrus bilaterally was reduced in patients with identi#ed as part of neural circuit that is involved in schizophrenia. a$ective processing, particularly in anxious individ- Relative metabolism in the posterior superior tem- uals (Simmons et al., 2006). Other structures in this poral region is decreased in patients with schizophre- circuit are the bilateral middle temporal and superior nia as they hallucinate (Cleghorn et al., 1992). Blood frontal gyri, and the right inferior frontal gyrus. !e "ow to the le& superior temporal cortex increases in le& posterior insula along with the other structures in patients with schizophrenia as they experience audi- this circuit showed signi#cantly greater activation in tory hallucinations. !e activity decreases as the anxiety-prone over normative subjects when perform- hallucinations resolve (Suzuki et al., 1993). A lower ing an a$ective appraisal task (Simmons et al., 2008b). glucose metabolic rate has been reported in patients with schizophrenia with predominantly negative Behavioral considerations symptoms in the ventral stream including the right inferotemporal area and fusiform gyrus (Potkin et al., Schizophrenia 2002). !is is consistent with di%culties seen in this !e insula is part of the articulatory loop that is import- group in correctly identifying and expressing the emo- ant in processing verbal material (Paulesu et al., 1993). tional content of both faces and scenes (Borod et al., It is activated during inner-speech generation (Shergill 1993; Bryson et al., 1998). 69 Temporal lobe: Neocortical structures

!ere is a strong correlation between the increase of was reduced further in patients experiencing auditory thought disorder and volume reduction in the le& pos- hallucinations. It was hypothesized that reduced fron- terior superior temporal gyrus (McCarley et al., 1993). totemporal connectivity is responsible for the failure of By comparison, there is a close association between normal constraint of inner speech. auditory hallucinations and volume reduction in more Meisenzahl et al. (2008) reported gray matter vol- anterior regions of the superior temporal gyrus espe- ume reductions in the le& superior temporal gyrus cially on the le& (Barta et al., 1990; Shapleske et al., and le& insula in a group of 40 untreated subjects at 2002). !e severity of hallucinations has been reported risk for schizophrenia. Fi&een of the group developed to correlate with volume loss in the le& Heschl’s gyrus a psychotic disorder within two and half years of the as well as the le& supramarginal gyrus (parietal lobe) date of the initiation of the study. Morgan et al. (2007) and the right middle and inferior frontal gyri (Gaser observed gray matter reductions in the le& insula and et al., 2004). !ese #ndings are consistent with the #nd- le& fusiform gyrus in patients with a$ective psychosis ings that there is greater impairment in auditory pro- when compared with controls. !e gray matter volume cessing than in visual processing in schizophrenia and and surface area of the insula were reduced in patients suggest that auditory hallucinations originate from the with schizophrenia. Abnormal activation of the insula le& hemisphere (Hugdahl et al., 2008). can result in auditory or visual hallucinations. It has Abnormalities are also seen in the middle and been suggested that hallucinations in the absence of inferior temporal gyri. Volume reductions of 13% external stimuli common to schizophrenia result from have been reported in both the le& superior and le& activation of the posterior insula (Nagai et al., 2007). A middle temporal gyri, accompanied by a 10% reduc- group of 22 patients with #rst-episode schizophrenia tion in the inferior temporal gyrus and fusiform gyrus showed signi#cant reduction in fusiform gyrus volume bilaterally. !e severity of hallucinations correlated (Lee et al., 2002). Di$erences are less in #rst-episode with the reduced volume of involved le& hemisphere patients, suggesting that tissue loss progresses over structures (Onitsuka et al., 2004). Smaller le& superior time (McIntosh and Lawrie, 2004). temporal gyrus and reduced gray matter volume of the A key feature of schizotypal personality disorder is middle temporal gyrus bilaterally have been reported language abnormalities. Greater activation is reported in patients with #rst-episode schizophrenia but not in in the superior temporal gyrus bilaterally in tasks patients with a$ective psychosis. In the same study, involving pure tones di$ering in pitch and duration. smaller posterior inferior temporal gyri were common Heschl’s gyrus volume did not di$er from controls to both groups. !ese results indicate that smaller vol- (Kiang and Kutas, 2006; Dickey et al., 2008). umes in the superior and middle temporal gyri may be speci#c to schizophrenia and related to auditory hal- Depression lucinations (Kuroki et al., 2006; Aguilar et al., 2008; !e insula is one of the most consistently identi#ed Galderisi et al., 2008). regions in a network that is associated with depres- !e planum temporale is also reduced in volume sion. Depression symptoms have been reported to in schizophrenia (Kwon et al., 1999). Schizophrenia correlate with increased metabolism in the right is associated with a decrease in the normal le&–right insula (Harrison et al., 2003). In contrast, activation asymmetry of the planum temporale (McCarley et al., is decreased in the insula of patients with depression 1993). Some patients exhibit a reversal of normal le&– (Fitzgerald et al., 2009). Other areas showing decreased right asymmetry (Petty et al., 1995; Kwon et al., 1999). activation include the le& middle frontal, anterior cin- In addition, gray matter reductions in the temporal gulate, inferior frontal, and right cingulate cortices (Li pole, middle and lateral superior temporal gyri (BA et al., 2005). 21, 22), and in the temporal-occipital junction (BA 37) Vagus nerve stimulation in patients has been have been reported in patients with particularly poor e$ective when used in patients with drug-resistant outcome schizophrenia (Metelman and Buchsbaum, depression. Vagus nerve stimulation was monitored 2007). Using functional MRI (fMRI), Lawrie et al. in a population of patients with depression. Decreased (2002) showed reduced coupling between the le& dorso- activation of ventral medial prefrontal cortex and other lateral prefrontal cortex and the le& superior temporal limbic areas has been reported, coupled with increased gyrus (frontotemporal connectivity) in patients with activity in the right insula (Kraus et al., 2007; Nahas 70 schizophrenia compared with controls. !e coupling et al., 2007). Behavioral considerations

Recalled sadness in normal individuals produces of unfamiliarity that results in the belief that the loved activation of the anterior insula (Lane et al., 1997). one is an impostor (Malloy et al., 1992). Cotard delu- Studies suggest that the anterior insular cortex partici- sion is an extreme example of depersonalization in a pates in the emotional response to particularly distress- misidenti#cation syndrome (Sno, 1994; see clinical ing cognitive or interoceptive sensory stimuli (Reiman vignette, page 67). et al., 1997). Activation of the insular cortex during emotional situations may re"ect its role in cardiac con- Seizures trol by altering heart rate (Oppenheimer, 1993). Temporal lobe seizures involving the posterolateral Disgust is believed to play a role in obsessive- cortex are characterized by aphasia if the seizure is compulsive disorder (Berle and Phillips, 2006). localized to the dominant lobe, as well as auditory, vis- Shapira et al. (2003) found that patients with obsessive- ual, and vestibular disturbances. In contrast, mesial compulsive disorder compared with controls showed temporal seizures are characterized by the presence signi#cantly greater activation in the right insula in of an aura, followed by staring and behavioral arrest. response to disgust-inducing photos. Oroalimentary automatism is common (Fried, 1997). !e observation that patients in complex partial One patient, while being stimulated in the le& infer- seizure status (continuous complex partial seizures) otemporal cortex, reported familiar music and vivid can be awake and even responsive can be explained visual images of personal importance, but was aware (at least partially) by the existence of anatomical con- that they were unreal (Fried, 1997). Epileptic discharges nections between the two temporal lobes that do not in the middle and inferior temporal gyri can result in involve most of the other brain regions (noncallosal complex hallucinations or confusional episodes, or connections). If a seizure is generalized through the may cause an abnormal attribution of emotional sig- corpus callosum, it is very likely that consciousness ni#cance to otherwise neutral thoughts and external will be totally lost (e.g., generalized seizures). One stimuli. Hallucinations become increasingly complex patient, while undergoing electrical stimulation of the as the disturbance expands from primary to more com- le& superior temporal gyrus as she counted out loud, plex association areas. A variety of emotional reactions reported that she heard her speech as an “echo” and at can occur during the course of a temporal lobe seizure. the same time felt “frightened” (Fried, 1997). Fear is the most frequently reported emotion during a seizure. Other reported emotions include anxiety, Reduplicative paramnesia pleasure, displeasure, depersonalization, depression, Reduplicative paramnesia is a delusional belief that a familiarity, and unfamiliarity. place has been duplicated. It is postulated that a combination of right posterior parietal lesion and frontal Receptive aphasia pathology leads to the development of this syndrome. Lesions of the posterior parts of the le& temporal lobe !e posterior right hemisphere lesion causes visuoper- with extension into the ventral parietal lobe can cause a ceptual dysfunction involving identi#cation of person receptive aphasia (Wernicke’s aphasia) in which a severe or place, and the frontal pathology makes it impos- comprehension de#cit to spoken language develops. sible to resolve the con"icting information, resulting Extension of the lesion up into the parietal lobe can in delusional ideas. !e related syndromes described produce a similar de#cit in the appreciation of written below may involve the temporal lobe more directly. language. Expressive speech may become hyper"uent, As many as 40% of patients with schizophrenia with the patient using nonsense words. Such patients exhibit symptoms of delusional misidenti#cation can be mistaken for being acutely psychotic, particu- syndrome (Cutting, 1994). !ese syndromes include larly if they have a past psychiatric history. !e arcuate Capgras delusion. !e patient with Capgras syn- fasciculus connects Wernicke’s area with Broca’s area in drome believes that well-known persons, including the frontal lobe. Lesions limited to the arcuate fascic- family members, are impostors or may be identical ulus cause a form of aphasia characterized by di%culty doubles, or both. Two lesions may be needed to prod- with repetition (conduction aphasia). uce this syndrome. Right temporal lobe lesions may cause distortion in the sense of familiarity of a per- Autoscopic phenomena son. Frontal damage (usually bilateral) results in the Vestibular signals reach the thalamus bilaterally and inability to resolve the con"ict and hence the feeling relay in the ventral posterolateral nucleus before 71 Temporal lobe: Neocortical structures

terminating in the posterior insular cortex. !e poster- room-tilt illusion in which there is a feeling of misalign- ior insular cortex adjacent to the parietal lobe is a ves- ment with gravity. !e inversion illusion is a feeling of tibular sensory area and may be involved in autoscopic being upside-down and is commonly experienced in phenomena (Duque-Parra, 2004). outer space (Lackner, 1992; Kornilova, 1997). Autoscopic phenomena are illusions involving the Vestibular sensations are o&en reported during entire body in terms of embodiment and body owner- autoscopic experiences. Several regions of the cortex ship. Four autoscopic phenomena are: autoscopic hal- receive vestibular information. !e vestibular area lucination, heautoscopy, out-of-body experience, and is de#ned as the temporoparietal junction and pos- feeling-of-a-presence. A #&h related phenomenon is terior insula, and has been referred to as the parie- the room-tilt illusion. !ey have been reported follow- to-insular vestibular cortex (Grüsser et al., 1994). ing damage to the temporoparietal, frontoparietal, or Projections from the parieto-insular vestibular cor- parieto-occipital cortex. More recently focus has been tex to the frontal eye #elds and the premotor and pri- on the temporoparietal junction (Blanke and Arzy, mary motor areas are believed to be in support of eye 2005). During an out-of-body experience the patient movement control. !e vestibular cortex appears to is o&en supine. !ey localize themselves outside the be more strongly represented on the right, and the body and see their body from the disembodied loca- integration of proprioceptive and vestibular signals tion. Lesions related to out-of-body experience involve seems to focus on the right temporoparietal junction the right temporoparietal junction (Blanke et al., 2004; (Bottini et al., 2001). De Ridder et al., 2007). A patient experiencing heautoscopy reports see- Autism ing a second own (illusory) body in their extraper- !e temporal lobe appears to be involved in autism. sonal space and localizes himself in the second body. Tasks requiring emotional processing in a social set- Heautoscopy may follow damage to the le& temporopa- ting have been shown to be associated with decreased rietal junction. Autoscopy is similar to heautoscopy in activation of the insula in autism (Di Martino et al., that there is a second, illusory body. However, in autos- 2009). Individuals with autism exhibit abnormal fold- copy the patient does not localize themselves in the ing of the cortex of the insula (Nordahl et al., 2007). second body. Autoscopy is associated with a lesion of !e fusiform face area has been reported to show the right parieto-occipital junction (Blanke and Mohr, signi#cantly little or no activity when viewing facial 2005; Blanke and Castillo, 2007; Lopez et al., 2008). images. Activation and volume of the amygdala was !e lesion associated with feeling-of-a-presence is also signi#cantly reduced when compared with con- lateralized to the right and usually involves the fron- trol subjects (Schultz et al., 2000; Pierce et al., 2001). toparietal cortex. It o&en accompanies hemineglect. In contrast, the le& dorsolateral superior temporal area !e patient feels (senses but does not see) the presence that includes Wernicke’s receptive speech area has been of another body in the extrapersonal space. !e body found to show increased activity in high-functioning may be attributed to a person familiar to the patient children with autism and/or Asperger syndrome during (Brugger et al., 1996). sentence comprehension tasks coupled with decreased !e room-tilt illusion is a sudden upside-down activity in the le& inferior frontal area (Broca’s area) reversal that lasts from seconds to hours. !e patient (Just et al., 2004). In addition, heightened activity has does not mislocalize their own body (Brandt and been reported in the superior temporal gyrus, peristri- Dieterich, 1999). !e room-tilt illusion may be due to ate cortex and inferior temporal gyrus when viewing a lesion of the brainstem and/or vestibulocerebellar images of faces (Critchley et al., 2000; Schultz et al., system but also may be due to lesions of the parieto- 1997). !ese latter areas are usually activated when occipital and frontal cortices (Solms et al., 1988). !e confronted with face versus nonface images. !e com- room-tilt illusion o&en has in common with autoscopic bination of reduced activity in higher order face pro- phenomena feelings of elevation and "oating, along cessing areas with increased activity in lower order face with a disturbance of personal and extrapersonal space processing areas have led to the suggestion that indi- (Blanke et al., 2004). It is suggested that the room-tilt viduals with autism rely on low-level processing. As a illusion is the result of a transient mismatch between result they rely on details for facial recognition and fail visual and vestibular information at the cortical level to completely integrate information regarding the per- 72 (Brandt, 1997). !e inversion illusion is similar to the son (Belmonte et al., 2004). !is reduces their ability Behavioral considerations to form a model of the mental state of another person facial expressions produce the same level of activation (theory of mind) (Levy, 2007). (Van den Stock et al., 2008). Body recognition is also a$ected. It is hypothesized that the network used in the Dyslexia initial process of face and body recognition is faulty A number of brain areas are identi#ed as associated (Righart and de Gelder, 2007). with dyslexia including the le& inferior frontal cortex, occipital cortex, thalamus, cerebellum, precuneus, and Stuttering superior temporal gyrus (Maisog et al., 2008). !e area Individuals who stutter are reported to be slower in most frequently reported is the le& middle and infer- phonological encoding, a task associated with the pla- ior temporal gyri (BA 21) and the fusiform gyrus (BA num temporale (Sasiekaran et al., 2006). Increases but 37). !ese areas are described as underactivated and no decreases in gray matter density have been reported show reduced gray matter density (Silani et al., 2005). in individuals who stutter. !e region exhibiting the A more anterior section of the fusiform gyrus of the greatest increase is the right superior temporal gyrus right side (BA 20) is also reported to be underactivated including Heschl’s gyrus (BA 41), the planum tem- with accompanying atrophy (Eden et al., 2004). porale and adjacent lateral BA 22 extending into the It is hypothesized that neurons in the le& fusiform middle temporal gyrus (BA 21) (Jäncke et al., 2004). A gyrus develop the ability to recognize the visual forms small increase has been reported in the same area on of familiar words. Injury or insu%cient/atypical activa- the le& (Beal et al., 2007). tion of this area may result in a speci#c reading de#cit Brown et al. (2005) reported that people who stutter such as dyslexia (Proverbio et al., 2008). It is suggested showed an increase in activity in the cerebellar vermis that during reading, dyslexic readers have a de#ciency and right anterior insula accompanied by a decrease in recruiting le& hemisphere language areas in the in activity in the auditory areas. !ey exhibited over- region of the temporoparietal junction (Maisog et al., activity compared with control subjects in the anter- 2008). ior insula, cerebellum, and midbrain bilaterally and Increased activity compared with controls has been reduced activity in the ventral premotor cortex, inferior reported in dyslexic adults in the primary auditory, frontal gyrus, and Heschl’s gyrus on the le&. Reduced posterior superior temporal and inferior parietal cor- white matter was also seen in the area underlying the tices when comparing pseudo-words and pure tones in premotor and inferior frontal gyrus. It is hypothesized auditory working memory (Conway et al., 2008). !e that stuttering is due to a disruption of the function of le& inferior temporal-occipital area has been reported the involved gray matter areas along with the under- to show increased activity in children with dyslexia fol- lying subcortical neural systems represented by the lowing remedial training (Simos et al., 2002). white matter connections (Watkins et al., 2008). Prosopagnosia Other behavioral considerations Prosopagnosia (face blindness) is a disorder in which Insular tumors have been reported to elicit partial sei- the ability to recognize faces is impaired while the abil- zures that begin with sensations of butter"ies in the ity to recognize other objects remains intact. One form throat or tingling in the arm followed by a warm "ush is congenital although most cases follow damage to the (Roper et al., 1993). Patients who develop panic symp- fusiform face area. Prosopagnosia is usually associated toms with lactate infusion exhibit blood "ow increase with bilateral occipitotemporal damage and the fusi- bilaterally in the temporal lobes, insular cortex, brain- form face area in particular (Moro et al., 2008). In some stem superior colliculus, and putamen (Reiman et al., instances damage to only the right fusiform face area 1989). can produce this de#cit (Yovel et al., 2008). A stroke involving the insula has been reported to Individuals with developmental prosopagnosia lead to the loss of the urge to smoke in patients who have good object recognition but are unable to recog- smoked prior to the stroke. It is proposed that the nize faces including those of family members. It may insula anticipates the pleasure that accompanies use of have a familial basis. Imaging studies indicate the the drug (Naquvi et al., 2007). An infarct involving the fusiform face area is functional in these individuals parietal lobe has a high association with a subsequent (Duchaine and Nakayama, 2006). Neutral faces trig- heart attack. !e authors proposed that the parietal ger lower activation level compared to controls but lobe has a bu$ering e$ect on the insular cortex that is 73 Temporal lobe: Neocortical structures

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Chapter 6 Frontal lobe

Introduction !e truth is likely to have elements of both schemas, with specialization as well as versatility contributing !e elusive functions of the frontal lobe continue to the proper functioning of this most fascinating of to fascinate the neuroscientist and the neuropsych- brain regions. Di$erent competing, and not neces- ologist. !e frontal lobe is impressively developed in sarily mutually exclusive, theories will be introduced humans and makes up more than a third of the entire throughout the chapter. cortical area (Damasio and Anderson, 1993). It controls the actions of our body through its motor areas. !e frontal lobe appears to be responsible for shaping Subdivisions of the frontal lobe our attitudes and organizing our repertoire of behav- !e frontal lobe lies anterior to the central sulcus and iors. Functions that are hallmarks of human behavior, is made up of three anatomically distinct regions: the such as intentionality, self-regulation, and self-aware- dorsolateral aspect, the medial aspect, and the orbital ness, are thought to be under the executive control of (inferior) aspect. !e motor cortex [Brodmann’s areas the frontal lobe. In fact, the prefrontal cortex provides (BA) 4, BA 6, BA 8, BA 44, and BA 45] makes up the the capacity for judgment, which can constantly adapt posterior portion of both the dorsolateral and medial behavior in order to optimize its outcome. aspects. Broca’s area (BA 44 and BA 45) and the frontal An ongoing controversy among researchers is eye #elds (BA 8) are considered by some to be part of whether the prefrontal area contains regions with the motor cortex. !e frontal lobe anterior to the motor discrete functions subservient to an overall executive area, including the orbital cortex, is the prefrontal cor- module that provides an integrated output of the sys- tex (Figures 6.1, 6.2, and 6.3). tem, or that the entire prefrontal region is involved in !e motor cortex is responsible for the origin of the this integrative function. !e latter hypothesis requires majority of the axons that make up the corticobulbar that the neural modules of the prefrontal regions be and corticospinal (pyramidal) tracts. !e corticobul- highly dynamic. Evidence for both theories exists. bar tract projects to the brainstem (the bulb is the lower

Prefrontal sulcus Figure 6.1. Lateral view of the frontal Superior frontal sulcus Primary motor cortex cortex indicating gyri, sulci, and func- Premotor cortex (precentral gyrus) tional areas. The prefrontal cortex is represented in this view by the dorso- 6 lateral prefrontal cortex and the orbital Frontal eye field cortex. The remainder of frontal cortex 8 seen here is motor cortex. F1, superior Dorsolateral F1 4 Central sulcus frontal gyrus; F2, middle frontal gyrus; F3, prefrontal inferior frontal gyrus. Stippling indicates F2 cortex approximate location of frontal lobe mirror neurons. F3

Broca's speech area Lateral fissure

Pars opercularis Pars triangularis Orbital cortex

84 Motor cortex brainstem). !e corticospinal tract projects to the spi- t Dorsolateral prefrontal cortex (DLPFC). nal cord. !e motor cortex consists of the: t Medial prefrontal cortex (MPFC). t Primary motor cortex. t Orbitofrontal cortex (OFC). t Premotor cortex. !e anterior cingulate gyrus is also served by the t Supplementary motor area (SMA). MD thalamic nucleus and is o&en included as part of t Frontal eye #eld. the prefrontal cortex (Figures 6.3 and 12.1). Distinct t Broca’s speech area. clinical syndromes can be identi#ed with lesions of !e prefrontal cortex is served by axons that arise each of the three prefrontal areas, but in practice there from the mediodorsal (MD) thalamic nucleus and con- is o&en overlap in resulting symptomatology. !e sists of the: MPFC and anterior SMC may overlap in function. Olfactory bulb !e gray and white matter of the prefrontal cortex and tract develop at di$erent rates. !e gray matter increases Temporal lobe in volume until somewhere between 4 and 12 years of age a&er which it decreases gradually (Giedd et al., 1999). Synaptic density decreases as gray matter volume increases (Huttenlocher, 1979), and white matter volume continues to increase beyond adolescence Brainstem into early adulthood (Sowell et al., 2001). It is believed that primary motor and sensory areas myelinate before association areas (Fuster, 2002). Motor cortex

Orbital prefrontal Primary motor cortex cortex !e primary motor cortex (BA 4) corresponds with Figure 6.2. Inferior aspect of the frontal cortex. the precentral gyrus on the lateral surface of the cortex and extends medially into the longitudinal cerebral

Paracentral sulcus Figure 6.3. Medial view of the Precentral sulcus frontal cortex. The prefrontal cortex is Primary motor cortex represented in this view by the med- Supplementary eye field Central sulcus ial prefrontal cortex and the orbital Supplementary motor complex prefrontal cortex, including the gyrus Superior frontal sulcus 4 rectus. The premotor cortex and supplementary motor complex represent PSMA SMA 6 the motor cortex on the medial surface. SMA, supplementary motor area; PSMA, pre-supplementary motor area; ul MdPFC, dorsomedial prefrontal cortex; Cing ate gy rus MvPFC, ventromedial prefrontal cortex; MdPFC OFC, orbitofrontal cortex. The arrows

Reflective represent two dimensions of a three- dimensional model of the prefrontal cortex. See text for details (Olsson and MvPFC Ochsner, 2008). OFC Stimulus driven Complex Simple

85 Frontal lobe

#ssure where it makes up the anterior paracentral lobule Premotor cortex (Figures 6.1 and 6.3). About a third of the #bers that make !e premotor cortex (BA 6 on the lateral surface; up the corticospinal (pyramidal) tract arise from nerve Figure 6.1) receives the majority of its input from the cell bodies found in BA 4. !e remainder of the pyram- superior parietal cortex (Wise et al., 1997). !e great- idal tract originates from cell bodies located in other areas est number of axons that leave the premotor cortex ter- of the cortex, including the premotor, supplementary minate in the primary motor cortex. Approximately motor, and somesthetic (parietal) cortex. Axons from BA 30% of the axons in the corticospinal tract arise from 4 also terminate in the cranial nerve motor nuclei of the neurons in the premotor cortex. !e actions of pre- brainstem, the basal ganglia, the reticular formation, and motor corticospinal neurons di$er from primary the red nucleus. Projections from the red nucleus (rubro- motor corticospinal neurons in that premotor neurons spinal tract) along with the corticospinal tract make up control more proximal limb musculature. the major lateral descending motor system. A number of axons descend from the premotor A pattern of the body is represented by neurons dis- cortex through the internal capsule to the reticular for- tributed across the primary motor cortex, producing a mation of the brainstem where they in"uence the retic- motor homunculus. !e extent of each body part over ulospinal tracts. !e reticulospinal tracts are part of the the cortex corresponds with the degree of motor con- major medial descending motor system that functions trol over each of the represented parts. For example, in support of body posture and locomotion through the #ngers, lips, and tongue are represented by large control of axial and proximal limb musculature. regions of cortex, whereas the toes are represented by Premotor areas are activated when new motor pro- a relatively small region. !e primary motor cortex grams are initiated or when learned motor programs located along the midline controls the body below the are modi#ed. Premotor neurons begin to #re in antici- waist. !e primary motor cortex located on the lateral pation of a movement. Just the presence of a learned surface of the brain controls the muscles of the body cue can set o$ a burst of #ring. !e action of these neu- found above the waist. Control exerted by the primary rons may represent a rehearsal or intent of a particular motor cortex by way of the pyramidal tract is greatest motor response. Premotor areas appear to be involved over the musculature of the hand. Note that in contrast in the generation of a motor sequence from memory to the legs, which function in locomotion, the face, that requires precise timing (Halsband et al., 1993) and head, and hands are more commonly used to transmit appear to play an important role in sensory conditioned signals that express emotion. motor learning. Patients with lesions of the premotor A lesion of the primary motor cortex will result in par- area exhibit de#cits in visually guided movements and alysis of contralateral musculature. !e a$ected muscles are unable to match sensory stimuli with previously are "accid at #rst; then, over the course of several days, learned movements (Halsband and Freund, 1990). re"exes become brisk and the muscles exhibit spasticity. Passive viewing of faces has been reported to lead Gross movement control reappears a&er several weeks to activation of the right ventral premotor area, and or months, but #ne movements, especially those of the imitative viewing to bilateral activation. !is suggests hand, are usually lost permanently (Brodal, 1981). that the right hemisphere may play a key role in the production of empathetic facial movements (Dimberg Clinical vignette and Petterson, 2000; Leslie et al., 2004). Individuals A 65-year-old man, experienced a right hemisphere who score high on empathy tests also demonstrate the stroke that resulted in left arm paralysis. After dis- chameleon e$ect (Sonnby-Borgström, 2002), that is, charge from the hospital he noted that his wife as well they unconsciously tend to mimic the facial expres- as other people around him were not as responsive to sions of the individual with whom they are speaking him as they were before the stroke. He found that just and even experience the mood of their interactive part- being angry or trying to look or sound angry had no ner (Levenson et al., 1990). e#ect on people. He had to explode in a rage to get his Clinical studies suggest that the descending in"u- point across. His wife demanded that he see a psych- ence of the premotor cortex is over axial and proximal iatrist. On examination the patient was found to have limb musculature. Unilateral lesions of the premotor severe expressive aprosodia. He was totally unable to cortex result in moderate weakness of contralat- express anger, happiness, sadness, surprise, or even 86 inquisitiveness. eral shoulder and pelvic muscles. Forearm strength remains una$ected, but grasping movements are Motor cortex impaired when they are dependent on the supporting Figure 6.4. Horizontal mag- action of the shoulder. Movements are slow and there is netic resonance a disturbance of their kinetic structure. Normal prox- image [!uid imal-distal sequencing of muscle action is disturbed. attenuated inversion recovery Windmilling movements of the arms below shoulder (FLAIR) sequence] level are normal in the forward direction but abnormal showed an infarct when attempted in the backward direction. Bicycling in the region of the right supplemen- movements of the legs are una$ected (Freund and tary motor area. Hummelsheim, 1984). (Reprinted with permission from Mendez and Clark, Clinical vignette 2004.) A 55-year-old right-handed man had an acute onset of hesitant, e#ortful speech. Examination showed predominant di!culty with articulatory $uency. His forward $ow of speech was disrupted by speech sound repetitions and by lengthy pauses while preparing for the next utterance. He also had frequent vowel cup (Turella et al., 2009). A broader de#nition is a neu- distortions and substitutions, $uctuating resonance, ron that #res for “logically related actions” (Iacoboni and a halting and harsh vocal quality. In contrast, his and Mazziotta, 2007). language abilities were preserved, including reading and writing.This patient had di!culty due to a right Since their discovery, mirror neurons also have supplementary area lesion. Neuroimaging revealed been found in the anterior inferior parietal lobule in a right hemisphere stroke of probable embolic origin monkeys (Rizzolatti et al., 2001; Fogassi et al., 2005). involving the pericallosal branch of the right anterior A similar system is believed to exist in the human. cerebral artery (Figure 6.4). His de"cit illustrates the Imaging studies have show activation in the inferior disruption of complex motor routines for speech from parietal lobule of the human as well as the ventral pre- a supplementary area lesion. motor area and posterior inferior frontal gyrus under test conditions designed to activate mirror neurons (Figures 4.2 and 6.1) (Rizzolatti and Craighero, 2004). Mirror neurons !e mirror neuron system is believed to be a mech- Mirror neurons were #rst observed in the premotor cor- anism used by the brain to appreciate the actions of tex of monkeys. !e investigators were monitoring indi- others. Activation of the mirror neurons provides a vidual premotor neurons and found that if the monkey blueprint that can be used to imitate another’s action observed a particular grasping movement made by the (Iacoboni et al., 1999; Buccino et al., 2004). It is specu- investigator that neurons in the premotor cortex would lated that this system is useful in the motor sphere to #re even though the monkey made no movement. !e learn new motor skills including language. Since only same premotor neurons discharged if the monkey goal-directed movements are mirrored, this system is made a similar grasping movement. !e investigator’s believed to support the understanding of the intent of movement that produced the e$ect was particular in another’s movement. !is is interpreted to mean that that it was a goal-directed movement. Random arm/ the system is a foundation for the concept of empathy, hand movements had no a$ect (Di Pellegrino et al., sympathy, and other aspects of emotional feeling. !ese 1992; Gallese et al., 1996; Rizzolatti et al., 1996a). !e emotions are important for developing appropriate human homologs of the monkey’s mirror neuron areas social skills (Fabbri-Destro and Rizzolatti, 2008). are believed to be located in the pars opercularis of the inferior frontal gyrus (Petrides et al., 2005). However, Supplementary motor area and several studies have not shown convincing mirror neu- supplementary motor complex ron activity in this region (Makuuchi, 2005; Williams !e supplementary motor complex (SMC) is found et al., 2006; Jonas et al., 2007). !e strict de#nition of on the medial side of the frontal lobe along the lon- “mirror neuron” requires that the neuron #res when gitudinal cerebral #ssure (Figure 6.3). It corresponds the subject is observing an action and the same neuron approximately with BA 6 on the medial surface, 87 #res when executing a similar action, e.g., grasping a although the exact boundaries are debated (Wise et al., Frontal lobe

Clinical vignette with anticipation, errors and con"icts (Schall and The relationship between actual frontal lobe ictal Boucher, 2007). All parts of the SMC have connections activity and the exhibited psychopathology is com- with the basal ganglia. A group of special #bers from plex, as exempli"ed by the following case reported by both the pre-SMA and SMA project directly to the sub- Boone and associates in 1988. A 13-year-old girl was thalamic nucleus of the basal ganglia. !ese are called admitted to a psychiatric hospital for deteriorating “hyperdirect” #bers. Activation of these #bers would behavior. Before hospitalization she was becoming rapidly “brake” any ongoing activity in the cortical- increasingly inattentive and was sexually active with basal ganglia circuit (Frank et al., 2007). a number of partners. She was becoming progres- !e SMC becomes activated before the primary sively more volatile and unpredictable with verbal and motor area (i.e., when the subject imagines perform- physical aggressiveness. She also exhibited pressured ing an activity or intends to perform an activity) and speech with periodic incoherent and bizarre output. She had one episode in which she cut the super"- is activated during complex motor subroutines. It is cial skin over her wrists with a razor. Concurrent with suggested that the SMC assembles a sequence of motor the deteriorating behavior, spells developed during actions into a motor plan and is involved in the inten- which she turned brie$y to the right, stared and picked tional preparation of movement (Gra&on et al., 1992a). at her clothes. The episode was usually followed by !e SMC and anterior cingulate cortex became active urinary incontinence. Computed tomography and in preparation for both internally generated and envir- magnetic resonance imaging "ndings were normal. onmentally cued movements, indicating involvement Electroencephalography demonstrated ictal activity with motor planning (Sahyoun et al., 2003). Activation of 2.5 Hz spike and slow wave complexes that origi- of the pre-SMA has been reported to be more extensive nated primarily in the left frontal lobe but also occa- for self-initiated movements as opposed to visually sionally in the right frontal regions. triggered movements (Deiber et al., 1999). !is has led to the suggestion that the pre-SMA is specialized for 1996). Two major subdivisions are recognized; the pre- internally guided rather than externally cued actions supplementary motor area (pre-SMA) and the SMA (!aler et al., 1995). However, evidence indicates that proper (Picard and Strick, 1996; Nachev et al., 2008). the primary responsibility of the SMC is to use a time- A third subdivision, the supplementary eye #eld (SEF) linked blueprint to sequence potential action pat- lies at the junction of the pre-SMA and SMA close to terns (Tanji et al., 1985). !e more anterior pre-SMA the precentral sulcus (Figure 6.3). !e SEF is consid- appears to function as a clearinghouse for cognitive ered an ocular motor extension of the SMA. and motivational information arriving from the pre- !e SMC receives a$erents from the primary som- frontal and cingulate areas before distribution to the esthetic area of the parietal lobe as well as from the more posterior SMA proper (Rizzolatti et al., 1996b). superior parietal lobule, the prefrontal cortex, and Activity in the pre-SMA is enhanced when an individ- the cingulate gyrus. A$erent #bers from the thalamus ual attends to the task to be performed (“attention to arise from both the ventral anterior and ventral lateral intention”) (Lau et al., 2004). Deiber et al. (1999, 2005) nuclei, making the SMC a recipient of feedback from reported that the SMA proper was activated when both the basal ganglia and the cerebellum. sequential rather than repetitive (#xed) movements E$erent #bers from the SMC include reciprocal, were elicited. transcortical #bers to the premotor and primary motor !e SMC assembles a new sequence of actions and areas. !e SMA also provides projection #bers to the becomes activated when a familiar motor sequence red nucleus and spinal cord. !e SMA, but not the pre- must be altered (Nakamura et al., 1999; Parton et al., SMA, makes a signi#cant (~10%) contribution to the 2007). !e pre-SMA is activated when perform- corticospinal tract. Many of the SMA axons, such as ing unfamiliar motor tasks, e.g., a pianist playing an those from the primary motor area, make direct con- unfamiliar piece of music (Parsons et al., 2005). In nections with motor neurons (Dum and Strick, 1996). learning a new motor sequence, familiar sequences In contrast, output of the pre-SMA and SEF is to the must be inhibited. Inhibition is also a product of the DLPFC. !ese two areas are believed to be involved SMC. !e SMA may be involved in procedural mem- in executive control in situations of response con"ict ory –the process responsible for acquisition and recall (Nachev, 2006). Neurons in the SEF do not directly of motor programs (e.g., how a novice learns to grip 88 control saccades. !ey become activated when dealing and swing a golf club). Blood "ow studies suggest that Motor cortex the SMA acts as an executor during the acquisition !ere are basically two important cortex-generated and articulation of new motor skills (Gra&on et al., eye movements. !e saccade is a fast eye movement 1992b). It may be involved in more fundamental proc- that functions to reset eye position onto a new target. esses such as preattentive inhibition of incoming irrele- Visual signals from the retina to the cortex are inhib- vant or redundant sensory input (i.e., sensory gating) ited during a saccade.!e second eye movement is pur- (Grunwald et al., 2003). suit. Pursuit eye movements occur once the target of Clinical de#cits resulting from surgery (tumor interest is positioned on the fovea. Pursuit allows the resection) or anterior cerebral artery infarction prod- eye to track a moving object. uce a lesion of the SMC. Either or both anterior cerebral Saccadic eye movements are the only voluntary arteries may be involved. !e surrounding structures conjugate eye movements (Buttner-Ennever, 1988). that are a$ected may include the dorsomedial pre- !e posterior parietal cortex plots the position and frontal area, the anterior corpus callosum, and the cin- movement (“where”) of all visual targets simultan- gulate gyrus (Chapter 12). Such a lesion of the SMC can eously and provides this information to the brainstem result in motor neglect (Laplane et al., 1977; Krainik (superior colliculus). !e parietal and temporal cor- et al., 2001). Motor neglect is characterized by under- tex also provide the frontal eye #eld with information utilization of the contralesional side, without defects of about the identity (“what”) of each of the targets. !e strength, re"exes, or sensibility. More severely a$ected frontal cortex acts as the executive and selects one tar- patients may present with akinetic mutism. In this case, get out of all the available visual targets. It then gener- the patient may be mute or exhibit markedly reduced ates and triggers a saccade to move the eyes onto the speech. Akinetic mutism is accompanied by akinesis or selected target. An intimate relationship exists between weakness, especially on the right side. Comprehension the function of the DLPFC and the frontal eye #eld in remains normal and speech may return, however, spon- the voluntary control of eye movement, which is one of taneous and propositional speech is reduced. Initial the highest orders of cognitive processing in primates e$ects are profound, but rapid recovery ensues over including humans (Goldberg and Bruce, 1986). several months, with speech defects recovering more !e supplementary eye #eld, DLPFC, and anter- slowly. Recovery may appear complete in several years. ior cingulate gyrus also play a role in eye movements. Even a&er this time, however, mistakes may be observed !eir individual contributions are unclear but it is in repeated complex movements of the hand (alternat- thought they play a central role in planning eye move- ing supination and pronation), with the hand hesitating ments in response to target location information to reverse movement (Bleasel et al., 1996; Nagaratnam received from the parietal lobe (Johnson and Everling, et al., 2004). !e alien hand sign has been reported in 2008; Medendorp et al., 2008). !e anterior cingulate some cases (Chapter 14; Feinberg et al., 1992). gyrus becomes activated when task demands increase (Johnson and Everling, 2007). It is suggested that the Frontal eye "eld DLPFC functions to add excitatory drive to either #x- !e traditional frontal eye #eld is found on the dorso- ation or inhibitory neurons in the superior collicu- lateral frontal cortex and corresponds with BA 8 lus, which acts to suppress saccade-related neurons (Figures 2.3 and 6.1). !e portion of the frontal eye (Kaneda et al., 2008). Eye tracking dysfunction (ETD) #eld actually involved with generating eye move- appears to be a genetically determined trait marker ments appears to be localized deep within the junc- of schizophrenia. One hypothesis suggests that ETD tion of the precentral sulcus and the superior frontal re"ects dysfunction of the DLPFC (Gooding and sulcus (Rosano et al., 2003). !e frontal eye #eld con- Talent, 2001). tributes to voluntary eye movements but is not necessary for initiation of all types of eye movements. !e Saccade eye movements frontal eye #eld projects to the superior colliculus, to Saccades are fast eye movements used to reset the eyes the caudate nucleus, and to the paramedian pontine onto a new target. Generation of a saccade relies on reticular formation (PPRF), which is the pontine cen- basic, largely brainstem circuitry coupled with over- ter for lateral gaze and to the midbrain (rostral inter- sight from the parietal and frontal lobes. Two major stitial nucleus of the medial longitudinal fasciculus classes of saccades are those that are triggered auto- (riMLF), which is the midbrain center for vertical matically by the sudden appearance of an external gaze). visual target and those that are triggered internally. 89 Frontal lobe

Internally triggered saccades may be produced on studies involving adult patients with attention-de#cit command (i.e., voluntarily) to a remembered location hyperactivity disorder, bipolar disorder, obsessive- even in the dark. Saccades can be measured in terms of compulsive disorder (OCD), and major depression latency, velocity, and accuracy. Two saccade tasks can have been equivocal. In general, results of visually reveal information about basic saccade circuitry and guided prosaccade tasks have been unremarkable. An oversight control. In both tasks the subject #xates on increase in errors is more o&en reported in the antisac- a central target. A prosaccade is generated to a periph- cade task (Maru$ et al., 1999; Gooding et al., 2004; Carr eral target when the central target is extinguished and et al., 2006; Winograd-Gurvich et al., 2006). peripheral target appears. A prosaccade is a test of the !ese # ndings suggest that in all groups tested basic saccade circuitry. An example of a more complex the basic saccade generating circuitry is intact. !e saccade paradigm is the antisaccade. An antisaccade antisaccade task places demands on higher order eye tests for function of the oversight controls, especially movement control systems. It is hypothesized that that of the frontal lobe. To prepare for an antisaccade antisaccade task errors represent dysfunction in the the subject is instructed to note the location of the per- DLPFC (McDowell and Clementz, 2001; Gooding and ipheral target when it appears but to inhibit a saccade Basso, 2008). Greater error rates have been reported in to its location. !e subject is instructed to not look at subjects with reduced gray matter volume in the right the target when it appears, but to generate a saccade to medial superior frontal cortex, including the frontal a location equidistant and in the direction opposite to eye #eld and supplementary eye #eld (Bagary et al., the peripheral target. 2004; Tsunoda et al., 2005). It is further suggested that It has been recognized for some time that patients antisaccade errors in schizophrenia represent impair- with schizophrenia have abnormalities in eye movements in working memory, including elements of ment control (Diefendorf and Dodge, 1908). Saccadic inhibition (Hutton et al., 2004). eye movements have been the focus of study and some abnormalities have been documented. Broca’s speech area Testing of schizophrenia patients using basic tests Broca’s speech area occupies BA 44 and BA 45 on the such as the visually guided prosaccade tasks that meas- inferior frontal gyrus and consists of the pars opercula- ure saccade latency, average and peak velocity, gain, ris and pars triangularis (Figures 2.3 and 6.1). It is con- and #nal eye position in most cases has revealed these sidered to be part of the prefrontal cortex and consists to be within normal limits (Krebs et al., 2001; !ampi of both heteromodal prefrontal cortex and premotor et al., 2003). However, more sophisticated tests such cortex. !is region is specialized on the dominant side as the antisaccade task have revealed an error rate of of the cortex for the production of speech.!e major 20%–75% among schizophrenia patients (Gooding and input to this region is from Wernicke’s area by way of Basso, 2008). Test results indicate patients understand the arcuate fasciculus. Wernicke’s area corresponds instructions and are motivated (Gooding and Talent, with the posterior region of the superior temporal gyrus 2001; Polli et al., 2008). Schizophrenia patients make a (BA 22). Fibers that originate from cells in Broca’s area large number of glances to the peripheral target instead project to the facial region of the primary motor cor- of generating a saccade in the direction opposite (Harris tex which directly controls the muscles of speech. !e et al., 2006). !ey consistently produce fewer correct area comparable to Broca’s on the nondominant cortex responses and make signi#cantly more directional is responsible for the emotional/melodic component of errors when generating a saccade away from the target speech (Joseph, 1988). (Reuter et al., 2005; Radant et al., 2007). It is interesting Broca’s speech area is activated during the produc- to note that some components of antisaccade perform- tion of both overt and covert speech as well as when an ance are reported to improve in patients taking risperi- individual imitates another person’s speech (Figure 6.5; done and nicotine (Burke and Reveley, 2002; Hutton, Smith et al., 1992; Sukhwinder et al., 2000). Evidence 2002; Larrison-Faucher et al., 2004). Antisaccade task indicates that this region is active during inner speech errors also are reported in individuals with schizotypal in normal subjects and may be critical in verbal hal- traits and/or symptoms (Ettinger et al., 2005; Gooding lucinations experienced by patients with schizophre- et al., 2005; Holahan and O’Driscoll, 2005). nia (McGuire et al., 1993, 1996). Impairment in verbal Fewer saccade studies have been reported on "uency (“Say as many words beginning with ‘s’ in the 90 other psychiatric patient populations. Results of next 30 seconds”) is seen in patients with lesions in Prefrontal cortex

Broca’s area as well as in other regions of the DLPFC. Clinical vignette Broca’s area is involved in word retrieval as well as in A 67-year-old right-handed man with frontotempo- verbal "uency (Caplan et al., 2000). Verbal "uency ral dementia (FTD) was hospitalized with a gradual activates le& BA 44 and BA 45, whereas semantic pro- personality change. He sold his successful business, cessing preferentially activates only BA 45 (Amuts stopped paying the bills, and ran up large debts on et al., 2004). merchandise from a television home shopping net- A lesion of Broca’s area on the dominant side results work. He became impulsive and disinhibited, fondled in an inability to produce speech (motor or expres- his wife in public, sexually propositioned his daugh- sive aphasia). !e patient retains the ability to under- ters, and uttered uncharacteristic racial slurs at social stand the written and spoken word. With recovery, gatherings. At the same time, he became distractible the patient learns to speak with di%culty producing and hyperactive, with compulsive behaviors such as repeatedly pulling the hair of his arms (trichotilloma- only key nouns and verbs and leaving out modifying nia) and exhibited hyperoral behavior such as overeat- adjectives and adverbs.!e same cortex on the non- ing. The patient met the criteria for FTD, probably of dominant side is believed to be responsible for the a familial nature. His family history was positive for a musical intonation of speech (prosody). A lesion on similar dementing illness in his father and in a pater- the nondominant side results in expressive aprosodia nal grandparent. Single photon emission tomography in which the patient is unable to e$ectively modulate scans showed extensive hypoperfusion in both frontal speech (i.e., speech becomes monotone without facial lobes, more extensive in the right hemisphere (Figure expressions). 6.6). His initial personality changes including poor Depression o&en accompanies Broca’s and other judgment, disinhibition, and inappropriate behaviors, non"uent aphasia. Some of the depression is a result were consistent with involvement of the orbital pre- of le& hemisphere damage, not just a reaction to the frontal cortex. psychosocial loss (Benson and Ardila, 1993). Severe depression correlates with deep le& frontal lesions, especially if the lesion includes the anterior limb of Prefrontal cortex the internal capsule (Starkstein et al., 1987). Blood !e prefrontal cortex is loosely de#ned as the cortex "ow to Broca’s area is decreased in patients with post- that receives of #bers from the MD nucleus of the thal- traumatic stress disorder (PTSD) when provoked amus. It is divided into a dorsolateral region (Figure (Figure 11.8; Rauch et al., 1996). A signi#cant volume 6.1), an orbital (inferior) region (Figure 6.2), and a med- reduction was reported in only BA 44 and 45 on both ial region (Figure 6.3). All three regions receive #bers the le& and right side in patients with schizophre- from the MD thalamic nucleus, which relays informa- nia when the entire prefrontal cortex was compared tion from the temporal cortex, the pyriform cortex, and 91 (Buchanan et al., 1998). the amygdala. It also has direct, reciprocal connections Frontal lobe

Figure 6.6. The patient’s 18-!urodeoxyglucose positron emission tomography scan showed prominent hypometabolism of the frontal lobes. Note the near absence of activity in the anterior part of the brain. (Reprinted with permission from Mendez et al., 1997.)

with the amygdala. !e orbital and dorsomedial subdi- Prefrontal neurons respond in situations that visions of the prefrontal cortex are included as part of re"ect learned associative relationships between goal- the limbic association cortex. !e dorsolateral region relevant tasks. !ey appear to form ensembles that functions in the cognitive sphere dealing with percep- represent commonalities across past experiences that tion, memory and motor planning. !e orbital and have proven to be e$ective in achieving a particular medial regions function in support of social and emo- goal (Miller, 2000). Prefrontal areas are involved in tional behavior. Prefrontal output to the basal ganglia storage and retrieval related to sequential and temporal and to the frontal motor regions (BA 6 and BA 4) also aspects of planning (Goel et al., 1997). !is planning indicates a signi#cant role of the prefrontal cortex in and the ability of the prefrontal cortex to rearrange the motor behavior. Output from the prefrontal cortex sequence and complexity of planning have earned the prefrontal cortex the title “organ of creativity” (Fuster, 2002). Clinical vignette An increase in blood "ow in the frontal lobes has A 17-year-old female student, was involved in com- been associated with introversion. Extraverts show petitive piano and ballet. Her grades were consistently lower blood "ow in the frontal lobes and hippocam- outstanding. She had no personal or family history of psychiatric problems. She was out with friends on a pus. !ese #ndings suggest that introverts are engaged Saturday night when she was involved in an accident. in frontally based cognition, including remembering She fell o# the back of a pickup truck and landed on her events from their past, making plans for the future, or head. At the accident scene she was alert and oriented solving problems (Johnson et al., 1999). but felt dazed. In the emergency room, computed tom- Patients with lesions in the le& frontal cortex dem- ography and neurological examinations were normal. onstrate a higher frequency of depression than patients She was observed for two hours and discharged. The with more posterior lesions or patients with either patient’s mother was told that her daughter was "ne anterior or posterior right hemisphere lesions (Morris and that she should return to school and full activity et al., 1992; Starkstein and Robinson, 1993). Glucose on Monday. For the following few weeks, the patient metabolism studies in both teenagers and adults with a was unable to perform either piano or ballet at school, history of attention-de#cit hyperactivity disorder show although she had no problem practicing at home. Her grades deteriorated. She became depressed decreased metabolism in the le& anterior frontal areas and attempted suicide. Neuropsychological testing (Zametkin et al., 1990; Ernst et al., 1994). showed that the patient had a problem performing !e inhibition of glutamatergic transmission in the in the presence of interference (i.e., di!culty in main- prefrontal lobes correlates with cognitive dysfunction taining a mental set). This is evidence of damage in the seen in patients with schizophrenia. It is hypothesized prefrontal region. The patient responded well to anti- that this inhibition is responsible for dysregulation of depressant therapy. Her frontal lobe de"cit resolved dopamine in the corpus striatum (Breier, 1999). spontaneously over time with continued nonpres- Generalized, bilateral damage to the prefrontal sured practice. lobes can produce severe behavioral changes. Characteristically these patients become apathetic to the limbic system takes both direct and indirect and exhibit disinhibition of impulsive behavior. !ey routes. !e indirect route exits via the cingulate gyrus appear unconcerned (abulia) and exhibit slowness and and these prefrontal #bers distribute to many cortical lack of spontaneity in speech and slowness in thought 92 regions throughout their long course around the cor- and in emotional expression. !e movements of frontal pus callosum. lobe patients are slow (bradykinesia), and they exhibit Prefrontal cortex

a slow, uncertain “magnetic” gait (frontal ataxia or gait Clinical vignette apraxia). In contrast, their behavior may change, and A 52-year-old woman presented with a personality they may become irritable and euphoric. change over 2–3 weeks characterized by disinterest, An intriguing prefrontal syndrome called the disengagement, and decreased ability to solve prob- environmental dependency syndrome (EDS) has lems. She was a school teacher and could no longer been described (Lhermitte, 1986). Two patients with plan her lessons, process feedback from her students, focal unilateral frontal lobe lesions were observed in a or follow-through on her assignments. Her general doctor’s o%ce, in a lecture room, in a car, in a garden, and neurological examinations were normal except and while visiting an apartment. In each situation the for mental status testing which showed decreased patients assumed behavior appropriate to the environ- verbal output, diminished motor initiation, lack of concern, and poor sequencing and set-shifting abil- ment, including treating the physician as a patient while ities. Magnetic resonance imaging (MRI) showed an in the doctor’s o%ce. !e patients’ behavior was strik- enhancing dural mass over the left cerebral convex- ing, as though implicit in the environment was an order ities with e#acement of the sulci in both frontal lobes to respond to the situation in which they found them- (see Figure 6.7). Biopsy of the lesion revealed changes selves. EDS implies a disorder in personal autonomy. consistent with dural neurosarcoidosis.The patient’s !e orbitofrontal region like the anterior temporal personality changes resulted from pressure of the region (Chapter 4) is in close proximity to bony pro- neurosarcoid mass on her dorsolateral prefrontal cor- trusions. Both are vulnerable to injury, particularly tex. She was treated for neurosarcoidosis with corti- when rotational acceleration is imparted to the freely costeroids (prednisone). One month after initiation of moving head (Levin and Kraus, 1994). !e injury may therapy, a second MR scan showed decreases in the include white matter damage that may be di$use and dural lesion, and repeat neuropsychological testing showed coincident improvements in all measures of not detectable using structural imaging. Orbitofrontal frontal function. damage alone or combined with temporal pole damage can result in complex behavioral changes. !e orbital prefrontal cortex may be damaged by trauma or tumors (e.g., meningiomas). Since lesions in this area impact complex psychological functions, neuropsychological impairment may go unnoticed for years. Subtle personality changes may be the only early clue before the eventual development of signs of increased intracranial pressure, including seizures in the case of a space-oc- cupying lesion. Extensive orbital cortex damage blunts emotional reactions, and the patient may sit quietly and silently. If su%ciently stimulated, animals and humans respond in an irritable and aversive manner (Butter et al., 1968). Social responses are lacking or inappropriate. Human mothers with orbital lesions neglect or beat their children or both without provocation (Bro$man, 1950). Monkeys with orbital lesions separate themselves from their social group (Myers et al., 1973). !e pseudopsychopathic subject usually has sustained an orbital prefrontal lesion. !e patient’s attention is easily distracted by irrelevant stimuli. !ere is also excessive and aimless motility, disinhibition and hypomanic stance. Paranoid tendencies may develop. !e pseudodepressed subject o&en has sustained a lesion to the dorsomedial prefrontal region. !ere is general decrease of awareness, and a state of apathy with Figure 6.7. Magnetic resonance imaging demonstrating dural basic lack or weakness of drive. In extreme cases, this mass over left cerebral convexities resulting in dorsolateral frontal can lead to an akinetic-abulic syndrome and mutism. personality changes (Mendez and Zander, 1992). 93 Frontal lobe

Clinical vignette processing are selective attention and task manage- A 59-year-old man who was admitted to a psychiatric ment. Both activate the anterior cingulate and dorso- hospital in a $oridly hypersexual state. He had a his- lateral prefrontal cortex (Smith and Jonides, 1999). tory of subfrontal meningioma that was surgically Working memory and attention are closely related. For removed two years before presentation. The patient example if we anticipate a friendly face within a crowd reported that after the surgery his desire for sexual of strangers, we must hold the visual memory of the activity increased from once a week to as much as familiar face at the ready as we attend to the di$erent three to four times a day. Intercourse frequently lasted individuals in the crowd. more than an hour in duration and he had di!culty in !e DLPFC samples and regulates the "ow of infor- achieving orgasm. Other than an absence of olfaction, mation to the motor cortex by way of direct connec- his neurological exam was normal. A recent CT scan tions with the motor cortex and indirect connections revealed bilateral basal medial frontal lucencies consistent with old infarctions (Miller et al., 1986). with the mediodorsal and reticular nuclei of the thalamus. !e reticular thalamic nucleus regulates and directs sensory information to the cortex (Yingling Dorsolateral prefrontal cortex and Skinner, 1977). In contrast, the projections from !e DLPFC extends between the longitudinal cere- the orbital prefrontal region to the motor cortex regu- bral #ssure above and the lateral #ssure below on late arousal and control the degree to which the limbic the lateral surface of the brain centered in BA 46. It system in"uences motor behavior. !e DLPFC moni- receives input from the motor cortex as well as from tors and adjusts behavior. !e more superior portions the multimodal temporoparietal junction area. In of the DLPFC direct behavior in terms of sequential contrast to the orbital cortex, the connections of the or temporal cues (Knight et al., 1995). More infer- DLPFC place it in a position to evaluate and regu- ior portions regulate behavior in terms of spatial late information from the somatic sensory system cues. Neurons involved with memory (~40% of total) that can be used by the motor cortex to produce a decrease their #ring rate over time a&er a stimulus. response. !e DLPFC has been described as a place In contrast, neurons involved with encoding a motor “where past and future meet.” It looks backward in response (~60% of total) increase their #ring rate time to create memories from sensory input. It looks as the time to act approaches (Quintana and Fuster, forward in time to assemble a motor plan of action 1992). (Fuster, 1995). Symbolic representations retrieved from long- !e DLPFC is heavily involved in working mem- term memory as well as from current sensory cues are ory. Working memory is the act of bringing to mind “sketched out” in the DLPFC as a function of work- and processing limited amounts of information, for ing memory (Figure 6.8). Working memory allows example, reading and recalling a telephone number the representations to be manipulated and associated or solving a math problem “in your head” (Baddeley, with other ideas along with incoming information in 1992; Goldman-Rakic, 1997). Studies indicate that the order to guide behavior. !ere appears to be no one events that take place in the DLPFC make up what is locus of a central executive processor. Instead, visuo- considered working memory (Goldman-Rakic, 1996). spatial processing takes place throughout the DLPFC. Brodmann’s areas 6, 8, and 9 become preferentially !e working memory for faces and objects takes place activated when a working memory task must be con- in more lateral and inferior regions of the prefrontal tinuously updated and revised for temporal sequence cortex. Semantic encoding and verbal representations (Wager and Smith, 2003). are found in more inferior, insular, and anterior pre- Two components of working memory are recog- frontal regions (Goldman-Rakic and Selemon, 1997). nized. !e short-term component operates on the order Activity in the le& inferior prefrontal cortex corre- of seconds.!e second represents executive processing lated with retrieval of words and was more active for and operates on information retrieved from storage. remembered versus forgotten words. !e more active Di$erent frontal regions are associated with the stor- the region, the better is the memory performance age of di$erent kinds of information. Use of verbal (Reynolds et al., 2004). material activates Broca’s area and le& supplementary A second hypothesis recognizes a similar dorso- and premotor areas. Use of spatial information acti- ventral gradient, but distinguishes between types of 94 vates the right premotor area. Two forms of executive processing rather than material types. In this second Prefrontal cortex

is signi#cant. Verbal "uency is reduced in patients with Parkinson disease (Gurd and Ward, 1989). It is believed l this is a result of impaired dopaminergic projections to tia a ct p je S b l the DLPFC in this population (Amuts et al., 2004). O rba e V Patients with dorsolateral lesions are able to order words within a sentence but fail to properly sequence words when describing a plan of action. Prefrontal lesions seem to produce impairments in long-term planning whereas inferior parietal lesions produce Figure 6.8. The approximate location of working memory for visuospatial processing (spatial), for features of faces or objects impairments in short-term sequence execution (Sirigu (object), and for semantic encoding and verbal processes (verbal), et al., 1998). Lesions of the le& dorsolateral area a$ect on the prefrontal cortex. Compare with Figure 6.10. semantic speech that requires searching within a category (e.g., naming fruits or cars) (Gurd et al., 2002). view the superior frontal cortex is involved in monitor- In contrast, over-learned sequence speech (e.g., naming and manipulation of information whereas the more ing days of the week) does not activate the DLPFC but ventral dorsolateral cortex is responsible for rehearsal does activate Broca’s area on the le& (Bookheimer et al., during short-term storage (Owen, 2000). More recent 2000). evidence supports this second hypothesis (Wager and Anderson et al. (2004) reported that subjects suc- Smith, 2003). cessful in repressing unwanted nonemotional mem- Goal-directed behaviors related to short-term ories showed bilateral dorsolateral prefrontal cortical planning (e.g., hammering) activates the le& middle activation coupled with right hippocampal deactiva- frontal gyrus, supramarginal gyrus, inferior temporal tion. !e degree of hippocampal deactivation corre- gyrus, and middle occipital gyrus. Activity in BA 46 has lated with the magnitude of repression. !ese results been found to be associated with willed actions includ- support the concept of an active process of repression. ing #nger movements and freely generated words. It In another study, successful suppression of emotional is hypothesized that activation of the DLPFC re"ects memories also showed bilateral prefrontal activation selection of a single action out of a number of potential but was coupled with suppression of activity in the actions (Lau et al., 2004). amygdala (Ochsner et al., 2002). Lesions of the dorsolateral area cause abnormalities in complex psychological functions that are classi#ed Ventrolateral prefrontal cortex as executive function de#cits. !e patient demonstrates !e ventrolateral prefrontal cortex (VLPFC) includes di%culties in planning, feedback, learning, sequencing, BA 44, BA 45 and the lateral aspect of BA 47. !is establishing, maintaining, and changing a set behavior. includes pars opercularis, pars triangularis, and pars !e ability to organize events in temporal sequence is orbitalis, and Broca’s speech area (Figure 6.1). !e le& most a$ected. Perseveration, stimulus-bound behav- VLPFC and is involved with semantic processing and ior, and echopraxia may be seen (Sandson and Albert, is better understood. !e right VLPFC is linked to 1987). !e Wisconsin Card Sorting Test is valuable in emotional aspects of faces (Marumo et al., 2009). !e evaluating the status of the dorsolateral area (Drewe, le& VLPFC is important in the control of memory and 1974). Blood "ow to the DLPFC increases during provides multimodal integration and executive func- the performance of the Wisconsin Card Sorting Test. tion that underlies goal-directed behavior. It receives !is increase is not seen in schizophrenia patients semantic memory information from the lateral and (Weinberger et al., 1986). Performance on this test is inferior temporal areas (Zhang et al., 2004; Croxson more adversely a$ected with high dorsolateral or dorso- et al., 2005). !e information received can be the result medial lesions (Milner, 1995). !e patient may present of a bottom-up "ow or it may be selected in a top-down with a general disinterest, apathy, shortened attention manner by the VLPFC. If the currently available data span, lack of emotional reactivity, and di%culty in are insu%cient, the anterior portion of the VLPFC can attending to relevant stimuli. !e patient o&en #nds call for additional information from the temporal cor- comfort in following established routines and thought tex in a top-down manner. !e VLPFC acts to interpret processes (Fuster, 1996). A reduction in verbal "uency information using a competitive selection process that 95 may be seen if involvement of the le& dorsolateral area may activated even before completion of the retrieval Frontal lobe

stage. !is indicates that processing in the VLPFC is in In a general sense, the OFC is concerned with parallel rather than in series with other cortical areas the appreciation of emotions of either one’s self or of (Badre et al., 2006). It uses a two-stage process. !e others in terms of positive or negative reward. Activity #rst operates in a top-down manner to provide con- is reported to be associated with anticipated regret trolled access to memory. !e second is a post-retrieval (Coricelli, et al., 2005). !inking about feelings of selection process, which acts to resolve competition others (emotional perspective taking) also produces between simultaneously active representations (Badre activation of the OFC (Hynes et al., 2006). !ere appear and Wagner, 2007). to be di$erences in function between the medial and !e VLPFC and amygdala are part of a network that lateral OFC. !e medial OFC is more o&en activated monitors and selects a response to threat (Hariri et al., during the anticipation of reward (Cox et al., 2005; 2003). In this report, adolescents with generalized Galvan et al., 2005; Ursu and Carter, 2005; Kim et al., anxiety disorder compared with controls, exhibited 2006), when viewing attractive faces (O’Doherty et al., greater activation of the right ventrolateral prefrontal 2003; Ishai, 2007; Winston et al., 2007), or when enjoy- cortex in response to images of angry faces and showed ing chocolate (Small et al., 2003). On the other hand attentional bias away from the angry faces. !e authors the lateral OFC is more activated during the absence stated that the VLPFC may be involved in the manifest- of reward (Markowitsch et al., 2003; Ursu and Carter, ation of anxiety symptoms and through connections 2005), experiencing an unpleasant smell or touch with the amygdala may regulate responses to anxiety- (Rolls et al., 2003a, b), when viewing aversive pictures provoking stimuli, thereby reducing the severity of (Nitschke et al., 2006), and when eating chocolate to symptoms (Monk et al., 2006). excess (Small et al., 2003). A primary role of the OFC is the acquisition of Orbitofrontal cortex appropriate behaviors and the inhibition of inappro- !e OFC is de#ned as the ventral surface of the frontal priate behaviors based on reward contingencies (Elliot lobe from the gyrus rectus on the ventral surface to the et al., 2000, 2004). !e medial OFC is related to cognitive ventrolateral convexity laterally, and from the limen of and emotional processes and the sense of reward when insula posteriorly to the frontal pole. !is includes BA making the correct choice. Choosing between small, 11, BA 12, and the medial portion of BA 47. Brodmann’s likely rewards and large, unlikely rewards activates the area 13 is o&en included although it is usually desig- OFC (Rogers et al., 1999), which modulates behavioral nated to be part of the insula. Its inclusion as part of and visceral responses to emotionally provoking stim- the OFC underscores the close relationship of the OFC uli. Its close ties with the olfactory and taste cortices and anterior insula. Some authors include BA 24, BA put it in a position to evaluate and select food items. It 25, and BA 32, however, these areas are more o&en rec- can establish and recall the rules that lead to visceral/ ognized as MPFC or as part of the anterior cingulate emotional reward, and it calculates risk/reward ratios gyrus including the subgenual anterior cingulate gyrus when selecting behaviors. !is function is expanded (Phillips et al., 2003). beyond food selection to include many aspects of !e OFC receives input from the temporal asso- social behavior. !e OFC evaluates the emotional sali- ciation cortex, amygdala, and hypothalamus, making ence of stimuli and selects behavioral responses based it the highest integration center for emotional pro- on the level of reward provided by the response. It has cessing. It also receives inputs from the visual system, the ability to redirect behavior if the level or probability taste, olfaction, and somatosensory regions. !e sec- of reward changes (Rolls and Grabenhorst, 2008). !e ondary taste cortex is localized to the posterior, lat- medial OFC plays a key role in the circuitry of posi- eral part of the orbitofrontal cortex (Rolls, 1990). A tive emotion. Lateral OFC regions are more involved smell (olfactory) region medial to the taste region is with inhibiting the more familiar response when the also described (Rolls et al., 2003a). Visual input seems novel, less familiar response produces a reward (Zald to reach this region via temporal lobe structures. and Kim, 1996). A particular feature of the OFC is sup- Somatosensory and auditory inputs also arrive from pression of distracting internal and external signals the primary sensory regions. !e insula is similarly during the performance of current behavior (Fuster, connected to the OFC. !e more posterior regions 1996). Olfactory signals converge with taste signals in of the OFC receive strong input from the amygdala the OFC to create the representations of "avor. Other 96 (Price et al., 1991). sensory signals converge with "avor in the OFC and Prefrontal cortex visual-to-taste associations occur here as well (Rolls, from lack of social tact to the commission of antisocial 1997). !is is re"ected by its activation in response to acts. Patients with OFC lesions are emotionally labile, pleasant and painful touch, rewarding and aversive irritable, and impulsive. !ey appear to no longer rec- taste and by odor (Rolls, 2000). ognize the inappropriateness of their actions. !is may !e OFC receives information about faces. Face- be in part because the patient is impaired in the abil- responsive neurons of the orbitofrontal region may ity to interpret and respond to emotional voice or face convey information about which face is being seen expressions (Hornak et al., 2003; Shaw et al., 2005). (Rolls et al., 2005). Attractive faces have been shown !e patient with an OFC lesion may be hyperactive, to produce activation of the medial OFC, which is even hypomanic, especially if the lesion involves the enhanced by a smiling expression (O’Doherty et al., posterior OFC. Although overt sexual aggression is 2003). Some of the OFC face-responsive neurons seem rare, sexual preoccupation and improper sexual com- to be sensitive to facial expressions and movements. In ments are frequent. !ey may lose interest in personal one study, individuals showed greater activation in the appearance and hygiene, eat excessively and show lack medial OFC to more attractive than less attractive faces. of concern for others (Fuster, 2008). Symptoms may Homosexual individuals showed greater activation to appear sporadically, o&en accompanied by irritabil- attractive same-sex faces and heterosexual individuals ity, distractibility, and childish behavior (puerilism) showed greater activation to attractive opposite-sex (Clark and Manes, 2004). Disinhibition from normal faces (Ishai, 2007). !ese #ndings relate to the func- social controls is o&en seen with the patient exhibit- tion of social reinforcement since facial expressions are ing inappropriate social behavior. !ey may engage crucial for conveying social approval or disapproval. It in risky and dangerous behavior suggesting they are is likely that most of the associations developed in this unable to balance risk against reward. Patients are eas- region occur in a subconscious or unconscious (auto- ily distracted, and o&en they are unable to complete matic) fashion. !is area plays a role in reexperiencing tasks because they are distracted by ordinarily insig- emotions. Most patients with lesions here #nd it dif- ni#cant stimuli. Patients with OFC lesions have been #cult to reexperience emotions with the exception of compared with drug users. !ey choose instant reward fear and have di%culty in attaching emotional tone to over waiting, and they have great di%culty in decision images (Bechara et al., 2000). making in part because they are unable to anticipate !e OFC plays a dominant role in mediating the possible negative consequences of their immediate arousal (Joseph, 1996). It is also postulated to regulate actions. !ey also tend to take risks whether or not the the experience of anxiety (Gray, 1987). Inhibitory con- outcome produces positive reward. Lesions early in life trol over emotion and social behavior arises from the have greater e$ects. orbital and MPFC. Inhibition can help prevent distrac- Apathy can be seen following a lesion involving the tion and support the focusing component of selective OFC although apathy is more commonly associated sensory attention (Fuster, 2002). with an extensive lesion involving the lateral aspect. Acts of imagined social embarrassment produced Depressed mood can result from lesions involving signi#cant activation of the le& OFC (BA 10 and BA the anterior and lateral surfaces, especially le&-sided 47) (Berthoz et al., 2002). !e same region has been lesions. Apathetic or depressed patients will avoid reported to be activated on viewing angry faces (Blair social contact. et al., 1999; Kesler/West et al., 2001). Activity was seen to increase bilaterally when a sample of mothers were Medial prefrontal cortex, default brain asked to view pictures of their own 3–5-month-old network, and the social brain infants over activity compared with viewing pictures !e MPFC includes BA 10 on the medial aspect, anter- of other 3–5-month-old infants (Nitschke et al., 2004). ior cingulate (BA 24 and 32) and BA 8 and BA 9 of the In other studies, male and female subjects viewing prefrontal cortex on the medial aspect (Buckner et al., erotic #lm excerpts showed increased bilateral activ- 2008). Some authors include BA 25, which is also iden- ity in the MPFC and OFC as well as ventral striatum ti#ed as the infralimbic, subgenual cingulate gyrus. (nucleus accumbens) and amygdala (Redoute et al., Major connections of the MPFC are with the poster- 2000; Karama et al., 2002). ior cingulate gyrus, retrosplenial area, superior tem- Lesions in the orbital region result in a syndrome poral gyrus and hippocampal formation. It is closely 97 that is characterized by disinhibition, which varies linked with the anterior insula, temporal pole, medial Frontal lobe

temporal lobe and hippocampus, inferior parietal lobe !is recollection is applied to the current social situ- and amygdala. !ese connections relate it to long-term ation and recalls feelings (e.g., con#dence, embarrass- memory as well as to emotions processed through the ment, etc.) related to similar past situations (Damasio limbic system. et al., 2004). Mirror neurons located in many areas of !e default brain network includes the MPFC and the brain allow us to experience feelings of others as is a group of interconnected structures that become they move, feel pain, pleasure, etc. (Wicker et al., 2003; active when the brain is at rest. !e precuneus, retros- Rizzolatti and Craighero, 2004; Jackson, et al., 2005). plenial cortex and posterior cingulate form a posterior We even tend to imitate their actions, e.g., yawn when core and are sometimes referred to as the “posterome- they yawn (Chartrand and Bargh, 1999). Much of this dial cortex” (Cavanna and Trimble, 2006). is brought together in the posterior superior temporal !e default brain network is tonically active dur- sulcus and temporoparietal junction. It is here that ing a resting, mind-wandering, baseline state (Mason body, limb and eye movements of other are evalu- et al., 2007). When questioned, subjects report that ated. !e movement trajectory or direction of gaze is while resting, they are remembering the past, envi- determined and we take the perspective of the other sioning future events, and considering the thoughts person, (e.g., What are they are looking at? What are and perspectives of other people (Buckner and Carroll, they afraid of?) (Pelphrey et al., 2004; Frith 2007). All 2007). !e medial temporal lobe subsystem is activated of this is used to judge risk and reward of alternative during retrieval of episodic memories that may provide behaviors we might select to be successful in a social “the building blocks of mental exploration” (Wagner situation. et al., 2005; Buckner et al., 2008). !e MPFC may be subdivided into a ventral and !e MPFC is believed to be involved in reason- dorsal part. Some authors include portions of the anter- ing about the contents of other person’s thoughts ior cingulate gyrus in both parts (Phillips et al., 2003), (mentalizing) as they relate to the self (Gallagher and and both not only respond to environmental stimuli Frith, 2003). Other components of the mentalizing but also operate in a top-down manner to determine network include the temporal poles, posterior super- self-relevance. ior temporal sulcus, and the ventral striatum. !e MPFC appears to involve analysis and appreciation of Dorsomedial prefrontal cortex the mental self as well as the mental status of others !e dorsomedial component of the prefrontal cortex (Uddin et al., 2007). It is activated in response to infor- (MdPFC) lies within an arc that extends from the SMC mation about another person that is socially or emo- downward to the orbital component of the prefrontal tionally relevant. It became activated in individuals cortex (Figure 6.3). It contains portions of BA 9, BA hearing socially relevant adjectives such as “curious” or 10, and BA 32. It is dorsal and anterior to much of the “friendly” but abstract adjectives such as “celestial” or cingulate gyrus, but many authors include the anterior words referring to body parts (“liver”) or object parts cingulate gyrus as part of the MdPFC (Figures 2.3, 6.3, (“pedal”) (Mitchell et al., 2006). and 12.1). !is entire region is mainly supplied by the !e MPFC along with the anterior cingulate gyrus, anterior cerebral artery. Aneurysms of this artery are amygdala, insula, superior temporal sulcus, and tem- a common cause of medial frontal lobe damage. !e poroparietal junction has been described as the “social involved cortex may include the supplementary motor brain” (Figure 6.9; Frith, 2007; Blakemore, 2008) (see area as well. also social brain in Chapter 5). !e social brain allows !e MdPFC has particularly strong connections us to interact with other people. !e MPFC and adja- through a network that involves the anterior and pos- cent subgenual cingulate gyrus are activated when terior cingulate gyri (Gusnard et al., 2001). It is also the subjects think about mental states of self or others in target of signals from the anterior insula. !is network a social situation (mentalizing) (McCabe et al., 2001). has a high baseline activity and is believed to be active !inking about the feelings of others activates the OFC independent of external stimuli (Fransson, 2005). In (Hynes et al., 2006). !e amygdala in a social context, fact, sensory input is missing (Price, 2007). It is thought pre-judges faces, facial expressions, etc., based on pre- that the role of the MdPFC is to engage in introspec- vious experience with similar faces. !e temporal pole tion. It has shown to be activated when re"ecting on the brings together and stores facts about people and social intentions behind and consequences of actions, and 98 situations in which they have been found in the past. when forgiving the transgressions of others (Farrow Prefrontal cortex

Mirror Pre-judgment neurons Amygdala Mentalize MPFC pSTS Predicting movement path ACC TPJ Perspective taking Probable action What are you of self looking at? Temporal pole Social scripts; how feelings affect behavior

Figure 6.9. The social brain. The amygdala stores expectations based on past experience (pre-judgment). The mirror neurons from various areas of the brain react to actions of others re!ecting their movements and sensations. The posterior superior temporal sulcus (pSTS) and temporoparietal junction (TPJ) monitor others to determine social importance of their gaze and movements. The medial prefrontal cortex (MPFC) and subgenual cingulate cortex (sgACC) account for mentalizing, i.e., thoughts and emotions of self and others and how these may impact on actions taken by self or other. The temporal pole helps to apply general knowledge of social situations to the current social situation. (After Frith, 2007.) et al., 2001; Gallagher et al., 2002). !e introspection responses to a particular context or situation (Winston involves recollection, self-re"ection, and evaluation et al., 2002; Cunningham et al., 2004; Iacoboni and (Schmitz and Johnson, 2007). Dapretto, 2006; Todorov, et al., 2006). It appears to play !e MdPFC is important in motivation and the ini- a unique role in the perception of others’ perception of tiation of activity (Figure 6.10). It is sensitive to gaze the self (Ochsner et al., 2005). Brunet et al. (2003) found and was activated when subjects evaluated the emo- that the MdPFC of control subjects was activated bilat- tional aspect of gaze (Wicker et al., 2003). A more ven- erally when viewing images of people, whereas schizo- tral area appeared to be involved in emotion processing. phrenia patients viewing the same images showed no !e MdPFC is o&en activated by theory-of-mind tasks activation of either side of the MdPFC. (Happé et al., 1996; Brunet et al., 2000). Social/emotional cognition has been organized !e MdPFC regulates our own emotional responses in a three-dimensional pattern in the prefrontal cor- in two ways. First, it can allow one to focus on the tex (Figure 6.3) (Olsson and Ochsner, 2008). Along a behavior of another and evaluate other’s intentions or medial–lateral axis, midline cortical areas are inter- feelings. !e MdPFC evaluates the social situation and connected with visceral centers including the amyg- determines the meaning of others’ intentions or feel- dala and striatum. Midline areas are concerned with ings. Simply estimating the feelings or intentions of internal states. Lateral areas are concerned with exter- others has been shown to interrupt amygdala-medi- nally generated representations and are interconnected ated negative judgments of them. Second, the MdPFC with visuospatial centers. allows one to focus on one’s own involvement in an !e anterior–posterior axis involving the midline emotionally charged situation and to imagine one’s prefrontal and cingulate cortices follows the degree position from the point of view of a third emotion- of complexity of the mental state. Less complex rep- ally detached person. It is speculated that this activity resentations are processed beginning in the anterior may also modulate stimulus-driven amygdala activity cingulate cortex. As processing proceeds anteriorly (Olsson and Ochsner, 2008). along the axis, representations become more com- !e MdPFC also responds to interoceptive and plex providing awareness of, and judgments about, the exteroceptive stimuli, especially those involved in meaning of a$ective mental states. !e third prefrontal social situations. !e MdPFC is activated during the cortex dimension extends from the inferior surface perception of pain in one’s self and in others. It responds where stimulus-driven processes take place to super- to information that represents a more complex, three- ior regions where re"ective speculation of mental state place (triatic) scenario: ‘You, me, and this’ (Saxe, can occur. 2006). !at is, the MdPFC monitors others’ actions, !e MdPFC along with the thalamus was activated sensations, and personalities as well as our own social when a group of 12 women were asked to recall recent 99 Frontal lobe

Prefrontal cortex Temporal lobe Parietal lobe Occipital lobe

Cingulate and Medial retrosplenial areas Superior and medial (motivational realm) parietal lobule Tr unk and leg Dorsolateral (integrative and temporal functions) Dorsomedial and Peripheral vision medial temporal areas

Inferotemporal and Central vision ventral temporal areas Ventrolateral and orbital (Emotional realm) Inferior parietal lobule Head, face, and neck Parahippocampal gyrus and temporal pole

Figure 6.10. The dorsolateral and medial prefrontal areas receive input from dorsal temporal and superior parietal lobes and portions of the occipital lobe that mediate peripheral vision. This dorsal system appears to function in the motivational and planning realm, closely associated with the trunk and lower limb, and with the location of an object in space (where). The ventrolateral and orbital prefrontal areas receive input from inferior temporal and inferior parietal lobes and portions of the occipital cortex that mediate central vision. This ventral system appears to function in the emotional realm, closely associated with the head, face and neck, and with the identi"cation of an object (what). (After Pandya, D.N., and Yeterian, E.H. 1990. Prefrontal cortex in relation to other cortical areas in rhesus monkey: Architecture and connections. In: H.B.M. Uylings, C.G., Van Eden, J.P.C., DeBruin, M.A., Corner, and M.G.P., Feenstra (eds.) The Prefrontal Cortex: Its Structure, Function and Pathology. Amsterdam: Elsevier, pp. 63–94.)

emotional events. Additional brain areas were acti- Ventromedial prefrontal cortex vated when they viewed an emotion-evoking #lmstrip. !e ventromedial prefrontal cortex (MvPFC) is Activation was independent of the nature of the emo- located inferior to the MdPFC and occupies portions tion –happiness, sadness, disgust. A similar experi- of BA 10, BA 12, and BA 32 (Figure 6.3). It may extend ment revealed activation in the MdPFC and cingulate posteriorly to include portions of the infralimbic, sub- cortex, but only on the right side (Teasdale et al., 1999). genual anterior cingulate gyrus (BA 25). A key di$e- !e authors suggested that the MdPFC and thalamus rence from the MdPFC is that the MvPFC receives are important in the appreciation of emotion in the input from all sensory modalities. It functions in basic absence of concurrent sensory input (Lane et al., 1997; stimulus-reinforcement association learning involv- Reiman et al., 1997). ing social/emotional cues. It has connections with the !e patient with a lesion of the MdPFC is apath- ventral anterior cingulate gyrus, insula, amygdala, etic. !e area a$ected may include parts of the SMC. and nucleus accumbens. !ese structures function to He or she exhibits a lack of spontaneous movement. identify valence and emotional tone of both interocep- Immediately a&er the onset of the lesion, the patient tive and exteroceptive stimuli. !e role of the MvPFC o&en presents with akinetic mutism. Paresis of the with respect to these other structures is to determine lower limb may be seen if the lesion extends posteriorly the degree to which these stimuli are relevant to the to infringe on the primary motor cortex. !e patient self. It may use past experience to predetermine self- o&en fails to respond to commands. Incontinence is relevance to current or anticipated stimuli (Schmitz frequently seen, and the patient appears indi$erent to and Johnson, 2007). It responds when an individual 100 the problem. experiences empathy, a component of social cognition Prefrontal cortex

(Saxe, 2006). One report showed that the MvPFC, dealing with multiple options and response choices. along with the bilateral temporoparietal junction, was Certain choices can be either eliminated or endorsed, activated when subjects were asked to take the per- thus decreasing the number of choices available. In spective of another in a situation containing either the absence of this hypothesized process, options and emotional or cognitive content. Activation was more outcomes become more equalized and the process of intense in the OFC and MvPFC to scenarios contain- choosing will depend entirely on logical processes. ing emotional content (Hynes et al., 2006). It was con- !is strategy would be slower and may fail to take into cluded the MvPFC is involved with perspective-taking account previous experience. in situations involving empathetic and sympathetic Patients with damage to the MvPFC present with aspects of emotion, especially in situations that require severe impairment of social and personal decision more conscious and e$ortful reasoning (Hynes et al., making (Damasio, 1994). !ese patients have largely 2006). It may support a process in which we use our preserved intellectual abilities. Patients may have dif- own thoughts, feelings and desires as a proxy for those #culty planning their workday as well as di%culty of other people in order to infer the other’s mental choosing suitable friends, partners, or activities. !eir state: “You and me” (Jackson et al., 2006; Jenkins et al., choices are not personally advantageous, rather they 2008). are inadequate and usually lead to #nancial losses, Finally, the MvPFC has been proposed to be where losses in social standing, and losses to family and the capacity to develop theories of the mind resides. friends. Human social behavior is characterized by the unique Individuals with lesions involving the MvPFC capability to make inferences regarding others’ men- score abnormally low on self-rating scales of emo- tal states, needs, feelings, and intentions (so called tional empathy but not on scales of cognitive empathy. theory-of-mind) (Happaney et al., 2004). More recent Degeneration of the MvPFC in the frontal variant of data indicate that cognitive and a$ective theory-of- frontal temporal dementia correlates with a rapid drop mind may be mediated by di$erent regions. While the in empathetic concern (Lough et al., 2006). MvPFC may be mediating a$ective theory-of-mind, a wider region of the prefrontal cortex including the Prefrontal networks dorsolateral cortex may be necessary to develop a cog- !ere are two networks associated with the prefrontal nitive theory-of-mind (Shamay-Tsoory and Aharon- cortex. Both act to regulate emotional behavior and Peretz, 2007). interact with each other. !e “orbital prefrontal net- Based on the nature of the connections of the work” (ventral system) is centered in the OFC. !e MvPFC with sensory input and output to autonom- orbital network receives input from the sensory asso- ic-visceral control, and to other limbic as well as ciation cortex of the parietal and temporal lobes as well other frontal cortical regions, a hypothesis known as olfactory and taste cortices that make up the poster- as the “somatic marker hypothesis” was advanced by ior orbital cortex. !e network also includes the insula, Antonio Damasio (1994) to shed light on the process amygdala, and ventral striatum (nucleus accumbens). of decision making by humans. !e somatic marker Taken together this network can be interpreted histor- hypothesis suggests that structures in the MvPFC ically to provide a basis for assessment of food ("avor, hold representations of the associations between cer- appearance, texture). !e orbital prefrontal network is tain complex situations and the visceral sensations recognized to evaluate sensory stimuli, identify emo- or emotions previously linked to that situation. !e tionally salient components, and in response, generate actual memories are not held here thus damage to this an appropriate a$ective state. It also signals other areas region will not a$ect the memories themselves but (hypothalamus and brainstem) to activate appropri- will a$ect the link between them. When an individ- ate autonomic responses. !e orbital system forms ual experiences a situation similar to one experienced a cortico-striatal-thalamic-cortical loop, with con- in the past, the ventromedial region is activated and nections with the ventromedial putamen and lateral the visceral/emotional memory tied to the previous caudate nucleus (Price, 2007; Saleem et al., 2008). !is situation is recalled. !e recall may be an actual vis- system integrates sensory and emotional aspects and ceral reexperience of emotions and feelings or just a assigns characteristics such as reward, aversion, and cognitive representation. !is evocation process func- relative value to sensory input (Drevets et al., 2008). tions as a constraint over the process of reasoning Of particular interest is its close connection with the 101 Frontal lobe

dorsolateral and ventrolateral prefrontal cortices. It is Behavioral considerations proposed that the orbital prefrontal network provides Blood "ow to the brain is decreased in major depres- for a top-down, e$ortful, voluntary regulation of emo- sion in elderly patients to about the same extent as in tional behavior (Ochsner and Gross, 2007; Phillips Alzheimer disease (Baxter et al., 1985). Reductions are et al., 2008). particularly evident in the parietal, superior temporal, !e DLPFC bilaterally along with the right anterior and frontal cortices (Sackeim et al., 1990). Positron cingulate gyrus and right parietal cortex is believed to emission tomographic scanning in patients with function in support of voluntary suppression of atten- major depression reveals decreased metabolism in the tion to the emotionally salient stimulus or inhibition DLPFC. Both blood "ow and metabolism have been of the emotional response. !e actions are hypoth- reported to be decreased in the DLPFC in patients with esized to be carried out through pathways involving primary depression (Baxter et al., 1989; Bench et al., the OFC. 1992; Dolan et al., 1992). Increases in hypometabolism !e “medial prefrontal network” (dorsal system) and hypoperfusion to normal levels have been reported is centered in the medial prefrontal cortex. It receives following successful drug therapy but not a&er unsuc- input from the region of the superior temporal gyrus cessful drug therapy (Mayberg, 1997). !e dorsolat- that lies anterior to Heschl’s gyrus as well as from the eral prefrontal cortex is usually easy to evaluate by posterior superior temporal sulcus. !e medial net- computed tomography (CT) and is the region of the work includes the hippocampus, DLPFC, and dorsal prefrontal lobe sampled by routine electroencephalog- anterior cingulate gyrus, and has close links with the raphy (EEG). Depressed patients exhibit hypometabo- amygdala and insula (Price, 2007; Saleem et al., 2008). lism in the le& anterolateral prefrontal cortex (Baxter Unlike the orbital network, the medial network receives et al., 1989). little sensory input. It sends #bers to the hypothalamus Patients with schizophrenia showed abnormal and midbrain, including the periaqueductal gray. !e prefrontal activation, particularly in response to tasks medial prefrontal network integrates visceromotor that require executive function such as working mem- information and provides for the automatic control of ory (Manoach et al., 2000). Pfe$erbaum et al. (2001) emotion. Automatic control acts by either disengage- found that alcoholic subjects, showed diminished ment of attention away from the emotional stimulus or activation of BA 9, BA 10, and BA 45 when compared by reassignment of emotional salience (Phillips et al., with normals in a visual spatial task requiring work- 2003, 2008). ing memory. At the same time the alcoholic subjects !e medial prefrontal cortex is central to the “med- showed increased activation in BA 47, suggesting ial prefrontal network.” It receives input from the region they were using the more inferior “what” stream and of the superior temporal gyrus as well as the poster- declarative memory as compared with the more dorsal ior superior temporal sulcus. !e medical prefrontal “where” stream used by the controls. Subjects at high network includes the DLPFC and cingulate gyrus. It is risk for alcoholism showed decreased bilateral acti- closely connected with the amygdala, hypothalamus vation of BA 40 and 44 and the inferior frontal gyrus and insula (Price, 2007; Saleem et al., 2008). Unlike the when compared with low risk subjects (Rangaswamy orbital network, the medial prefrontal network receives et al., 2004). little sensory input. It is activated during self- referential Information processing in the dorsolateral pre- processing (i.e., appraisal of stimuli as they relate to frontal lobes of schizophrenic patients is de#cient. !is one’s own person). !e DLPFC and posterior cingulate correlates with the #nding that an abnormally high gyrus are coactivated. Activation of the cingulate gyrus density of neurons is found in the prefrontal cortex may represent retrieval of autobiographical memory. of brains of patients with schizophrenia (Figure 6.11). Coactivation of all three provides for con"ict moni- !e increased density corresponds with a slight, non- toring between the current self and an inner standard. signi#cant decrease in cortical thickness (Selemon Interaction with the DLPFC suggests cognitive con- et al., 1995). !e le& dorsolateral region has been trol that allows for directing attention elsewhere or by shown to have decreased cerebral blood "ow corre- reassigning of emotional salience (Phillips et al., 2003, sponding with psychomotor poverty seen in schizo- 2008). Connections from the MPFC to the amygdala phrenia (Liddle et al., 1992). Negative symptoms of and hypothalamus allow for autonomic expression of schizophrenia correlate with a decrease in glucose util- 102 emotions (e.g., blushing). ization in the frontal and parietal cortex (Tamminga Behavioral considerations

Other behavioral considerations Schizophrenia An increased number of axospinous synapses (225%) and a decrease in axodendritic synapses (-40%) has been reported for the frontal lobe in schizophre- Normal nia (Aganova and Uranova, 1992). Increased neuron density has been observed in the prefrontal cortex (Figure 6.11) and a decrease in GABAergic axon terminals reported in the dorsolateral prefrontal cortex (Woo et al., 1998). Abi-Dargham et al. (2002) reported

that dopamine D1 binding was increased in the pre- Schizophrenia frontal cortex and correlated with poorer working Figure 6.11. An increase in density is seen in prefrontal neurons memory performance. in postmortem tissue of schizophrenia patients. (Reproduced by Pathology in the prefrontal region in schizophrenia permission from Selemon, L.D., Rajkowska, G., and Goldman-Rakic, predicts increased dopamine release in the striatum P.W. 1995. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital (Bertolino et al., 2000; Meyer-Lindenberg et al., 2002). area 17. Arch. Gen. Psychiatry 52:805–818.) !is may occur through activation of corticostriatal glutamatergic pathways (Carlsson and Carlsson, 2006). It is speculated that dopamine release in the striatum et al., 1992). !ought disorder in schizophrenia may conveys assignment of positive or negative valence to represent the breakdown of working memory and is otherwise neutral cues (Schultz, 2006; Kéri, 2008). hypothesized to correlate with abnormalities in the It is theorized that positive symptoms of schizo- DLPFC (Goldman-Rakic, 1996). It has been hypoth- phrenia are caused by an overactivity of the mesolim- esized that the increased density is due to a reduction bic system or an excessive number of D2-like dopamine of the neuropil, suggesting a decrease in the number of receptors. (D2-like receptors include D2-, D3-, and D4- synapses (i.e., excessive synaptic pruning; Glantz and receptor subtypes; Chapter 3.) !is is because all clin- Lewis, 1993; Tamminga, 1999). ically e$ective antipsychotic drugs are antagonists of

Synaptic pruning in the frontal cortex is seen nor- D2-like dopamine receptors (Nestler, 1997). !e nega- mally in adolescence, preceded somewhat by cell death tive symptoms may be due to a loss of function of the (Huttenlocher, 1979). More e%cient word processing mesocortical system. It is hypothesized that there is an may be the natural result of pruning. Excessive synap- increase in activity of the mesolimbic system, which tic pruning is hypothesized to result in the hallucinated responds to antipsychotic drugs (D2-like receptors); speech of schizophrenia (Ho$man and McGlashan, and a decrease in activity in the prefrontal area, which 1997). Protection provided by estrogens may account does not respond to antipsychotic drugs. for later age of onset of schizophrenia in women It is postulated that the greatest development of the (Seeman, 1997). dopamine system in evolution is the increased abun-

A decrease in interstitial neurons found in the dance of D1 receptors in the prefrontal cortex (Lidow white matter of the middle frontal gyrus of the DLPFC et al., 1991). Investigators propose that dopaminergic of schizophrenics has been reported (Akbarian et al., transmission in the prefrontal cortex modulates neur- 1996), and it was suggested that this decrease re"ects onal circuitry in a manner that augments signi#cant an abnormal migration pattern during the second tri- incoming signals while attenuating irrelevant incom- mester of pregnancy. ing noise (Winterer et al., 2006). !ere are reduced

!ere is no longer any doubt that the intactness of numbers of the D1-like dopamine receptors, which prefrontal function is essential for our normal func- include D1- and D5-receptor subtypes in the prefrontal tion in society. !rough the integration of sensory cortex of patients with schizophrenia. Dopamine is input, emotional tone, and motivation of cortical, believed to be important in working memory largely subcortical, and limbic sources, the prefrontal cortex through action on the D1-like receptors. !e reduced critically intervenes in the initiation and guidance of number of D -like receptors may underlie cogni- 1 103 behavior. tive de#ciencies common to schizophrenia patients. Frontal lobe

Reduction in the density of D1-like receptors which of the most consistent #ndings. !e superior, middle, are found on the dendrites of pyramidal cells may and inferior gyri of the DLPFC are particularly a$ected be responsible for the reduction in cortical thickness (Ketter et al., 2001; Brooks et al., 2009). !e e$ect may (Selemon et al., 1995). appear bilaterally (Ketter et al., 2001) or on either Overactivity of the MPFC and posterior cingulate the right or le& side (Cohen et al., 1989). Depressed gyrus has been reported in patients with schizophre- patients exhibit hypofrontality, with the e$ect more nia at rest, suggesting excessive introspection. Positive marked in the medial orbital region than in the dorso- symptoms (hallucinations, delusions, and confused lateral region (Ho et al., 1997). Decreased blood "ow thoughts) were found to correlate with increased activ- to the medial frontal pole appears to be the critical ity in the medial prefrontal cortex and posterior cin- abnormality in depression-related cognitive impair- gulate gyrus (Garrity et al., 2007; Harrison, et al., 2007; ment (depressive pseudodementia; Figure 6.12) and Zhou et al., 2007). may be associated with emotional states such as with- Ventrolateral prefrontal cortex metabolic activity drawal and apathy (Dolan et al., 1992; Ho et al., 1997). in schizophrenic patients was not di$erent from con- Activity in the MdPFC is reduced (Drevets et al., 2002) trols when examined during working memory tasks and the size of the neurons and density of the glial is (Manoach et al., 2000; MacDonald and Carter, 2003). also reduced in the unmedicated, depressed condition However, when presented with working memory or (Uranova et al., 2004). executive tasks there was hypoactivation in the dorso- In contrast, increased metabolism in the frontal lateral prefrontal cortex accompanied by increased lobes has also been reported (Drevets et al., 2002; activation in the anterior cingulate and le& frontal Ketter and Drevets, 2002). Activity in the orbital pre- pole relative to controls (Hazlett et al., 2000; Glahn frontal cortex, VLPFC, and insula has been reported et al., 2005; Ragland et al., 2007). During episodic to be abnormally increased in unmedicated depressed memory recall both decreased and increased activity patients while resting (Drevets, 2001, 2003). Activity were reported. !e literature remains confusing. Some authors found that hypoactivity in the le& prefrontal area was predominant (Hofer et al., 2003; Reichenberg and Harvey, 2007). Decreased activity during episodic memory encoding was more likely, especially on the right (Barch, 2005). Di$erences in results between studies conducted under di$erent conditions suggest that frontal activity is ine%cient (Keshavan et al., 2008). In one study, when viewing images of people the DMPFC of control subjects was activated bilaterally. Schizophrenia patients viewing the same images showed no activation of either side of the DMPFC (Brunet et al., 2003). Depression A signi#cant decrease has been reported in glial density and glial number in the OFC of patients with a history of major depression or bipolar disorder. Neuron cell Figure 6.12. Statistical parametric maps (SPM) showing signi"- cant (p<0.05 Bonferroni corrected) decreases (left) and increases size but not number was reduced (Torrey et al., 2000; (right) in relative cerebral blood !ow. The light areas represent Cotter et al., 2002). Decreased glial density and reduced mathematical di#erences between patients with depression- neuron size has been observed in the dorsolateral (BA related cognitive impairment and control subjects. The pixels at which there is a signi"cant change have been projected onto sagit- 9) as well as the orbitofrontal cortices (Rajkowska et al., tal, coronal, and transverse renderings of the standard brain volume 1999, 2001). of Talairach and Tournoux. (Reproduced by permission from Dolan, Imaging studies have shown that decreased activ- R J., EBench, C J., Brown, R.G., Scott, L.C., Friston, K.J., and Frackowiak, R.S.J. 1992. Regional cerebral blood !ow abnormalities in depressed ity in the prefrontal cortex of patients with unipolar patients with cognitive impairment. J. Neurol. Neurosurg. Psychiatry 104 or bipolar depression compared with controls is one 55:768–773.) Behavioral considerations in these regions decreased with antidepressant therapy 2001; Brooks et al., 2009).!e anterior cingulate gyrus (Drevets et al., 2002). Alterations in activity in other has also been reported to exhibit reduced metabolism areas has also been reported, including in the anter- in patients with bipolar disorder and major depressive ior cingulate gyrus, amygdala, insula, and ventral stri- disorder (Drevets et al., 1997, 2007; Brooks et al., 2009). atum (Drevets et al., 1997; Kimbrell et al., 2002). In one !e reduced metabolism in the subgenual anterior cin- report, activity was increased in subjects with anxiety gulate gyrus was accompanied by reduced gray matter disorders during induced anxiety and obsessional volume and a reduction in glia but no loss of neurons states (Charney, 2002), and in another it was decreased (Ongür et al., 1998). !e neuron density appeared in subjects under antidepressant treatment (Drevets increased because of the loss of neuropil. !e loss was and Raichle, 1998). observed early in the illness and in young adults at high Metabolism was increased throughout the brain familial risk (Hirayasu et al., 1999; Botteron et al., 2002; during nonrapid eye movement (non-REM) sleep in Boes et al., 2007). !e posterior subgenual anterior cin- major depression (+30%), which supports the hypera- gulate gyrus (infralimbic cortex) has been reported to rousal theory of depression. Regional increases have exhibit an increase in gray matter a&er two years of nat- been seen in the occipital, temporal, parietal, and uralistic treatment (Coryell, et al., 2005; Drevets and frontal lobes. By comparison, an increase in blood "ow Savitz, 2008). has been reported during transient sadness in healthy A reduction in activity has been reported in the individuals (Mayberg, 1997) and in patients with sim- right OFC during mania compared with controls ple phobia during provocation (Rauch et al., 1995). (Rubinsztein et al, 2001; Blumberg et al., 2003; Elliot Increased activation of the medial prefrontal network et al., 2003). Patients with the longest duration of mania correlates with increased self-focus and cortical control episode showed the least right orbitofrontal activity (Lemogne et al., 2009). A large decrease in perfusion (Altshuler et al., 2005a). Greater activity in the amyg- was reported in the inferior frontal lobe of a woman dala in manic versus controls was observed during a who developed catatonia during a depressive episode task that normally activates the amygdala (Altshuler (Galynker et al., 1997). et al., 2005b). Patients with depression and Parkinson disease An anterior network that includes reciprocal con- or Huntington disease have diminished metabolism nections between the right OFC and the amygdala bilat- in both the orbital prefrontal cortex and the caud- erally has been proposed to be dysfunctional in bipolar ate nucleus. Depression has been diagnosed in 60% disorder. Reduced right orbitofrontal activity may of patients with anterior frontal lesions (Cummings, result in impulsivity or unstable mood through dys- 1993). !is is consistent with a neuropsychiatry prin- regulation of the inhibitory prefrontal-amygdala cir- ciple that suggests a contingent but not an obligatory cuit (Strakowski, 2002; Blumberg et al., 2003; Altshuler anatomical relationship for speci#ed behavioral syn- et al., 2005a). !ere is evidence that tracts in the OFC dromes. Le& anterior lesions increase the patient’s are reduced in volume (Kieseppa et al., 2003; Adler vulnerability to depression, but the occurrence of et al., 2004). However, it was not clear to the research- depression may also require environmental or psycho- ers if these tracts connect with the amygdala. social factors. !is is in contrast to most neurological syndromes, in which an obligatory relationship is Obsessive-compulsive disorder typical (Cummings, 1993). Decreased le& prefrontal Reduced volume of the OFC is the most consistent activity on positron emission tomography is con- reported morphological #nding in OCD (Choi et al., sistently found in actively depressed patients. !e 2004; Kang et al., 2004; Atmaca et al., 2006, 2007; decrease is more pronounced if the patient reports Menzies et al., 2008). An increase in gray matter dens- being more depressed on the day of scanning (Ketter ity has been reported in the le& OFC (Kim et al., 2001). et al., 1994). Metabolism was found to be increased in the OFC along with the whole cerebral hemispheres, caudate nuclei, Bipolar disorder and cingulate gyri in patients with OCD (Figure 12.9; Depressed bipolar disorder patients showed decreased Baxter, 1992; Swedo et al., 1992; Rauch et al., 1994). !e metabolism in the DLPFC, lateral OFC, anterior increase may be in response to reduced striatal inhib- insula, and ventral striatum; this is greater on the le& ition and therefore re"ects an attempt on the part of than on the right (Martinot et al., 1990; Ketter et al., the OFC to inhibit obsessions and compulsions (Baxter 105 Frontal lobe

et al., 1990). !e increased metabolism in the OFC has the right dorsolateral prefrontal cortex was reported been shown to be accompanied by a similar increase to have a therapeutic e$ect on ten patients with PTSD in the bilateral anterior cingulate gyrus. A signi#cant (Cohen et al., 2004). decrease in OFC metabolism was seen a&er successful drug treatment, and the decrease in the right OFC Borderline personality disorder region correlated directly with two measures of OCD !e three main symptoms of borderline personality improvement (Swedo et al., 1992). disorder (BPD) are impulsivity, emotional instability, van den Heuvel et al. (2005) found that increased and disturbed interpersonal relationships. Brain areas activity at rest was replaced with decreased activity showing reduced metabolism and volume reductions compared in the premotor cortex, anterior cingu- in BPD patients include the orbital prefrontal cortex, late gyrus, DLPFC, precuneus, lateral parietal cortex, cingulate gyrus, hippocampus, and amygdala (Solo$ and putamen when subjects were presented with a et al., 2000; Rusch, et al., 2003; Schmahl et al., 2003). task requiring planning aspects of executive function. Volume reductions in the le& OFC (24%) and amyg- !is is believed to re"ect a decreased responsiveness dala (23%–25%) were found to correlate and led to a in DLPFC-striatal circuits in OCD. !e OFC is a com- fronto-limbic hypothesis (Tebartz et al., 2003) which ponent of the orbitofronto-striatal loop. !is loop has included the suggestion that the reduced volumes been proposed to be dysfunctional in OCD (Menzies correlated with impulsivity and aggressive behavior et al., 2008). Models of OCD re"ect results of studies (Solo$ et al., 2003; Tebartz et al., 2003). A decrease in showing changes in activation of prefrontal areas in metabolism seen in the DLPFC of patients with BPD response to activity in the caudate nucleus of the stri- is speculated to correspond with chronic feelings of atum (Chapter 7). depersonalization and unreality (De La Fuente et al., 1997). Posttraumatic stress disorder Decreased serotonin synthesis capacity has been !e medial prefrontal cortex has been found to be less observed in the posterior superior temporal gyrus, active in patients with PTSD in several studies (Semple anterior cingulate gyrus and in the medial frontal cor- et al., 2000; Shin et al., 2001; Bremner, 2002) but not in tex (BA 10) (Leyton et al., 2001). Reduced activity in others (Mirzaei et al., 2001; Osuch et al., 2001; Pissiota the OFC is hypothesized to associate with impulsive- et al., 2003; Lindauer et al., 2008). PTSD is character- aggressiveness in BPD (Solo$ et al., 2003). Reduced ized by abnormal reactions to fear-provoking stimuli. OFC serotonin levels may also be a contributing factor Some patients exhibit hyperactive responses in the (Siever et al., 1999). Smaller volume and reduced meta- autonomic and emotional spheres. Others exhibit dis- bolic activity reported in the amygdala may be respon- sociative phenomena, including emotional numbing, sible for impaired emotional processing and emotional psychogenic amnesia, psychogenic amnesia, deper- instability (Lyoo, 2005). sonalization and derealization symptoms (Falconer In subjects with BPD, increased metabolism was et al., 2008). Individuals who exhibit a hyperarousal observed in the right VLPFC and le& medial prefrontal PTSD response to traumatic narratives, with increased cortex along with the amygdala bilaterally when view- autonomic and emotional responses, have reduced ing emotionally aversive images as well as sad, neutral activity in the medial prefrontal cortex and anter- and fearful faces, but not happy faces (Donegan et al., ior cingulate gyrus compared with controls (Lanius 2003; Herpertz et al., 2001). A task requiring response et al., 2001). Patients with PTSD who exhibit a disso- inhibition produced increased activity in the pre- ciated response exhibit increased activity in the med- frontal in control subjects. When challenged with the ial prefrontal cortex and anterior cingulate gyrus. It same task BPD patients exhibited more widespread is hypothesized that the areas activated in dissocia- activity that extended to the inferior, middle, super- tive PTSD re"ect increased emotional regulation and ior frontal gyri, and anterior cingulate cortex (Vollm inhibition of the limbic emotional networks (Lanius et al., 2004). et al., 2002). Liberzon and Sripada (2008) suggest the Siever et al. (1999) suggested that serotonergic MdPFC allows heightened reactivity to salient emo- modulation decreased in BPD patients as a result of tional stimuli and fails to reevaluate the reaction. In reduced metabolic response to administration of a 106 their model the MvPFC fails to reduce conditioned serotonin-releasing agent (*,+-fen"uamine) com- fear. Transcranial magnetic stimulation focused on pared with controls. !is was localized to the medial Select bibliography

OFC (BA 9, BA 10, and BA 11). It was suggested that (e.g., parent, guardian, sibling). !ey show improve- the decreased activity is associated with impulsive- ment in eye contact, physical contact, and social aggressiveness (Solo$ et al., 2003). interaction skills when interacting with a familiar as opposed to an unfamiliar individual (Knott et al., 1995; Autism spectrum disorders Oberman et al., 2008). Consistent frontal lobe structural abnormities in aut- Frontotemporal dementia ism are lacking. However, behavioral studies have !e pathology in frontotemporal dementia (FTD) is indicated a link between frontal lobe hyperplasia more localized to the frontal and anterior temporal and autism. Frontal lobe size was found to correlate regions than in Alzheimer disease. Consequently, inversely with cerebellar vermis size in a group of 42 more behavioral disturbances (e.g., disinhibition, autistic boys (3–9 years) (Carper and Courchesne, hypersexuality, irritability, depression, apathy) are 2000). At the microscopic level, abnormal minicolumn seen in association with FTD than in Alzheimer structure in the frontal lobe was reported (Casanova disease. et al., 2002). One theory of autism suggests some symptoms Seizures are due to impaired theory-of-mind (Penn, 2006). Frontal lobe seizures are particularly di%cult to diag- !eory-of-mind structures include the MPFC. Some nose, but they are common and are usually secondary theory-of-mind tasks result in abnormal frontal lobe to head trauma. !ey can be brief, odd, or misleading, activation in subjects with autistic spectrum disorder and can be misinterpreted as pseudoseizures. Extensive (ASD) (Castelli et al., 2002). Joint attention, the abil- connections of the orbital prefrontal cortex to limbic ity to follow the gestures of others, share interest in structures (mainly amygdala and hippocampus) via objects, and appropriately shi& gaze during interaction the uncinate fasciculus help in understanding the di%- with others has been reported to be dysfunctional in culty in di$erentiating between ictal events that occur children with autism (Whalen and Schreibman, 2003). in those areas. Laughter, crying, moaning, and verbal !ese tasks rely on normal function of the OFC, med- automatisms have been described with lesions of the ial prefrontal cortex and DLPFC areas (Henderson superior frontal gyrus and cingulate gyrus. In addition, et al., 2002). Working memory, also associated with the complex gestures such as body rubbing, rearrangement DLPFC, is impaired in ASD (Luna et al., 2002). of clothes, sexual automatism, mood changes, wander- Autism and Asperger syndrome are suggested ing, and agitation have all been reported with frontal to involve dysregulation of the limbic-orbitofrontal lobe lesions. Finally, nonconvulsive frontal seizure circuitry (Bachevalier and Loveland, 2006). Several states can produce prolonged behavioral disturbances regions in the default brain network are a$ected in (Riggio and Harner, 1992). ASD. !e volume of the MdPFC is reported to be Lesions in the orbital prefrontal cortex are di%cult reduced (Abell et al., 1999; McAlonan et al., 2005). to evaluate utilizing procedures such as EEG due to Compared with control subjects, activity in the default their proximity to the eye. Eye movements cause major network has been reported to be signi#cantly reduced artifacts that mask EEG abnormalities. in individuals with ASD. More serious social impairment correlated with greater atypical activity in the Miscellaneous conditions vMPFC and posterior cingulate gyrus (Kennedy et al., Decreased metabolic activity has been reported in the 2006). OFC and particularly in the le& hemisphere during It is speculated that the di%culty that autis- protracted cocaine abstinence (Volkow et al., 1992). A tic children have in relating to other people may decrease in cerebral blood "ow in both the OFC and re"ect a dysfunction in their mirror neuron system. the DLPFC has been reported in patients with depres- Neurophysiological and brain imaging studies have sion. Decreased blood "ow has been seen in the orbital provided some evidence in favor of this hypothesis prefrontal cortex in phobic patients when presented (Dapretto et al., 2006; Oberman and Ramachandran, with visual phobogenic stimuli (Figure 4.6). 2007). Autistic children appear to have a functioning fusiform face area and mirror neuron system (Calvo- Select bibliography Merino et al., 2005). However, they appear to be sen- Fuster, J.M.!e Prefrontal Cortex (4th ed.). (New 107 sitive to only individuals with whom they are familiar, York: Academic Press, 2008.) Frontal lobe

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Chapter 7 Basal ganglia

Introduction area (mesencephalic nuclei) and the pedunculopontine tegmental nucleus (a midbrain–pontine nucleus; !e basal ganglia (basal nuclei) have been regarded trad- Chapter 10) have been added for the same reason itionally as a motor control system. Lesions in the basal (Figure 7.1). Some authors describe the nigral complex ganglia almost always result in movement disorders. as consisting of the substantia nigra proper and the Recently, these structures have been found to in"uence ventral tegmental area, which lies just medial to it. other emotionally related behaviors. Research on the !e basal ganglia are divided into dorsal and ven- behavioral in"uence of the basal ganglia was prompted tral divisions [Figure 7.2; see Haber and Fudge (1997a) by the repeated observation that emotional and cog- for a detailed review]. In a general sense the dorsal div- nitive dysfunctions frequently accompany movement ision is concerned with motor function whereas the disorders of basal ganglia origin. In some cases, psy- ventral division functions in support of behavior in chiatric manifestations precede the onset of motor the emotional realm. Included as part of the substantia symptoms. With the advent of neuroimaging tech- innominata is the basal nucleus (of Meynert). niques, investigation into the anatomy and metabolic !e basal ganglia receive signals from the cere- physiology of these structures in the awake human has bral cortex and route integrated responses to these revealed intriguing behavioral relationships. Motor activity is controlled by the intricate interaction of three major systems: the cerebral cortex, the cerebellum, and the basal ganglia. !e few milliseconds that intervene between thought and action are crucial for our adjustment in modern society. Increased CC Cl understanding of structures such as the basal ganglia Lateral CN vent. IC that in"uence those few milliseconds is helping unravel Ex Septal Put some of the mysteries of human behavior. It is interest- IC nuclei GPl ing that the main input to the basal ganglia comes from Acc the cerebral cortex and that its output returns (via the Third GPm thalamus) to the frontal cortex (motor, premotor, and vent. SubTh prefrontal cortex). !e frontal cortex, including the SNpc prefrontal areas, thus mediates and plays a signi#cant SNpr Midbrain role in the various functions of the basal ganglia. Originally the basal ganglia were described as a VTA group of cerebral (telencephalic) nuclei. !ese clas- PPTg sical basal ganglia included the caudate nucleus, puta- Pons men, globus pallidus, claustrum, and amygdala. Since the time the classical basal ganglia were described, the Figure 7.1. A schematic representation of the basal ganglia and nearby structures. Clinically signi"cant basal ganglia are shaded. amygdala has been reassigned to the limbic system. Acc, nucleus accumbens; CC, corpus callosum; Cl, claustrum; CN, Little is known of the function of the claustrum, and caudate nucleus (head); IC, internal capsule; Ex, external capsule; it is not considered here. A diencephalic nucleus, the GPl, lateral segment of globus pallidus; GPm, medial segment of globus pallidus; PPTg, pedunculopontine tegmental nucleus; Put, subthalamic nucleus, has been added to the group putamen; SNpc, substantia nigra pars compacta; SNpr, substantia since it is closely tied to the caudate/putamen–globus nigra pars reticulata; SubTh, subthalamic nucleus; VTA, ventral teg- 122 pallidus. !e substantia nigra and ventral tegmental mental nucleus. Dorsal striatopallidum and associated nuclei

Pallidal complex Striatal complex the current situation. !e basal ganglia also operate Paleostriatum Neostriatum in close harmony with the frontal lobes in the acquisition, retention, and expression of cognitive behavior Caudate nucleus Dorsal division Globus pallidus + (Graybiel, 1997). Regions of the caudate nucleus (dor- putamen sal striatum) as well as the ventral striatum seem to be important in cognitive function. Nucleus accumbens Substantia Ventral division + Clinical vignette innominata olfactory tubercle The appearance of the movement abnormality and Figure 7.2. The basal ganglia consist of a dorsal division and a the psychiatric symptoms may be separated by many ventral division. The dorsal division contains the globus pallidus years. Casanova and associates (1995) reported the (paleostriatum) and the caudate nucleus and putamen (neostria- case of a woman who was diagnosed with Sydenham tum). The paleostriatum is continuous ventrally with the substantia chorea at age 5. The abnormal movements abated innominata. The neostriatum is continuous ventrally with the spontaneously after a few months and never returned. nucleus accumbens and the olfactory tubercle. At age 28, she developed auditory and visual hallucinations, delusions of persecution, and antagonistic behavior. Her a#ect was inappropriate, and she had no insight. She did not respond to treatment with typical Frontal Frontal lobe Pa neuroleptics and died at the age of 60. Microscopic rietal Te examination revealed basophilic concretions track- C mporal er ing the vessel walls of the basal ganglia. Moderate eb ra l co Occipital amounts of mineral deposits, including iron and cal- rt ex cium, were seen lying free in the basal ganglia tissue. Thalamus 1 Neostriatum

2 Dorsal striatopallidum and associated nuclei

pallidus Globus Neostriatum (dorsal striatum) !e neostriatum is made up of the putamen and the caudate nucleus (Figure 7.2). !e putamen and caudate are separated anatomically by #bers of the internal Figure 7.3. The generalized pattern of connections involving the basal ganglia form a loop from the cortex to the basal ganglia capsule (Figure 7.1). !e caudate nucleus occupies a and back to the cortex by way of the thalamus. 1, caudate nucleus; position in the "oor of the lateral ventricle dorsolateral 2, putamen. Compare with Figure 7.1 and the direct pathway of to the thalamus. It consists of a head, body, and tail. Figure 7.4. !e body continues caudally, lateral to the thalamus, and tapers gradually to form the tail, which curves ventrally into the temporal lobe to end near the amyg- signals back to the cerebral cortex (Figure 7.3). !e dala. !e putamen lies behind the anterior limb of the cortical information is processed through a series of internal capsule and medial to the external capsule multiple parallel channels as the signals pass through (Figure 9.1). the basal ganglia. !e basic mechanism of operation !e neostriatum is the gateway to the basal ganglia of the basal ganglia is through a process of disinhib- (Figure 7.3). It receives #bers from all portions of the ition. Consequently, damage to the basal ganglia o&en cerebral cortex and from the intralaminar nuclei of the results in the release of behavior, usually in the form of thalamus. !e neurotransmitter from the cortex is glu- uncontrollable motor activity (e.g., the tremor seen in tamate. A$erent #bers from regions of the frontal and Parkinson disease). parietal lobes may have preferential targets within the !e basal ganglia are viewed as part of a planning neostriatum. Fibers from the motor area of the frontal mechanism that drives motor pattern generators. lobe [Brodmann’s area (BA) BA 6) and from the pri- !ey work closely with executive levels of the frontal mary somesthetic cortex (BA 1, BA 2, and BA 3) end 123 lobe to help select the motor response appropriate to predominantly on cells in the putamen. Fibers from Basal ganglia

the dorsolateral prefrontal cortex and from the somesthetic association cortex (BA 5 and BA 7) terminate on cells in the caudate nucleus. !ese di$erences in cortical projection #bers support the concept of di$erences in function between the caudate nucleus and putamen. Neurons located within the neostriatum (interneurons) use acetylcholine as a neurotransmitter. E$erent #bers from both components of the neostriatum are γ-aminobutyric acid (GABA)ergic. GABA is one of the major inhibitory neurotransmitters of the central nervous system. E$erent #bers from the neostriatum terminate in the substantia nigra and in both the lateral and the medial segments of the globus pallidus (Figure 7.3). It has been theorized that the neostriatum is a repository of common motor programs and acts as a comparator that serves gating and screening functions. Figure 7.4. A magnetic resonance image (T1-weighted), coronal It can act in response to external sensory signals or to view, taken two months after the patient’s acute event showed pre- commands from various regions of the cortex. Normally dominant dorsolateral involvement of the right caudate nucleus. (Reprinted with permission from Mendez et al., 1989.) the neostriatum works in conjunction with the frontal cortex to inhibit motor and thought impulses that are inappropriate to the task at hand. For example, it is nor- cingulate area. !is correlation is lost in early stage mal to generate a waving action of the arm in response Parkinson patients (Carbon et al., 2004), however, these to the sight of a person leaving the house. However, it is patients show an increase in cortical activation, suggest- inappropriate to generate the same arm-waving motor ing cortical compensation for loss in striatal function in response to the sight of a spouse leaving the house to sequential learning (Nakamura et al., 2001). put the trash out on the kerb. It is suggested that the Continuous administration of *-amphetamine putamen deals with motor behaviors whereas portions over three days produces degeneration of axons in the of the caudate nucleus deal with thoughts and sensa- neostriatum as well as in the motor frontal cortex of tions (Baxter et al., 1990). rats. !e damage to dopamine axon terminals appears !e caudate nucleus plays a key role in the ser- much like that seen in the neostriatum a&er adminis- ial order of movements and behavior (Aldridge and tration of 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyri- Berridge, 1998). Dopaminergic input from the sub- dine (MPTP) (Ryan et al., 1990). stantia nigra correlates with learning-related activation In the motor sphere, lesions in the rostroventral of the le& dorsolateral prefrontal cortex and anterior caudate nucleus can produce choreoathetosis on the contralateral side. In the behavioral sphere, abulia is Clinical vignette the most common disturbance reported with lesions A 52-year-old hypertensive man developed delirium, of the caudate nucleus. Abulia includes apathy, loss of which slowly cleared leaving a profoundly apathetic initiative, and loss of spontaneous thoughts and emo- state. He remained detached and disinterested and tional responses (Bhatia and Marsden, 1994). would not initiate any activity. When spoken to he A suggestion of reduced caudate nucleus volume would reply in a few words, and he would never initi- in schizophrenic patients has been reported by DeLisi ate a conversation. A computed tomography (CT) scan and associates (1991). More recently a marked (14%) showed a recent infarct in the head of the right caud- reduction was seen in the volume of the caudate nucleus ate, which was clearly delineated on magnetic reson- in neuroleptic-naïve schizophrenic patients (Keshavan ance imaging (MRI) two months later (Figure 7.4). One et al., 1998). !is reduction does not appear to be diag- year following the event he was distractible, irritable, nostically speci#c, since reductions in caudate nucleus and easily frustrated. There was decreased initiative, disengagement from prior activities, and decreased volume have been reported in nonschizophrenic psych- attention to his appearance and weight. He eventually otic patients and in patients with depression (Krishnan lost his job as school principal. et al., 1992). !ese reductions were not accompanied 124 by volume reductions of the putamen. Dorsal striatopallidum and associated nuclei

Striatal binding sites have been reported to be sig- Figure 7.5. A magnetic res- ni#cantly more abundant in cocaine users. !e severity onance image of cocaine use is correlated with the number of binding (T2-weighted) sites (Little et al., 1999). demonstrated increased signal intensity in the Dorsal pallidum (paleostriatum) ventrolateral glo- !e globus pallidus is the dorsal division of the pale- bus pallidus on the right. (Reprinted ostriatum (Figure 7.2) and lies medial to the putamen with permission (Figures 7.1, 7.3, and 9.1). It consists of a lateral segment from Mendez et al., and a medial segment separated by a band of #bers. Cell 2004.) bodies in the lateral segment project #bers that terminate in the medial segment. !e medial segment is a major output nucleus of the basal ganglia. !e putamen and the globus pallidus lie directly adjacent to one another and collectively are called the lentiform nucleus. Depression is a common #nding in diseases that Subthalamic nucleus (subthalamus) a$ect the globus pallidus. A neuroanatomical model of !e subthalamic nucleus lies below the thalamus and is depression a&er pallidal lesions focuses on enhanced contiguous with the substantia nigra at its caudal end. inhibition of the prefrontal cortex (Lauterbach et al., Cell bodies located in the lateral segment of the glo- 1997; Lauterbach, 1999). bus pallidus project to the subthalamus (Figure 7.6). Ames et al. (1994) found that of 46 patients with E$erent #bers from the subthalamus project to the frontal lobe degeneration, 78% demonstrated repeti- medial segment of the globus pallidus and to the sub- tive behaviors ranging from motor stereotypies to com- stantia nigra pars reticulata. !e subthalamus is a key plex obsessive-compulsive behavior. !ese patients component of the indirect pathway through the basal had additional damage in the basal ganglia, caudate, ganglia. Strokes or tumors that a$ect the subthalamus and pallidal regions. It is postulated that the combined produce contralateral hemiballismus. !e a$ected damage to the frontal lobe, caudate nucleus, and globus extremities o&en exhibit a decrease in muscle tone. pallidus may account for the repetitive behavior seen in the frontal lobe degeneration and possibly in idiopathic Substantia nigra obsessive-compulsive disorder (OCD). Anoxic injury, !e substantia nigra is one of the basal ganglia and is such as that produced by carbon monoxide poisoning, located in the midbrain (Figure 7.1). Neuromelanin can result in bilateral infarctions of the globus pallidus found in the substantia nigra pars compacta is a by- and can cause obsessions, compulsions, and a Tourette- product of dopamine metabolism and gives the “nigra” like syndrome (Salloway and Cummings, 1994). its dark appearance as seen at autopsy. !e substantia Clinical vignette nigra consists of two distinct divisions, the pars reticu- A 59-year-old, right-handed man underwent a right lata and pars compacta. pallidotomy for long-standing Parkinson disease. !e substantia nigra pars compacta contains cells Immediately after the pallidotomy, he began demand- that produce dopamine and give rise to #bers that pro- ing sex up to 12–13 times a day. He masturbated fre- ject to the caudate nucleus and to the putamen. !ese quently and propositioned his wife’s female friends #bers make up the nigrostriatal (mesostriatal) tract. for sex. He began hiring strippers and driving around !e axons that make up the nigrostriatal projection town searching for prostitutes. He spent hours on the are believed to interact with dopamine receptor sites, internet looking for sex and buying pornographic where neuroleptics cause movement disorders. !e materials. The patient also had increased irritabil- substantia nigra pars compacta sends dopaminergic ity and energy suggesting hypomanic behavior. The #bers to the neostriatum, involving both the direct variation in placement of the pallidotomy (Figure 7.5), pathway and the indirect pathway. or its extension beyond the appropriate site, could have caused hypersexuality, and possible manic-type Dopaminergic #bers that act on D1 dopamine behavior. The pallidotomy could have a#ected the receptors activate the direct pathway and increase patient’s ventral striatopallidal system. motor activity. In contrast, dopaminergic #bers that 125

act on D2 receptors activate the indirect pathway and Basal ganglia

Direct pathway Indirect pathway Figure 7.6. There are two pathways (activation facilitates thalamus) (activation inhibits thalamus) through the basal ganglia: the direct pathway and the indirect pathway. + + When the body is at rest, the thalamus Cerebral cortex Cerebral cortex is inhibited. When muscular activity is called for, the thalamus is disinhibited. Glutamate Glutamate When activated by the cerebral cortex, + + the direct pathway increases the output of the thalamus. The indirect pathway Neostriatum Neostriatum decreases the output of the thalamus. Substantia nigra identi"ed in this illus- GABA + Enk tration represents only substantia pars reticulata. γ-Aminobutyric acid (GABA) in - the neostriatal direct pathway is accom- GP-Lat panied by the cotransmitter substance P (P). GABA in the neostriatal indirect pathway is accompanied by the cotransmitter GABA + P GABA Normally enkephalin (Enk). GP, globus pallidus; active Med, medial; Lat, lateral. - Subthalamic nucleus

Glutamate - + GP-Med Substantia nigra GP-Med

GABA Normally GABA active - -

Thalamus Thalamus

decrease motor activity. D2 receptors tend to be con- behavior (Redgrave and Gurney, 2006). Overall they centrated in the lateral segment of the globus pallidus. modulate the anticipated reward value of an impending Overall it appears that an increase in the level of dopa- action (Hikosaka et al., 2006; Nakamura and Hikosaka, mine in the neostriatum shi&s the balance toward the 2006). direct pathway and an increase in activity (Figure 7.6). Evidence from mouse studies supports the hypoth- Dopamine is a relatively slow-acting neurotrans- esis that midbrain stem cells result in neurogenesis in mitter, and because of this slow action, some authors the substantia nigra. !e rate of turnover is less than describe it as a neuromodulator. Release of dopamine that of the dentate gyrus (Chapter 11). Lesions result precedes motor activity. Dopamine is inhibitory on in an increase in neuronal replacement (Zhao et al., neurons of the striatum; when released, it decreases the 2003). spontaneous #ring rate of these neurons. !e suppres- !e substantia nigra pars reticulata is an output sion of spontaneous #ring makes individual striatal nucleus of the basal ganglia much like the medial neurons more sensitive to excitatory signals from the segment of the globus pallidus. !is division of the cerebral cortex. In this manner, the release of dopa- substantia nigra gives rise to the nigrothalamic #b- mine primes the striatum for motor activity under the ers. !e substantia nigra pars reticulata and the med- direction of the cerebral cortex. ial segment of the globus pallidus are the two major Dopamine neurons from pars compacta project output nuclei of the basal ganglia. Both project to the mainly to the dorsal and ventral striatum, where they thalamus. are crucial for reward-based motor control. !eir Extrapyramidal side e$ects of antipsychotic drugs

signals provide a reward prediction error (di$erence are due to their ability to block D2 receptor sites. !ese between actual reward value and expected reward side e$ects include dystonia, akathisia, pseudopar- value) for motor behavior to maximize reward (Schultz, kinsonism, and tardive dyskinesia. Akathisia is motor 126 1998). !eir signals also encode novel environmental restlessness and may be mistaken for psychotic rest- events that can produce an immediate change in motor lessness and agitation. Tardive dyskinesia is the worst Connections of the dorsal striatopallidal system of the side e$ects and is associated with long-term 1992; Starkstein and Mayberg, 1993). Depression cor- therapy. It is seen in up to 50% of patients who are relates with lowered metabolism in the head of the receiving long-term treatment and may not disappear caudate and the orbitofrontal cortex (Mayberg et al., even when the drug is discontinued. Although dopa- 1990). mine or dopamine receptors or both may be involved in schizophrenia, Okubo et al. (1997) found no di$e- A 79-year-old man presented to medical attention with rence in the density of D2 receptors in the neostria- an acute personality change. He had suddenly begun tum of drug-free schizophrenic patients and control to act strangely, telling strange stories, and doing subjects. unusual things such as serving his wife tuna in milk. Atrophy of neuron cell bodies in the substantia nigra His neighbors complained that he had stopped car- pars compacta leads to dopamine loss and Parkinson ing for his house and allowed his dogs to urinate and disease. Side e$ects of dopamine replacement therapy defecate throughout the interior. On examination, the (levodopa, +-dopa) include dyskinesias and hallucina- patient was found to be distractible, disinhibited, and tions. Intracerebral transplantation of dopaminergic unconcerned, particularly about his unkempt appear- fetal mesencephalic tissue has few reported psychiatric ance. He was friendly, loquacious, and winked and made sexual innuendoes toward the female hospital sequelae; however, transplantation of adrenal medul- sta#. There were no other neurological "ndings, and lary tissue o&en causes psychosis or delirium (Price computed tomography showed a recent left caudate et al., 1995). Patients with Parkinson disease have been lacunar stroke. shown to exhibit cognitive impairment. Impairments in visuospatial function, executive function, and memory have been described (Savage, 1997). Neuroimaging studies have revealed that metabol- Connections of the dorsal ism in the caudate nuclei and orbitofrontal cortex of depressed patients with Parkinson disease is lower than striatopallidal system (skeletomotor that of nondepressed patients with Parkinson disease circuit) (Mayberg et al., 1990). Le& anterior lesions involving the caudate nucleus have the greatest risk of depres- Parallel circuits sion regardless of the level of disability caused by the Four distinct circuits are recognized involving the stroke (Starkstein et al., 1987). !ese and other results basal ganglia. !ese circuits run parallel to each other, (George et al., 1993) indicate that depression associ- but each serves a separate behavior. !e best known ated with Parkinson disease may involve the caudate circuit is associated with the movement disorders of nucleus (Lafer et al., 1997). basal ganglia disease. It is called the skeletomotor cir- Patients with Parkinson disease are diagnosed cuit and consists of both a direct and an indirect cir- with depression signi#cantly more frequently than cuit (Figure 7.6). !e oculomotor circuit controls the are patients with other disabilities (Ehmann et al., action of the extraocular muscles. Two additional 1990; Menza and Mark, 1994). !e mean frequency circuits are recognized but are less well known. !ese of depression in Parkinsonian patients is 40%, and are the association circuit, which is believed to serve the depression is accompanied by a high rate of anx- cognition, and the limbic circuit, which is thought to iety symptoms (Cummings, 1992; Starkstein and serve emotions. All four circuits have certain elements Mayberg, 1993). Parkinson patients with depression in common. First, each receives input from many areas show signi#cant cell loss in the ventral tegmental area of the cortex. Second, each sends signals through the (Torack and Morris, 1988). !is area lies just medial basal ganglia, but the speci#c regions used by each of to the substantia nigra and supplies dopamine to the the circuits may di$er. !ird, all four circuits relay in limbic system and cortex (see later in text). It has been the thalamus before sending signals back to the cortex. suggested that depression in Parkinson disease is seen Fourth, all four circuits send signals back to the frontal more commonly in patients with more prominent lobe, but the exact portion of the frontal lobe targeted dopamine-responsive signs such as gait disturbance by each circuit di$ers. Although each of the circuits is and rigidity. Parkinson patients with le& brain dys- separate, it is thought that each of their actions is in"u- function have a higher incidence of depression than enced by actions of the others by way of interneurons do patients with right brain dysfunction (Cummings, located within the basal ganglia. !ree of the circuits 127 Basal ganglia

are associated with the dorsal striatopallidal system. Indirect pathway !e fourth, the limbic circuit, is associated with the !e components of the indirect pathway are similar to ventral striatopallidal system. those of the direct pathway but with the addition of a detour through the lateral segment of the globus pal- Skeletomotor circuit lidus and the subthalamic nucleus (Figure 7.6). In the case of the indirect pathway, the ventrolateral nucleus of Direct pathway the thalamus is inhibited by the activity of GABAergic !e connections of the classical basal ganglia are rela- neurons of the medial segment of the globus palli- tively well known even though their exact mode of dus –just the same as with the direct pathway. However, operation remains unclear (Graybiel, 1995). !e dir- these GABAergic neurons are encouraged to #re more ect pathway is a loop that has its origin in the cerebral rapidly only when the normally active GABAergic neu- cortex (Figures 7.3 and 7.6). !e pathway loops down rons of the lateral segment of the globus pallidus are into the basal ganglia and then returns to the cortex inhibited. by way of the thalamus. Fibers from many areas of the !e overall e$ect of activation of the direct path- cortex project into the neostriatum (caudate nucleus way is to increase cortical activity. !e overall e$ect of and putamen), e$ectively funneling many #bers onto activation of the indirect pathway is to decrease cor- relatively few cells. Fibers from the neostriatum course tical activity. During a normal resting state the two to the medial segment of the globus pallidus. E$erents pathways are in balance with a slight edge given to the from the globus pallidus terminate in the anterior indirect pathway. Note that the neostriatal GABAergic division of the ventrolateral nucleus of the thalamus, neurons serving the two pathways each carry a di$er- which projects back to the frontal lobe. Cortical neu- ent cotransmitter (Figure 7.6). rons that receive input from the basal ganglia seem A number of parallel circuits, probably thou- to have common properties. !ey receive signi#cant sands, run from the prefrontal cortex to the basal gan- sensory input, they are commonly involved in pre- glia and then to the thalamus and back to the cortex. movement activities, and they respond to stimuli that Each of these circuits contains a direct and an indir- have motivational signi#cance. Lesions in these cor- ect pathway. !e striatum plays a role in supporting tical areas result in attentional de#cits and defective movement and thought and is active in procedural movements. learning. !e direct (basic) pathway functions on the prin- ciple of disinhibition. !e cells of the ventrolateral Oculomotor circuit thalamus project to the supplementary motor cortex !e oculomotor circuit is involved with the control of and facilitate motor activity. !ese cells would #re con- eye movements and arises from more restricted areas stantly if it were not for the fact that the output cells of of the cortex than the other circuits. !e input to the the medial segment of the globus pallidus are tonically oculomotor circuit arises from cell bodies located in active. !ese tonically active cells contain GABA, which the frontal eye #eld (see “Frontal eye #eld,” Chapter 6, inhibits activity in the ventrolateral nucleus of the thal- page 89) and the posterior parietal cortex. !e oculo- amus. E$erent # bers from the cortex contain gluta- motor circuit targets oculomotor control areas in the mate, an excitatory neurotransmitter. When a signal frontal cortex. arrives in the neostriatum from the cortex requesting a particular motor response, glutamate causes selected Association circuit cells in the neostriatum to #re. !e cells of the neos- !e association circuit receives input from many triatum contain GABA, which inhibits the tonically areas of the cortex. It is hypothesized that this cir- active GABA cells of the medial segment of the globus cuit is responsible for relating motor activity to tar- pallidus. !e action of the neostriatal GABA inhibits gets in the extrapersonal space and may play a special the action of the GABAergic cells of the globus palli- role in eye–hand coordination. !e association cir- dus, which normally inhibit the action of the thalamus. cuit projects to the frontal association area. !is By inhibiting the action of inhibitory globus pallidus area, especially the dorsolateral prefrontal cortex, neurons, the neurons of the ventrolateral nucleus of the is important in organizing behavior in space and in thalamus are released (disinhibited); the thalamus #res 128 time (see “Dorsolateral prefrontal cortex,” Chapter 6, and activates motor regions of the frontal lobe. page 94). Ventral striatopallidum and associated nuclei

Ventral striatopallidum and may facilitate autonomic and goal-directed behavior (Alheid and Heimer, 1996). associated nuclei !e nucleus accumbens has been described as a limbic–motor interface. It is in a position to bring together Ventral striatum (limbic striatum) input from limbic “motivational” structures, and its !e ventral striatum is also known as the limbic stri- output goes to structures associated with motor proc- atum and includes a number of structures found in the esses, including the globus pallidus, substantia nigra, basal forebrain, including the nucleus accumbens, the and pedunculopontine tegmental nucleus (Winn et al., olfactory tubercle, and the ventral extensions of the 1997). caudate nucleus and putamen. Much of the ventral pal- !e nucleus accumbens and dopamine have been lidum appears to be a ventral extension of the globus closely associated with the rewarding e$ects of carbo- pallidus and includes the substantia innominata and hydrates as well as abusive drugs including alcohol, basal nucleus (of Meynert). cocaine, amphetamine, and morphine (Blum et al., 1996a). !e nucleus accumbens is also involved with Nucleus accumbens both withdrawal e$ects related to these drugs and !e nucleus accumbens is a small nucleus near the mid- e$ects of antipsychotic drugs (Alheid and Heimer, line just rostral to the diencephalon. It lies at the base of 1996). One model of schizophrenia proposes that an the septum pellucidum. !e nucleus accumbens is con- increase in the quantity of dopamine released in the tinuous above with the caudate/putamen and extends nucleus accumbens by the mesolimbic pathway from ventrally as the olfactory tubercle (Figure 7.1). Two the ventral tegmental area is responsible for positive major subdivisions of the nucleus are recognized: the psychotic symptoms (Gray et al., 1991; Gray, 1998). core and the shell. !e core represents a ventromedial Another model of the pathophysiology of schizophre- extension of the caudate/putamen. !ere is no distin- nia suggests that abnormalities in the projection from guishable border between the caudate/putamen and the the hippocampus to the nucleus accumbens are respon- core. !e shell of the nucleus accumbens surrounds the sible for the psychosis and thought disorganization of core on its medial and ventral borders. !e shell extends schizophrenia (Csernansky and Bardgett, 1998). caudomedially to blend with the central division of the extended amygdala, providing evidence of the close Ventral pallidum relationship between the nucleus accumbens and the Several nuclei within the substantia innominata along limbic system. !e bed nucleus of the stria terminalis is with the lateral preoptic area make up the ventral pal- part of the extended amygdala and is anatomically simi- lidum. !e ventral pallidum is continuous with the glo- lar to the shell of nucleus accumbens (Carboni et al., bus pallidus (dorsal pallidum), which lies above it. 2000). Distinctive cell clusters throughout the nucleus accumbens suggest that di$erent regions of the nucleus Basal nucleus (of Meynert) may operate selectively under di$erent functional con- !e basal nucleus makes up a large portion of the ditions (deOlmos and Heimer, 1999). substantia innominata. !e majority of acetylcho- Projections from the prefrontal cortex, from the line found in the brain arises from the neurons of midline nuclei of the thalamus, and from the hippo- the basal nucleus. It projects #bers to the neocortex, campus and basal amygdala terminate in both the core hippocampus, amygdala, thalamus, and brainstem. and the shell of the nucleus accumbens. Projections It receives #bers from the amygdala, hypothalamus from the shell terminate in the nucleus basalis (of (Chapter 8), pedunculopontine nucleus, and midbrain Meynert), which is the source of cholinergic #bers to (Chapter 10). the cortex. !ese connections through the nucleus !e basal nucleus is believed to be important in basalis may allow the shell of the nucleus accumbens integrating subcortical functions. Drugs such as sco- to in"uence arousal, attention, and cognitive func- polamine that block acetylcholine can cause confusion tion (Heimer et al., 1997). !e shell is di$erent from and memory disorders. Loss of the acetylcholinergic the core in that it has #bers that project directly to the neurons of the basal nucleus has been described in central nucleus of the extended amygdala and to the Alzheimer disease (Price et al., 1982). However, acetyl- lateral hypothalamus. !e connections of the shell choline disappears from the axon terminals before it to the amygdala suggest that the nucleus accumbens is reduced in the cell bodies in the basal nucleus. !is 129 Basal ganglia

suggests that nerve cell loss in the basal nucleus is sec- both from the ventral tegmental area and from adja- ondary to dying back of the axons (Sofroniew et al., cent areas of the midbrain. !e adjacent areas include 1983; Herholz et al., 2004). widespread regions of the substantia nigra and the retrorubral #eld. A few #bers even originate from within Ventral tegmental area the parabrachial nucleus. Although this is described !e ventral tegmental area has recently been included as a dopaminergic system, a surprising number of the as one of the basal ganglia (Figures 7.1, 10.3 and 10.4). #bers are not from dopamine-producing neurons. It It is located in the midbrain and appears as a ventro- appears that the mesocortical projections to the dorsal medial extension of the substantia nigra pars com- prefrontal cortex, to the ventromedial prefrontal cor- pacta. In addition to their close proximity, the ventral tex, and to the anterior cingulate cortex are served by tegmental area and substantia nigra pars compacta midbrain neurons from three di$erent regions of the serve similar functions and they have a similar histo- midbrain (Williams and Goldman-Rakic, 1998). chemical makeup. For this reason they have been iden- !e ventral tegmental area dopaminergic system ti#ed as the two components of the “nigral complex” is postulated to be involved in reward associated with (Ma, 1997). Like substantia nigra pars compacta, the newly learned behaviors in contrast to the mainten- ventral tegmental area contains a large population of ance of previously learned behaviors (Schultz et al., dopaminergic neurons. 1995). !is system responds to the novelty of an unex- Similarity between cells found in the substantia pected stimulus, to primary rewards, and to the con- nigra and the ventral tegmental area has suggested the ditioned stimulus associated with that reward (Haber existence of a dorsal tier and a ventral tier of dopamin- and Fudge, 1997a). Systemic injection of cocaine in rats ergic neurons. !e dorsal tier includes a band of neu- has been shown to produce an increase in extracellular rons stretching across the dorsal substantia nigra pars glutamate in the ventral tegmental area, and this may compacta and contiguous ventral tegmental area. !e underlie behavioral sensitization to cocaine (Kalivas ventral tier consists of cells of the ventral substantia and Du$y, 1998). nigra pars compacta and a corresponding ventral group Bogerts et al. (1983) found that the size of neu- of ventral tegmental area neurons. Evidence suggests romelanin-containing neurons in the ventral tegmen- that the dorsal tier neurons are tightly linked with the tal area was decreased and the volume of the substantia limbic system. !e ventral tier dopaminergic neurons nigra area was reduced in the brains of six schizo- are in"uenced by limbic regions but are more closely phrenic patients. !ere was no change in the number linked with areas of the striatum that are important in of neurons or glia cells. An increase in activity in the sensorimotor control (Haber and Fudge, 1997b). mesolimbic system has been reported in schizophre- Descending projections to the ventral tegmental nia (Kapur et al., 2005). !is is accompanied by a area include indirect connections from the hippo- decrease in activity in the prefrontal area. It has been campus by way of septal nuclei and the hypothalamus. suggested that the positive symptoms of schizophrenia !ese close connections with limbic system structures may re"ect mesolimbic hyperactivity, and the nega- led Nauta (1958) to include the ventral tegmental area tive symptoms may re"ect mesocortical hypoactivity as part of the “midbrain limbic area.” !e ventral teg- (Weinberger, 1987). mental area projects through the medial forebrain bundle to limbic areas (mesolimbic system) and to Pedunculopontine tegmental nucleus cortical areas (mesocortical system). Targets of the !e pedunculopontine tegmental nucleus extends dopaminergic #bers from the ventral tegmental area caudally from the substantia nigra just medial to the include the dorsolateral and medial prefrontal cortex, lateral lemniscus (Figures 7.1 and 10.3). It is usually the anterior cingulate gyrus (mesocortical system) and considered as one of the reticular formation nuclei nucleus accumbens, the hippocampus, and the amyg- (Chapter 10); however, its connections with the basal dala (mesolimbic system). !e midline and medial ganglia and importance in motor control have moti- thalamic nuclei are considered part of the limbic thal- vated some authors to include it among the basal gan- amus and are also targets of ascending dopaminergic glia (Winn et al., 1997). Like the nucleus basalis, the #bers (Chapter 9). pedunculopontine tegmental nucleus is an important !ere is evidence that many of the #bers that make source of acetylcholine; however, it also contains non- 130 up the mesocortical projection arise from neurons cholinergic neurons, much the same as the substantia Connections of the ventral striatopallidal system nigra contains dopaminergic and nondopaminergic 7.3 and 7.8). Limbic #bers to the ventral striatopallidal neurons. Fibers from the pedunculopontine nucleus system arise from the hippocampus and the amygdala project to the frontal cortex, septum, amygdala, glo- (Burns et al., 1996). Fibers from many cortical areas bus pallidus, substantia nigra, hypothalamus, and and from several brainstem nuclei, including the raphe thalamus. !e largest and most studied are those nuclei and locus ceruleus, funnel together and converge projections to the thalamus. !e pedunculopontine on the ventral striatum. A large contingent of #bers is tegmental nucleus receives #bers from the dorsal stri- from the ventral tegmental area. !e bulk of the e$er- atum (putamen, globus pallidus, substantia nigra pars ent #bers from the nucleus accumbens project to the reticulata, subthalamic nucleus), the ventral striatum ventral pallidum. !e ventral pallidum projects back (nucleus accumbens), amygdala, and brainstem reticu- to both cortical and brainstem targets. !e primary lar formation (raphe nuclei and locus ceruleus) (Jones, cortical target is the prefrontal cortex directly and via 1990; Wainer and Mesulam, 1990). the mediodorsal nucleus of the thalamus indirectly. Limbic connections of the pedunculopontine Brainstem targets include the pedunculopontine teg- nucleus (septum, amygdala, ventral pallidum, pre- mental nucleus. Evidence indicates that the ventral frontal cortex), along with behavioral studies, striatal system is involved in emotional behavior and underscore its importance in working memory and with motivational aspects of motor behavior (Graybiel, cognition. !e pedunculopontine nucleus plays a role 1995). in the regulation of the basal nucleus (Decker and Serotonin is much less studied than dopamine but McGaugh, 1991). Connections with other basal gan- also plays a role in the function of the basal ganglia glia nuclei suggest its importance in motor activity. It Cortical Figure 7.7. The is known to be important in locomotion and possibly association general pattern may be involved in the pill-rolling tremor of Parkinson areas of the limbic loop disease. It appears to be critical in the reward e$ects of including ventral striatal and ventral opiates and other stimulants and plays a role in atten- pallidal nuclei. Compare with tion and arousal (Steckler et al., 1994). !e peduncu- Ventral striatum lopontine tegmental nucleus like nucleus accumbens Figure 7.9. is considered a limbic–motor interface and may be involved with response switching and perseveration. It is speculated to be in a position to respond to signals from the ventral striatum in order to inhibit an Ventral pallidum ongoing response maintained by the dorsal striatum (Winn et al., 1997). Neuron cell loss in the pedunculopontine tegmental nucleus has been reported in Parkinson disease Mediodorsal (Jellinger, 1991), Alzheimer disease (Mufson et al., thalamic nucleus 1988), and progressive supranuclear palsy (Jellinger, 1988). Impairment of attentional processes is a common denominator of all of these disorders. Anterior cingulate cortex Orbitofrontal cortex Connections of the ventral striatopallidal system (limbic circuit) In addition to the other circuits of the basal ganglia, Direct pathway the ventral striatopallidal system forms yet another cir- More activity cuit called the limbic circuit (Figure 7.7). It is the least DA known of the circuits. It is believed to provide an interface between the limbic system and the motor systems. Less activity From what is known of the connections of the ventral Indirect pathway striatopallidal system, there appear to be many similar- Figure 7.8. The indirect system is the normally active pathway. ities between the general pattern of connectivity of this The action of an increase in the level of dopamine is to facilitate 131 system and the dorsal striatopallidal system (Figures motor activity. DA, dopamine. Basal ganglia

and is found throughout the caudate nucleus and (Leckman et al., 1997). A response bias exists toward putamen (Pazos and Palacios, 1985; Pazos et al., stimuli related to socioterritorial concerns about dan- 1985). Clomipramine, which acts on the serotoner- ger, violence, hygiene, order, and sex. !ese behaviors gic system, has been useful in treating symptoms of are mediated by orbitofrontal-subcortical circuits. OCD. It has been questioned whether serotonin may In healthy individuals socioterritorial concerns and play a role in this disorder (Insel and Winslow, 1992). responses to stimuli perceived as dangerous are processed through the orbitofrontal-caudate circuit and Deep brain stimulation inhibited when appropriate by the indirect pathway. Deep brain stimulation (DBS) involves the placement Patients with OCD are particularly sensitive to soci- of an electrode array in a speci#c part of the brain. !e oterritorial stimuli and related concerns of danger, electrode array is connected to an implanted pulse gen- violence, hygiene, order, etc., and have an imbalance erator (IPG) located subcutaneously usually just infer- in the direct/indirect pathway that prevents them ior to the clavicle. !e array is placed in the ventral from inhibiting behaviors related to these stimuli and intermediate (ventrointermedial) nucleus of the thal- switching to alternative behaviors (Saxena et al., 1998). amus for essential familial tremor. For dystonia and the Luxenberg and associates (1988) and Robinson and rigidity, bradykinesia/akinesia and tremor associated colleagues (1995) reported atrophy of the caudate in with Parkinson disease, the globus pallidus or subtha- patients with OCD. An increase in metabolism over lamic nucleus is targeted. !e ventral posterior medial control subjects has been reported in the whole cere- and ventral posterior lateral thalamic nuclei have been bral hemispheres, the orbital gyri, and the heads of stimulated for the control of pain. Stimulation of the the caudate nuclei in patients with OCD (Figure 12.7; subgenual region of the anterior cingulate gyrus (BA 25) Baxter, 1992; Saxena et al., 1998). It is theorized that has been e$ective in some cases of depression (Lozano small, restricted caudate lesions may be responsible et al., 2008; Mayberg et al., 2005). (See also lateral for OCD, whereas larger lesions of the caudate nuclei habenular nucleus in Chapter 8). A major advantage of result in more global symptoms such as those seen in DBS is that it changes brain activity in a controlled man- Huntington disease (Baxter et al., 1990). Baxter and ner and its e$ects are reversible (Krauss, 2002). coworkers (1990) have proposed that chronic motor !e mechanism of action of DBS is unclear and the tics are due to small lesions in the putamen. Baxter cellular pathway(s) are not fully understood. DBS has (1992) theorized that a de#cit in caudate function leads been shown to be associated with a marked increase in to inadequate repression (i.e., #ltering) of input from the release of adenosine triphosphate (ATP) by nearby the orbital cortex (“worry”). !is de#cit allows input astrocytes. ATP release results in accumulation of its from other cortical areas to continue on to the globus catabolic product adenosine. Activation of the adeno- pallidus, where it frees the thalamus to drive the cor- sine A1 receptor in mice depresses excitatory trans- tex to carry out a behavior (Figure 7.9). For example, mission in the thalamus and reduces both tremor- and sensations that signal dirty hands may normally match DBS-induced side e$ects. In addition intrathalamic with an appropriate response: hand washing. However, infusion of A1 receptor agonists in mice directly in the case of OCD, the screening capability of the reduces tremor. !ese #ndings implicate adenosine neostriatum is decreased, and the slightest sensory mechanisms in the production of tremor (Latini and input from the hands may trigger hand washing. In Pedata, 2001; Bekar et al., 2008). this scenario even sensory input unrelated to the hands Neuropsychiatric side e$ects have been reported, may cross over and produce hand washing. Motivation including cognitive dysfunction, apathy, depression, and the initiation of the activity may originate in the hallucinations, compulsive gambling, and hypersexu- anterior cingulate gyrus (Chapter 12). According to ality (Burn and Troster, 2004; Smeding et al., 2006). Houck and Wise (1995) the basal ganglia make use of old rules when presented with familiar environmental Behavioral considerations and contextual stimuli. It is up to the frontal cortex to alter a learned response pattern when old rules need to Obsessive-compulsive disorder (OCD) be rejected and new rules applied (Rapoport and Fiske, Obsessive-compulsive disorder is a multidimensional 1998). !e presence of dopamine in the frontal cortex disorder that includes obsessions, checking, symmetry may be important both in activating old rules and in 132 and ordering, cleanliness and washing, and hoarding learning new rules (Houck and Wise, 1995). Behavioral considerations

Caudate nucleus volume in both children and adults with Tourette, but + there is no correlation between size and severity of symptoms (Peterson et al., 2003). It is speculated that – the dysfunction of the caudate seen in patients with Tourette syndrome is responsible for the compulsive Globus pallidus component of tics (Wolf et al., 1996). It is suggested Other brain that patients with Tourette syndrome exhibit super- regions sensitivity of the D2 dopamine receptor or have an – excess of dopamine in the caudate nucleus (Singer, Thalamus 1997). !e similarity in caudate nucleus abnormal- + ities seen both in patients with OCD and in those with Tourette, along with the fact that OCD is frequently + a comorbid condition with Tourette syndrome, sug- Orbitofrontal cortex gests that the caudate may be involved in both conditions. !ese two disorders may represent overlapping Figure 7.9. It is proposed that overactivity in the orbital prefrontal neurobehavioral conditions, although OCD involves, cortex (“worry”) drives the caudate nucleus. The resulting increase in addition, the orbitofrontal and cingulate areas in the output of the caudate nucleus reduces inhibition on the thalamus. The thalamus becomes overactive and further drives the (Wolf et al., 1996). orbital prefrontal cortex. In the model, the orbital prefrontal cortex !e right putamen is larger than the le& in con- also drives the thalamus directly. Successful treatment may reduce trol subjects. Singer et al. (1993) reported that 13 of the input to the caudate nucleus and/or it may reduce the facili- tation of the thalamus by direct input from the prefrontal orbital 37 Tourette syndrome patients demonstrated reverse cortex. (After Baxter, 1992.) asymmetry, with the right larger than the le& putamen. !e abnormal anatomical asymmetry is paralleled by E$ective therapy allows the patient to enhance abnormal asymmetry in behavioral tests performed by the #ltering e$ect of the caudate to limit behavioral these patients (Yank et al., 1994). responses from signals from the orbital cortex. Positron emission tomography (PET) scans of OCD patients Hyperkinetic movement disorders revealed that the metabolic rates in the basal ganglia Chorea and athetosis are common hyperkinetic move- and in the orbital cortex are higher in OCD patients ment disorders. Choreoathetoid movements are typical than in controls (Baxter et al., 1990). !e increase in of Huntington disease. !ese movement disorders cor- metabolism may re"ect attempts by the patient to relate with loss of striatal neurons. Ballism is seen rarely control the disorder. Similar changes seen in caudate but is usually as a result of an infarction of the subtha- metabolism following successful therapy re"ect the lamic nucleus. !e violent movements of ballism may role played by the caudate in learning new habits and represent extreme choreoathetoid movements. Tics skills (Schwartz et al., 1996). are also a form of hyperkinetic movement disorder. Stereotaxic lesions of the bifrontal pathways !e forced vocalizations of Tourette syndrome may located beneath and in front of the head of the caud- represent a form of complex tic. Hyperkinetic move- ate nucleus (subcaudate tractotomy or capsulotomy; ments may be suppressed with D2 receptor antagonists. Chapter 12) have been used as a surgical treatment of Cholinergic agonists are sometimes used for control of intractable a$ective disorder (Kartsounis et al., 1991). chorea in Huntington disease. Capsulotomy has been found to bene#t intractable cases of obsessive-compulsive disorder. !e e$ect is Hypokinetic movement disorders believed to result from interrupting the connections Akinesia, bradykinesia, and rigidity are examples of between the caudate and frontal and anterior cingulate hypokinesis, which are seen in Parkinson disease. cortex (Rapoport, 1991). A loss of dopamine-producing cells in the substantia nigra pars compacta occurs in Parkinson disease. Tourette syndrome Tardive dyskinesia may appear a&er long-term treat- Neuroimaging studies provide evidence that the ment with antipsychotic agents (phenothiazines and head of the caudate is involved in Tourette syndrome the butyrophenones). !ese drugs appear to block 133 (Hyde et al., 1995). !e caudate nucleus is smaller in dopaminergic transmission and may eventually cause Basal ganglia

dopaminergic receptors in the basal ganglia to become (Folstein et al., 1990; McHugh, 1990; Folstein et al., hypersensitive to dopamine. 1991). Mayberg (1993) found that stroke patients iden- Pallidotomy and subthalamic DBS for Parkinson ti#ed as having mood disorders and unilateral lesions disease have demonstrated positive e$ects for motor restricted to the head of the caudate, with or without function. Decreased semantic verbal "uency has been extension into the internal capsule, exhibited depres- reported but unaccompanied by cognitive defects sion if the lesion was on the le& and mania if it was on (Gironell et al., 2003). Hypersexuality (Roane et al., the right. 2002; Mendez et al., 2004), transient manic behav- !ere is some evidence that the basal ganglia may be ior (Okun et al., 2003), and confusion have also been involved in schizophrenia (Buchsbaum, 1990; Liddle reported (Higuchi and Iacono, 2003; Hua et al., 2003). et al., 1992). Catatonia in schizophrenia may be related to cell loss and gliosis found in the globus pallidus Huntington disease (Falkai and Bogerts, 1993). In contrast other investiga- Atrophy of the caudate has been reported in patients tors have found an increase in size in the striatum and with Huntington disease (Luxenberg et al., 1988). Cell pallidum (Heckers et al., 1991), although more recent loss is seen #rst in the dorsomedial caudate nucleus. #ndings suggest that the increased size is due to the use !e greatest neuron loss is in the caudate, then the of neuroleptics (Heckers, 1998). putamen, with more subtle cell loss in the ventral teg- Wilson disease is a neurodegenerative disorder that mental area (Peyser and Folstein, 1993). Both motor results from an abnormality in copper metabolism and disturbances and mood disorder seen in Huntington manifests mainly through a movement disorder, psy- disease correlate with cell loss in the caudate nucleus. chiatric symptoms, and liver disease. !e abnormal Depression, seen in 41% of 186 Huntington patients movements include rigidity, coarse proximal tremor, in the study by Folstein et al. (1990), preceded other and choreoathetosis. Patients may have a facial expres- symptoms by an average of #ve years. In many cases sion of silliness or indi$erence, but their emotions patients experience episodes of depression before they are usually not a$ected. !e disorder may start at an are even aware that they are at risk for Huntington dis- early age (7–15 years) or at a late age (a&er 30 years). ease (Folstein et al., 1990). Psychiatric symptoms include impulsiveness, irritability, and a$ective changes. !e late form has been more Other behavioral considerations closely associated with psychosis, usually of a paranoid Trichotillomania (repetitive hair-pulling) has been type. In approximately 20% of patients, psychiatric referred to as compulsive and contains elements simi- symptoms precede other signs or symptoms of the dis- lar to the compulsions of OCD (Swedo and Leonard, ease (Lohr and Wisniewski, 1987).

1992). In studies, patients with trichotillomania exhibit !e A1 allele of the D2 dopamine receptor gene is signi#cantly smaller le& putamen volume (13.2%) than dysfunctional in some cases of alcoholism. Variants

control subjects. !ese di$erences more closely paral- of the D2 dopamine receptor gene have been corre- lel those seen in Tourette syndrome than those seen in lated with crack/cocaine dependency, obesity, carbo- OCD (O’Sullivan et al., 1997). hydrate binge eating, attention-de#cit hyperactivity Pearlson et al. (1995) reported that the density of disorder, Tourette syndrome, pathological gambling,

D2-like dopamine receptors is increased in the caudate and smoking. !e association of these various behav- nucleus of patients with bipolar disorder and psychotic ioral disorders with a single genetic anomaly supports symptoms compared with normal control subjects and the concept of a “reward de#ciency syndrome” (Blum with nonpsychotic patients with bipolar disorder. It has et al., 1996a, b). been suggested that changes in the dopamine system Lesions in the striatum on the dominant side can are secondary to primary abnormalities in the seroton- cause atypical aphasias. !is indicates a possible role of ergic and norepinephrinergic systems. the basal ganglia in language. Neurological conditions Peyser and Folstein (1993) propose that when the that commonly accompany psychotic episodes suggest caudate is damaged or caudate function is disrupted by basal ganglia involvement. lesions elsewhere in the brain, depression is o&en pro- In summary, evidence from several di$erent duced. !is #ts with the “subcortical triad” of depres- sources indicates that the basal ganglia may be partially sion, movement disorder, and dementia that o&en result involved in the regulation of attentional and cognitive 134 from damage to the caudate and nearby structures functions by correlating and integrating motor and References sensory information. Both operate by way of a simple obsessive-compulsive disorder: Seeking the loop from the cortex down into the basal ganglia and mediating neuroanatomy. In: M.A.Jenike, L.Baer, back to the cortex (Figure 7.3). !e motor loops are and W.E. Minichiello (eds.) Obsessive-Compulsive Disorders: !eory and Management. 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Chapter Diencephalon: Hypothalamus 8 and epithalamus

Hypothalamus Anatomy and behavioral considerations !e hypothalamus is the region of the mammalian !e hypothalamus lies on either side of the walls of brain that is most important in the coordination of the third ventricle below the level of the hypothal- behaviors essential for the maintenance and con- amic sulcus (Figures 8.2, 9.2, 9.3, and 14.6). It is tinuation of the species. Although the hypothal- bounded in front (anteriorly) by the lamina termi- amus occupies only about 0.15% of the volume of the nalis and optic chiasm, laterally by the optic tracts, human brain, it plays a major role in the regulation and behind by the mammillary bodies. Some hypo- and release of hormones from the pituitary gland, thalamic nuclei are continuous across the "oor of the maintenance of body temperature, and organization third ventricle. On the bottom (ventral surface) of of goal-seeking behaviors such as feeding, drinking, the hypothalamus is the infundibulum, to which the mating, and aggression. It is the primary center for the pituitary (hypophysis) is attached. !e median emi- control of autonomic function. It also is the region of nence forms the "oor of the third ventricle and is the the brain that is essential for behavioral adjustments staging area from which the hypothalamic releasing to changes in the internal or external environment factors leave to enter the hypothalamohypophyseal (Figure 8.1). !e hypothalamus is a very old struc- portal system (Figure 8.2). !e borders of the indi- ture with striking similarity between humans and vidual hypothalamic nuclei are o&en indistinct and lower animals. It is made up of a number of nuclei and the location of some borders varies from author to scattered cell groups. Some hypothalamic cell groups author. Some hypothalamic subdivisions are referred control speci#c functions (e.g., blood pressure, heart to as areas or zones because of the di%culty in estab- rate, etc.) through the coordinated action of short int- lishing distinct borders. rahypothalamic connections. Other nuclei operate by Hamann et al. (2004) found that the hypothalamus projections to structures outside the con#nes of the and amygdala showed greater activity bilaterally in hypothalamus. men than women when viewing identical sexual stimuli even when the females reported greater arousal. !e organization of the hypothalamus can be sim- External and internal stimuli pli#ed by viewing it as made up of one area and three d. id. Limbic zones (Figure 8.3). !e preoptic area makes up the system anterior (rostral) portion of the hypothalamus. Its major components are the medial and lateral preoptic nuclei (Figure 8.4). !e thin periventricular zone lies HYPOTHALAMUS just inside the walls of the third ventricle and makes up the most medial of the three zones. !e medial Regulation zone contains the majority of the hypothalamic nuclei Autonomic Somatic of behavior behavior (Figure 8.5). !e separation between the medial and hormones lateral zones is formed by the #bers of the fornix. !e Figure 8.1. The hypothalamus is positioned between incoming lateral zone contains incoming axons from limbic and sensory signals and the body’s response to those signals. Some other structures. !e lateral zone also contains the sensory signals arrive directly (d.) from the sensory receptor. Other sensory signals are processed through higher centers and are nerve cell bodies that give rise to many of the axons that considered indirect (id.). Output may involve only internal controls leave the hypothalamus. !e medial forebrain bundle 140 (e.g., change in heart rate) or may be more complex (e.g., eating is a di$use #ber system that passes through the lateral behavior). Hypothalamus

Hypothalamic nuclei: Figure 8.2. A three-dimensional view 1. Preoptic of the medial zone of the hypothal- 13 2. Suprachiasmatic amus showing the principal nuclei and 3. Paraventricular surrounding structures. (Reproduced 23 4. Supraoptic by permission from Young, P.A., and 5. Anterior Young, P.H. 1997. Basic Clinical Anatomy. 6. Dorsomedial 3 14 Baltimore: Williams & Wilkins.) 7. Ventromedial 1 6 9 8. Arcuate 22 9. Posterior 15 5 7 10. Mamillary 10 2 4 Tracts: 8 11. Hypothalamohypophyseal 21 12. Tuberohypophyseal 13. Column of fornix 12 Superior 14. Mammillothalamic Ant. Post. Other structures: 24 15. Mammillotegmental tr. 19 Inferior 16. Anterior pituitary 17. Posterior pituitary 18. Hypophyseal portal system 11 19 18 17 19. Hypophyseal arteries 20. Hypophyseal veins 21. Optic chiasm 22. Lamina terminalis 20 16 23. Anterior commissure 24. Infundibulum 20

Lamina terminalis Figure 8.2). Neurotransmitters (vasopressin and oxytocin) from these neurons are released directly into capillaries located in the posterior lobe of the pituitary. Preoptic area Preoptic area !e anterior lobe is controlled indirectly via “releasing substances.” Neurotransmitters (releasing substances) from many of the hypothalamic nuclei enter into the hypophyseal portal system to be passed downstream Lateral Medial Medial Lateral P P zone zone zone zone to the anterior lobe of the pituitary, where they control the release of many anterior pituitary lobe hormones III (Table 8.1). !ere are both monosynaptic (direct) and pol- MB MB ysynaptic (indirect) inputs to the hypothalamus (Figure 8.1). Both inputs re"ect sensory signals from internal (visceral) and external (somatosensory) Figure 8.3. The hypothalamus viewed from above consists of domains (Figure 8.6). Several monosynaptic pathways the preoptic area in front and three parallel zones behind. From the arise from within the dorsal horn of the spinal cord cavity of the third ventricle (III) moving laterally are the periventricu- and from within the trigeminal spinal nucleus. !ese lar zone (P), the medial zone, and the lateral zone. The medial zone is further subdivided and includes the mammillary bodies (MB). The #bers project directly to many areas of the hypothal- optic nerve, chiasm, and optic tract are shown by the dotted lines. amus. !e monosynaptic pathways provide a route for re"ex autonomic and endocrine behaviors (Katter zone interconnecting structures above and below with et al., 1991). !ese behaviors include heart rate change the hypothalamus. in response to pain, shivering in response to cold, milk !e pituitary is made up of the posterior lobe letdown in response to suckling, and so forth. and the anterior lobe (nos. 17 and 16, respectively, Polysynaptic pathways receive sensory signals Figure 8.2). !e posterior lobe of the pituitary is that are relayed from spinal cord and brainstem auto- innervated directly by neurons whose cell bodies lie nomic nuclei (e.g., solitary and parabrachial nuclei). in the hypothalamus. !e axons from these neurons !ese a$erent signals are processed through struc- 141 make up the hypothalamohypophyseal tract (no. 11, tures such as the amygdala, nucleus accumbens, and Diencephalon: Hypothalamus and epithalamus

Preoptic area Preoptic hypothalamic area Medial Lateral !e preoptic area (no. 1, Figure 8.2) includes the medial and lateral preoptic nuclei (Figure 8.4). Many neurons in the preoptic area and nearby anterior hypothal- SDN amus contain both androgen and estrogen receptors. Stimulation of these areas has been shown to initiate sexual behavior in animals. Lesions of the preoptic area reduce or abolish copulatory behavior in many species Male Release of (Van de Poll and Van Goozen, 1992). heterosexual gonadotropic Fibers that project to the medial preoptic area arise behavior hormones in the cingulate cortex, hippocampus, septum, and lat- Figure 8.4. The medial preoptic nucleus produces luteinizing eral habenular nucleus. !ese are all limbic structures hormone-releasing hormone and in!uences motor behaviors. SDN, (Corodimas et al., 1993). !e medial preoptic area sexually dimorphic nucleus. receives input from the olfactory system by way of the amygdala and the stria terminalis and projects heavily to the periaqueductal gray of the midbrain and to Pain Stress the anterior ventral medulla. Both of these brainstem Anxiety Retina areas have been implicated in the control of incoming pain signals, in sexual behavior, and in the initiation of maternal and defensive/aggressive behaviors PVN (Shipley et al., 1996). It is hypothesized that this path- SON way is important in the olfactory cues related to these Oxytocin SCN behaviors. Vasopressin Supraoptic region One or more nuclei found within the medial preoptic area are sexually dimorphic in animals; how- Brainstem DMN ever, the concept remains controversial in the human ARC (Martin, 1996). One cluster of neurons is called the sexually dimorphic nucleus (SDN). It is also known as VMN Appetite INAH1 (interstitial nucleus of the anterior hypothal- Tuberal region satiation Median amus, number 1). It contains at birth only about 20% eminence Hippocampus of the number of neurons that are seen at 2–4 years of

Pituitary MB age. A&er 4 years, the cell number decreases in girls but Post. lobe Ant. lobe remains constant in boys. No di$erence in cell number Mammillary region ACTH in the SDN is seen between homosexual and hetero- Thalamus sexual men (Swaab et al., 1995). !e anterior nucleus Adrenal gland (Figure 8.2), sometimes described as INAH3, is also Cingulate sexually dimorphic (LeVay, 1991; LeVay and Hamer, Cortisol gyrus 1994). It is larger in the male and contains approxi- Figure 8.5. The medial hypothalamic zone is rich in nuclei. mately twice the number of neurons in adult male E#erents link the medial zone of the hypothalamus with the pituitary and with other brain centers. Oxytocin/vasopressin from the than in adult female humans. However, Friedman and PVN/SON follow three separate pathways. ACTH, adrenocortico- Downey (1993) reported the size to be similar on aver- tropic hormone; ARC, arcuate nucleus; MB, mammillary body; PVN, age when comparing the brains of male homosexuals paraventricular nucleus; SON, supraoptic nucleus; SCN, suprachiasmatic nucleus; DMN, dorsomedial nucleus; VMN, ventromedial and female heterosexuals. Before birth the anterior nucleus. nucleus is similar in size in both male and female rats. It is smaller in male o$spring of rats that are stressed limbic association cortex before being relayed to the while pregnant. It is larger in sexually active male rats. hypothalamus. Polysynaptic pathways are responsible Many of the cells of INAH3 die in the female shortly for behaviors such as sleep, food intake, freezing and a&er birth. However, testosterone present from 4 days 142 "ight, and a$ects such as depression, rage, and fear before until 10 days following birth protects these (Burstein, 1996). neurons from cell death in the male rat. Di$erential Hypothalamus

Table 8.1. Hypothalamic releasing hormones and their actions on the anterior pituitary. Releasing hormone Action on anterior pituitary Corticotropin-releasing hormone (CRH) Stimulates secretion of adrenocorticotropic hormone (ACTH) Thyrotropin-releasing hormone (TRH) Stimulates secretion of thyroid-stimulating hormone (TSH) Gonadotropin-releasing hormone (GnRH), Stimulate secretion of follicle-stimulating hormone (FSH) Luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH) Growth hormone-releasing hormone (GHRH) Stimulates secretion of growth hormone (GH) Somatostatin, somatotropin release-inhibiting Inhibits secretion of growth hormone (GH) hormone (SRIH) Dopamine Inhibits biosynthesis and secretion of prolactin (PRL)

Figure 8.6. Both exter- Activity in the medial preoptic area increases in the External Internal nal and internal stimuli male monkey during sexual arousal but decreases dur- stimuli stimuli can a#ect the release of ing copulation and ceases a&er ejaculation. A lesion of hormones controlled by the hypothalamus. In this the medial preoptic area produces a major reduction in example the output of female-directed sexual behavior, although the capacity Drugs (EtOH) vasopressin (antidiuretic for masturbation continues. Electrical stimulation of Pain hormone) is increased Osmolality Stress by heat and dehydration the medial preoptic area initiates sexual behavior only of plasma Temperature and decreased by pain, if a receptive female is available. !e medial preop- stress, and alcohol. PVN, tic area shows the greatest testosterone uptake of any paraventricular nucleus; SON, supraoptic nucleus; region of the brain. E$erent connections from the EtOH, ethyl alcohol. medial preoptic area include projections to the dorso- PVN SON medial hypothalamic nucleus and to brainstem areas linked with penile erection. Stimulation of the medial Medial hypothalamus preoptic area in the female rat inhibits lordosis. In contrast, stimulation in the male rat induces copulation (Marson and McKenna, 1994).

Vasopressin Periventricular hypothalamic zone !e periventricular zone is a thin layer that lies just lateral to the ependymal cells that form the lining of the cell death accounts for the sexual dimorphism of this third ventricle. !is zone is important in regulating the nucleus. !ese same neurons in human females begin release of hormones from the anterior pituitary. to undergo programmed death at about 4 years of age. !e medial preoptic area contains neurons that Medial hypothalamic zone produce luteinizing hormone-releasing hormone. !e medial hypothalamic zone includes the majority of In the pituitary, this releasing hormone regulates the the well-de#ned nuclei of the hypothalamus (Figures level of gonadotropins. !e medial preoptic area plays 8.2 and 8.5). Several important regions in this zone an important role in maternal behavior (Numan and include, from front to back, the supraoptic, the tuberal, Sheenan, 1997). Surgical or chemical lesions of the med- and the mammillary regions. In addition to contain- ial preoptic area severely disrupt the induction as well ing important nuclei, the tuberal region is continu- as the maintenance of maternal behavior (DeVries and ous below with the infundibular stalk of the pituitary Villalba, 1997). !e ventral tegmental area (Chapter 7) gland. may be the target of #bers that arise from the medial preoptic area (Numan and Smith, 1984; Hansen and Supraoptic region Ferreira, 1986). !e supraoptic region is located directly above the !e medial preoptic area is also critical in the optic chiasm and includes the supraoptic, the paraven- 143 expression of male-typical heterosexual behavior. tricular, and the suprachiasmatic nuclei (Figures 8.2 Diencephalon: Hypothalamus and epithalamus

and 8.5). Clusters of magnocellular neurons within the mothers (i.e., the pups remain in olfactory and audi- supraoptic and paraventricular nuclei produce oxy- tory contact) markedly depletes oxytocin levels in the tocin and vasopressin. !e paraventricular nucleus mothers. It is speculated that stimuli that reactivate consists of one subdivision that projects to the median the mechanisms of attachment between mother and eminence and a second subdivision that projects to o$spring contribute to the sense of longing and other the posterior pituitary. A third subdivision, which also strong emotions that accompany the loss of a close rela- produces oxytocin and vasopressin, projects to brain- tionship in humans (Pedersen, 1997). !ese emotions stem and to spinal cord autonomic nuclei. !e axons may be related to a reduction in the level of oxytocin. from the third subdivision enter the medial forebrain Oxytocin released by the paraventricular nucleus may bundle and descend in the dorsolateral brainstem. play a role in the sedation, relaxation, and decreased Axons of some neurons pass through the infundibu- sympathoadrenal activity at the hypothalamic level lar stalk to terminate on capillaries in the posterior that occurs during friendly social interaction (Uvnas- lobe of the pituitary. When these neurons depolar- Moberg, 1997). ize, their neurotransmitter (oxytocin or vasopressin) !ere appears to be a central dysregulation of vaso- is released directly into the bloodstream. !ese neu- pressin secretion in patients with anorexia nervosa rons receive input from brainstem autonomic nuclei (Demitrack and Gold, 1988). !e number of vaso- (solitary nucleus) and from circumventricular organs. pressin- and oxytocin-expressing neurons in the para- !e latter are vascular neural structures that lack the ventricular nucleus of patients with mood disorder is blood–brain barrier. One of these, the subfornical signi#cantly increased (Purba et al., 1996). An increase region located in the wall of the third ventricle, sends in both vasopressin and oxytocin was reported in axons that terminate in the hypothalamus. It is pre- bulimic patients (Demitrack et al., 1990). !e levels sumed that the circumventricular organs sense osmo- of vasopressin and oxytocin are altered in the cerebro- lality and bloodborne chemicals. Many areas of the spinal "uid of depressed patients (Legros et al., 1993). hypothalamus are sensitive to hormones. Some hor- No correlation has been found between the extent of mones cross the blood–brain barrier, and others bind the depressive symptomatology and the level of reduc- to intracellular receptors. tion of vasopressin (Gjerris, 1990). Other neurons in the paraventricular nucleus !e suprachiasmatic nucleus (Figures 8.2 and 8.5) that also produce oxytocin and vasopressin project to is found in the supraoptic region of the medial zone. limbic structures, including the amygdala and hippo- It lies just above the optic chiasm and just below and campus. Descending #bers project to the brainstem to lateral to the supraoptic nucleus. !e suprachiasmatic terminate in the locus ceruleus and in the raphe nuclei nucleus is critical in controlling the day–night circa- (Chapter 10). Some oxytocin axons extend to the spinal dian rhythm of the body and functions as the “master cord where they terminate on presynaptic neurons of clock.” It receives primary visual a$erents from the ret- the sympathetic nervous system (Sofroniew, 1983). ina and secondary a$erents from the lateral geniculate Oxytocin release causes contraction of the smooth body of the visual system. !e suprachiasmatic nucleus muscles of the uterus during childbirth as well as con- has intimate connections with the pineal gland and traction of the myoepithelial cells of the mammary plays a key role in circadian functions as well as in sea- gland during nursing. Surprisingly, the number of sonal function (Pevet et al., 1996; Reuss, 1996). oxytocin-producing cells is about the same in the !e suprachiasmatic nucleus may be related to sea- female and male. Intraventricular injection of oxyto- sonal "uctuations in mood (seasonal a$ective disorder cin in the female rat rapidly stimulates maternal behav- or SAD), and the number of vasopressin-expressing ior (Pedersen and Prange, 1979). In contrast, oxytocin neurons is greatest in October and November, when infusion in males results in an increase in nonsexual the incidence of depression is greatest (Hofman et al., social interaction (Witt, 1997). Receptors for oxytocin 1993). Exposure to prolonged periods of light follow- in both the medial preoptic area of the hypothalamus ing transportation to a distant time zone can facilitate and the ventral tegmental area of the midbrain are crit- recovery from jet lag. More speci#cally, exposure to ical for the postpartum onset of maternal behavior in bright light in the morning delays the light–dark cycle the rat. !e oxytocin-producing neurons are located (phase advance), whereas exposure to bright light in the in the lateral preoptic area and in the paraventricular evening advances this cycle (phase delay). Most SAD 144 nucleus. Proximal separation of rat pups from their patients with winter depression experience abnormal Hypothalamus phase delays and therefore respond positively to bright sensed by the hypothalamus in a negative feedback morning light. !e bright light itself is not an anti- mechanism that regulates the output of CRH. !e depressant, but the reversal of the abnormal phase delay hippocampus also has many glucocorticoid receptors acts as an antidepressant (Lewy and Sack, 1996). and appears to play an important role in monitoring stress and regulating the production and release of CRH Tuberal region by the hypothalamus. Exposure to stress downregulates !e arcuate nucleus (Figures 8.2 and 8.5) as well as glucocorticoid receptors in both the hippocampus and other hypothalamic nuclei contain neurons that prod- hypothalamus. !erefore, the feedback receptors are uce various release and release-inhibiting hormones. less sensitive to circulating glucocorticoids and the !ese include gonadotropin-releasing hormone, hypothalamus secretes inordinately high levels of CRH luteinizing hormone-releasing hormone, and corti- (Herman et al., 1995). !e separation of partners which cotropin-releasing hormone (CRH). !e close con- show signs of emotional attachment, activates the HPA nections between the hypothalamus, the pituitary, and axis, whereas separation of partners which show little the adrenal gland are recognized as the hypothalamic– emotional attachment has little or no e$ect on the HPA pituitary–adrenal (HPA) axis. CRH is responsible for (Hennessy, 1997). Signi#cantly decreased bone density triggering the release of adrenocorticotropic hormone in women with depression is consistent with dysfunc- (ACTH) from the anterior lobe of the pituitary gland. tion of the HPA axis (Michelson et al., 1996). Abnormalities in the HPA axis have been linked to sev- Many neurons in the arcuate nucleus produce eral disorders. β-endorphin. !is peptide is known to play an import- !e neurons of the paraventricular nucleus that ant role in the control of pain. In addition, some of these control the HPA are strongly activated in depression same neurons project to the periaqueductal gray, which (Raadsheer et al., 1994). Excessive ACTH secretion and is a midbrain region known to function in the suppres- a concomitant increase in cortisol by the adrenal cortex sion of incoming pain signals (Chapter 10). !e arcuate are seen in 40%–60% of depressed patients, primarily nucleus and its connections with the paraventricular during a&ernoon and evening hours. !e hypersecre- nucleus also are a hypothalamic pathway involved in tion of cortisol is not dependent on stress. !e synthetic the control of body weight. !is pathway may be the corticosteroid dexamethasone, when administered to target of the hormone leptin, which is secreted by fat normal individuals, suppresses CRH. HPA activity can cells (Horvath, 2005; Schwartz and Seeley, 1997). A be assessed by measures of cortisol in the blood, urine, nucleus adjacent to the arcuate nucleus (the periven- saliva, and in cerebrospinal "uid (DeMoranville and tricular nucleus) produces dopamine, which inhibits Jackson, 1996). When synthetic corticosteroid dexa- prolactin release. methasone is administered to depressed patients dur- Abnormal levels of endorphins have been reported ing the evening, approximately 40% show no decline in the hypothalamic tissue of schizophrenia patients. in cortisol levels. Improvement in the dexamethasone Both “endorphin excess” and “endorphin de#ciency” suppression test is seen in successful antidepressant hypotheses of schizophrenia have been proposed treatment (Holsboer-Trachsler et al., 1991). (Wiegant et al., 1992). Goldstein et al. (2007) found Subtle alterations in HPA function have been that the total hypothalamic volume was increased observed in patients with panic disorder (Abelson and in patients with schizophrenia and in nonpsychotic Curtis, 1996). Weinstock (1997) hypothesized that relatives. !e increase was greater in the region of the prenatal stress impairs the ability of the child’s HPA to paraventricular nuclei and mammillary body and cor- cope in novel situations. related positively with anxiety. !ese #ndings suggest !e periventricular hypothalamus, the arcuate a relationship between schizophrenia and the high rate nucleus, and other hypothalamic regions that produce of endocrine disorders. CRH represent the origin of the HPA axis. !e regula- Neurons located in the arcuate (infundibular) tion of the HPA axis depends on three major factors. nucleus of the medial zone are hypertrophied in post- First, the pulsatile release of CRH is under the control menopausal women. Some cells of the arcuate nucleus of the suprachiasmatic nucleus. Second, psychological are sensitive to circulating levels of estrogen and regu- and physical stresses are mediated by way of pathways late the activity of substance P-producing neurons from the brainstem and limbic system to the hypothal- found there. Substance P production in neurons in the amus. !ird, circulating levels of glucocorticoids are arcuate nucleus varies with the sexual cycle and may 145 Diencephalon: Hypothalamus and epithalamus

regulate the release of gonadotropin-releasing hor- is a common side e$ect of these lesions (Nadvornik mone from the hypothalamus into the hypophyseal et al., 1975). portal system. It has been hypothesized that an increase !e ventrolateral portion of the ventromedial in the pulsatile release of substance P may coincide with nucleus is responsible for typical female sexual behav- menopausal "ushes (Rance, 1992). ior. Stimulation of this area produces lordosis in rats. !e dorsomedial nucleus (Figures 8.2 and 8.5) !e ventromedial nucleus is a site of action of estro- lies immediately above the ventromedial nucleus. gen and progesterone hormones. Projections from the Stimulation of the dorsomedial nucleus in laboratory ventromedial nucleus to the periaqueductal gray may animals produces unusually aggressive behavior that be the route by which this region of the hypothalamus lasts only as long as the stimulus is present. !is aggres- induces sexual behavior (Pfa$ et al., 1994). sive behavior is known as sham rage and can be produced A number of nuclei in the hypothalamus have by stimulation in other regions of the hypothalamus. receptor sites for estrogen. Under experimental con- !e ventromedial nucleus (Figures 8.2 and 8.5) ditions food intake is increased when estrogen levels lies near the midline just anterior to the mammillary decrease. !ere is evidence that during the second half bodies. It receives input from the amygdala. It projects of the menstrual cycle when estrogen levels drop there heavily to the magnocellular nuclei of the basal fore- is also an increase in food intake and preference for car- brain including the basal nucleus (of Meynert). !ese bohydrates (Bray, 1992). nuclei in turn project to all areas of the cerebral cortex. !e mammillary bodies and the cells of the poster- !e ventromedial nucleus has been described in the ior hypothalamic nucleus that lie dorsal to the mam- past as the satiety center. It regulates the amount of food millary bodies mark the posterior (caudal) extent of the consumed in order to maintain a normal body weight. medial hypothalamus. !e largest number of a$erents It is interconnected with the lateral hypothalamic zone to the mammillary bodies come from the hippocam- (see the following section), which has been described pus by way of the fornix (nos. 20 and 2, respectively, in the past as the hunger center. !e concept of hun- Figure 13.5). !is connection with the hippocam- ger and satiety centers is a convenient concept. Feeding pus suggests that the mammillary bodies are also control is probably more complex than this compari- involved in emotion as well as memory. For example, son would imply, however, and involves a number of the mammillary bodies have been implicated in penile additional structures (Kupfermann, 1991). erection (Segraves, 1996). Fibers from the mammillary bodies ascend to the anterior nucleus of the thal- Clinical vignette amus and make up the mammillothalamic tract (no. A 36-year-old man was found to have an anterior 8, Figure 13.5). !e anterior nucleus of the thalamus hypothalamic tumor when he was evaluated for a is a major component of the limbic thalamus (Figure 65-lb weight gain, hallucinations, paranoid delusions, 9.2). Cell loss is seen in the mammillary bodies as well and confusion. After surgical removal of the tumor, he as in the mediodorsal nucleus of the thalamus in alco- became apathetic and akinetic mutism developed. He holic Wernicke–Korsako$ syndrome (Delis and Lucas, responded well to treatment with dopamine agonists (bromocriptine) (Ross and Stewart, 1981). The case 1996; Sechi and Serra, 2007). suggests that akinesia may be related to loss of dopa- Lateral hypothalamic zone and medial minergic input to anterior cingulate or other frontal lobe regions. The postsurgical clinical picture may have forebrain bundle been produced by damage to the mesolimbic/meso- !e lateral zone contains several groups of cells, the lar- cortical dopamine "bers. These "bers are found within gest of which is the tuberomammillary nucleus, which the medial forebrain bundle, which courses from the extends in a posterior direction lateral to and below the ventral tegmental area to the cingulate cortex and mammillary body. !e lateral tuberal nuclei consist of passes through the lateral hypothalamic zone. two or three sharply delineated cell groups that o&en produce small visible bumps on the basal surface of the A lesion of the ventromedial nucleus results in hypothalamus. !e medial forebrain bundle courses appetite disorders and marked increase in body weight. through the lateral zone and makes delineation of spe- Stereotactic lesions of the ventromedial nucleus have ci#c nuclei di%cult. Axons from the limbic system ter- been used in an attempt to treat alcoholism, drug minate in the lateral zone, which, in turn, integrates and 146 addiction, and hypersexuality. Increase in body weight relays the signals to other parts of the hypothalamus Hypothalamus as well as to the midbrain. Of particular signi#cance Connections of the hypothalamus are projections from the infralimbic area of the cingu- Neural signals reach the hypothalamus over many late cortex (Chapter 12). !is is a key route by which pathways. Two major pathways that carry signals to the visceral motor cortex (infralimbic area) in"uences and from the hypothalamus are the medial forebrain autonomic tone, and the lateral zone is believed to be bundle and dorsal longitudinal fasciculus. !e dor- important as an integrative center for ingestive behav- sal longitudinal fasciculus connects the hypothal- ior (Bernardis and Bellinger, 1996; Saper, 1996). amus with the brainstem and spinal cord. Much of the !e lateral zone has been described as the hunger information is of a visceral nature and includes signals center. A lesion placed in this zone will eliminate an related to taste, blood pressure, and other autonomic animal’s motivation to seek food, and the animal will functions. !e medial forebrain bundle provides con- lose weight and will eventually die. Electrical stimu- nections between the hypothalamus, brainstem teg- lation of the medial forebrain bundle seems to induce mentum, limbic structures and cortex of the forebrain. pleasure in the animal. !e rate of self-stimulation (and It contains #bers of the mesolimbic pathway and has thus the amount of pleasure induced) is maximal when been nicknamed the “hedonic highway.” the stimuli are delivered directly to the lateral hypothalamus. Indeed, if the lateral region is destroyed, the Inputs experience of pleasure and emotional responsiveness Ascending input to the hypothalamus includes #bers is almost completely attenuated (Saver et al., 1996). from the locus ceruleus and raphe nuclei (Chapter 10). Electrical stimulation or the infusion of acetylcho- !ese inputs provide signals that have a general alert- line into the posterior lateral hypothalamus produces ing e$ect on the hypothalamus. In particular, #bers to aggressive attack behavior in animals (Kruck, 1991). the lateral hypothalamus from the locus ceruleus and !e lateral hypothalamic zone is important in the car- the amygdala have been implicated in the sympathetic diovascular response to fearful stimuli. Neurons in the activation and hormonal release associated with fear lateral zone project to the lower brainstem, which dir- and anxiety (Charney et al., 1996). Fibers from the ectly controls alterations in blood pressure (LeDoux, brainstem solitary nucleus provide speci#c informa- 1996). Signals arrive in the lateral zone of the hypothal- tion from visceral a$erents, including taste, as well as amus from the amygdala and from other regions. signals from the thoracic and abdominal viscera. !e medial forebrain bundle (fasciculus telen- Descending in"uences to the hypothalamus include cephalicus medialis) is a complex collection of #bers signals from the limbic system, especially from the that resembles a freeway with many on and o$ ramps hippocampus and amygdala (Figures 11.2 and 11.8). (no. 18, Figure 13.5). It extends from the midbrain to !e prefrontal cortex projects directly to the hypothal- the frontal cortex and passes through the lateral hypo- amus via the medial forebrain bundle. !e cingulate thalamus. Fibers representing many di$erent functions gyrus in"uences the hypothalamus by way of the septal enter the medial forebrain bundle, course through it nuclei and hippocampus (Figure 12.5). for a short or long distance, and then exit. Mesolimbic and mesocortical #bers are part of the medial forebrain bundle (Chapter 7). Descending #bers from the Clinical vignette hypothalamus extend caudally to the brainstem. Raphe A 19-year-old man sustained a fall with head injury serotonergic nuclei (Chapter 10) and basal forebrain and underwent neurosurgical evacuation of a right- acetylcholinergic nuclei (Chapter 13) both project sided epidural hematoma. Two months after the head trauma and surgery, he began eating excessively, through the medial forebrain bundle. particularly a great many sweets, and gained about Lesions of the lateral hypothalamus have been 176 lb. During the following 18 months, he had peri- responsible for anorexia in humans (Martin and odic episodes lasting six to ten weeks where he would Riskind, 1992). Signi#cant neuronal loss has been sleep up to 16 hours a night with continued drowsi- reported in the lateral tuberal nucleus in Huntington ness during the rest of the day. He was periodically disease, adult-onset dementia (Braak and Braak, 1989), irritable and aggressive, with mood alterations and and in a patient with severe depressive illness (Horn an increased interest in pornographic material. The et al., 1988). !e loss of neurons in the lateral hypothal- patient developed the Kleine–Levin syndrome prob- amus may be responsible for the weight loss that com- ably consequent to hypothalamic injury. His magnetic monly accompanies these disorders (Kremer, 1992). resonance imaging showed a posttraumatic lesion in 147 Diencephalon: Hypothalamus and epithalamus

Clinical vignette (cont.) Clinical vignette the right hypothalamus (Figure 8.7). The Kleine–Levin Tonkonogy and Geller (1992) reported two cases of syndrome includes hypersomnolence, hyperphagia craniopharyngioma presenting with and meeting and sexual disinhibition or other behavioral disorders. Diagnostic and Statistical Manual of Mental Disorders- III-R criteria for intermittent explosive disorder. In the "rst case, a 21-year-old man presented with Outputs frequent episodes of explosive behavior and threats E$erent signals from the hypothalamus tend to leave by to cut himself or to kill his mother. He complained of insomnia, depressed mood, periodic hypnagogic vis- way of long axons that arise from cell bodies located in ual and auditory hallucinations, and periods of 15–20 the medial and lateral hypothalamic zones. !e hypo- minutes of spacing out. He had a family history of alco- thalamus has reciprocal (back-and-forth) connections holism and personality disorder, and he grew up in with most of the structures that provide a$erents, foster homes. A decline in his IQ, progressive weight including the periaqueductal gray, the locus ceruleus, loss, dizziness, and fatigue prompted a medical exam- and the raphe nuclei in the brainstem. Descending #b- ination. Polydipsia, polyuria, lack of pigmentation, and ers to the brainstem are responsible for the direct con- diabetes insipidus eventually developed. Removal of trol of the sympathetic and parasympathetic systems. the tumor did not lead to behavioral improvement. E$erent #bers to the limbic system include connections In the second case, a 24-year-old woman presented with the septal nuclei, amygdala, and hippocampus. with episodes of explosive behavior, including threats to start "res and a history of assaults on sta#. She com- Some #bers project directly from the hypothalamus to plained of depressed mood and had attempted sui- the prefrontal cortex via the medial forebrain bundle. cide a number of times. She was markedly obese. At !e hypothalamus in"uences the cingulate cortex age 11, she had shown signs of growth retardation, indirectly by way of signals relayed in the anterior thal- weight loss, and other signs of hypopituitarism. A amic nucleus. Other e$erent #bers terminate in the craniopharyngioma was removed at that time. After mediodorsal thalamic nucleus, which relays informa- surgery, her assaultive and self-threatening behavior tion to the prefrontal lobe. manifested itself. She did not respond to neuroleptics, antidepressants, or substitute hormonal therapy. An abnormal encephalogram led to treatment with Other behavioral considerations carbamazepine, to which the patient responded with !e hypothalamus lies in a position between the a marked improvement in behavior. “thinking brain” (neocortex) and the “emotional brain” (limbic system) on the one hand, and the body systems Emotional stress can induce ulcers. In women, that are controlled by the autonomic and endocrine stress can block the menstrual cycle. Normally the systems on the other hand. Mental state can operate milk ejection re"ex is induced by the infant suckling at through the hypothalamus to alter endocrine function the nipple. An experienced nursing mother can some- and autonomic tone. times cause milk to trickle from her nipples by forming a mental image of her infant. !ere is some evidence that mental processes can operate through the hypo- Figure 8.7. A thalamus to in"uence the immune system (Michaelson magnetic res- and Gold, 1998; Petrovich, et al., 2005). onance image (T2-weighted) !e hypothalamus is in a position to control the demonstrating outward manifestations of emotion. Heart rate, blood a high-intensity pressure, pupil size, and vasoconstriction are all con- lesion in the right hypothalamus trolled by the hypothalamus. Other behaviors that (arrow). (Reprinted involve striated muscles are also controlled by the hypo- with permission thalamus. Shivering for heat conservation, piloerection from Kostic et al., 1998.) during rage and facial expression re"ecting emotion are all under hypothalamic in"uence. It is thought that much of the autonomic and somatic expression 148 of emotion is controlled by the hypothalamus. It is believed that emotional expression is controlled by Epithalamus the hypothalamus, whereas the feelings of emotion lie Epithalamus elsewhere, particularly within the limbic system. Sham rage in experimental animals can be seen when the Pineal (epiphysis) hypothalamus is electrically stimulated. !e animal’s !e pineal is found in the midline, above the third rage is nondirected and dies out quickly. For example, ventricle, and in front of the superior colliculus (P in cats exhibiting sham rage may alternately growl and Figure 13.5). It is glandular in appearance and contains purr when lapping warm milk (DeMoranville and a unique cell called the pinealocyte. It is richly vascular Jackson, 1996). with its rate of blood "ow second only to that of the kid- Delville et al. (1998) found that social subjuga- ney. In lower forms the pineal forms the parietal eye, a tion of hamsters during puberty resulted in males photosensitive organ important in circadian rhythms. that were more aggressive toward intruders and were !e prominent pinealocytes synthesize serotonin and signi#cantly more likely to bite smaller males than melatonin, both of which are released into the extra- were control males. !is behavior is not unlike that cellular space. of schoolyard bullies. Delville and colleagues’ analysis !e pineal has been called a “tranquilizing organ” revealed a 50% decrease in the level of vasopressin in due to the hypnotic properties of melatonin (Romijn, the anterior hypothalamus of the subjugated hamsters 1978) and is described as a neuroendocrine transducer but an increase in the number of serotonin-containing that transforms a neural signal into an endocrine signal #bers. !e number of vasopressin #bers suggested (Reuss, 1996). Exposure to light blocks the transmission that less vasopressin is produced and released in the of neural signals to the pineal gland from the hypothal- subjugated hamsters.!e increase in serotonin #bers amus and therefore blocks the production of melatonin. suggested to the authors that the capacity to release !e synthesis of melatonin and release into the blood- serotonin was increased. An increase in serotonin is stream are normally observed to take place only dur- consistent with reduced aggression and may account ing the nighttime hours. Blinded animals continue to for the fact that the subjected hamsters were less produce melatonin in rhythm with the day–night cycle. aggressive than controls when in the presence of males However, a lesion of the suprachiasmatic nucleus of of equal or greater size. the hypothalamus abolishes the rhythm. Pinealocytes Many case reports of intermittent explosive disor- found in the deep portion of the pineal give rise to long, ders associated with hypothalamic lesions appear in beaded processes that terminate in the pretectum and the literature. A number of these are remarkable since in the medial nucleus of the habenula (see the follow- the patients were diagnosed with behavioral disor- ing section). (!e pretectum is part of the visual system ders, sometimes years before the underlying tumor and is found in the midbrain in front of the superior was discovered. Visual hallucinations have been colliculus.) !e ends of these processes form neuron- reported by these patients (Tonkonogy and Geller, like connections with neurons located in these two 1992). An association between precocious puberty sites (Figure 8.8). !e pineal is usually considered an and hypothalamic lesions (particularly hamartomas) endocrine organ; however, the axon-like processes and has been repeatedly noted (Takeuchi et al., 1979). point-to-point organization suggest that it may have An even more interesting association is between neuronal connections as well (Korf et al., 1990). hypothalamic hamartomas, precocious puberty, and !e pineal is the most in"uential component of the gelastic (laughing) seizures (Breningstall, 1985). It is melatonin system. However, melatonin is also synthe- suggested that the area of the hypothalamus that is sized in photoreceptors of the retina. Retinal melatonin critical for the expression of intermittent explosive is secreted locally, whereas pineal melatonin is released disorder is the posterior lateral hypothalamic region. into the bloodstream. A well-recognized pathway to !is region was at one time surgically destroyed for the pineal originates with the retinohypothalamic the treatment of aggressive behavior (Tonkonogy and tract to the suprachiasmatic nucleus, paraventricular Geller, 1992). nucleus of the hypothalamus, medial forebrain bundle, In summary, at the hypothalamic level, the emo- lateral horn of the upper thoracic spinal cord, super- tional states elicited are primitive, undirected, and ior cervical ganglion, and sympathetic pre- and post- unre#ned. Higher-level emotions such as love or hate ganglionic nerves to the pineal (Figure 8.8). !is route require the involvement of other limbic, as well as neo- includes the sympathetic innervation of the pineal cortical, regions. 149 from the superior cervical ganglion. A second pathway Diencephalon: Hypothalamus and epithalamus

Retina a melatonin–GABA interaction is responsible for some of its behavioral e$ects (Golombek et al., 1996). Suprachiasmatic Parenchymatous pinealomas are associated with nucleus depression of gonadal function and delayed pubes- cence. Destruction of the pineal is associated with precocious puberty. !e pineal is frequently calci#ed Paraventricular nucleus in schizophrenia, and the melatonin system may be involved in SAD (Sandyk, 1992). !e level of melatonin normally rises at night. Spinal cord lateral horn Melatonin given during the day, when levels are normally low, induces fatigue. Exposure to bright light at night suppresses the normal nocturnal elevation Superior cervical LGB ganglion of circulating melatonin (Dollins et al., 1993). It has been suggested that melatonin or melatonin analogs may be therapeutic for the control of circadian clock PINEAL dysfunctions such as jet lag, shi&-work syndrome, and sleep disorders. Melatonin has been used e$ectively for treatment of insomnia to correct the sleep–wake Melatonin Medial cycle (Tzichinsky et al., 1992). However, it has not Pretectum (bloodstream) habenular nucleus always proved e$ective in the treatment of SAD (Wehr, 1991). Sleep patterns are o&en a$ected by depression, Figure 8.8. The connections of the pineal include a#erents from although it is believed that there is no primary disturb- the retina and lateral geniculate body (LGB). Exposure to light inhibits melatonin production by the pinealocytes. The lines leaving ance of the circadian rhythm system in this disease the pineal represent cytoplasmic extensions of the pinealocytes. (Moore, 1997). Feedback from the pineal to the suprachiasmatic nucleus is by way of melatonin in the bloodstream. Habenula !e habenula (habenular nucleus) is located in the wall of the third ventricle anterior to the pineal (Figure 9.3, involves the lateral geniculate nucleus, which sends and nos. 9 and 23, Figure 13.5). It consists of a smaller e$erent #bers to both the suprachiasmatic nucleus and medial nucleus, which contains small cells, and a larger to the pineal (Reuss, 1996). lateral nucleus, which contains larger cells. Both may !e suprachiasmatic nucleus and the anterior pitu- be further divided into multiple subnuclei (Andres itary are two regions where melatonin exerts its major et al., 1999). !e stria medullaris is the major a$erent e$ects. Melatonin feedback to the suprachiasmatic bundle serving the habenular nucleus, and brings sig- nucleus regulates the output of melatonin by the pin- nals from the medial forebrain and septum, limbic lobe eal. !e e$ect of melatonin in the anterior pituitary hypothalamus, and ventral striatum. !e fasciculus is to regulate neuroendocrine and gonadal function retro"exus (habenulointerpeduncular tract; no. 11, (Morgan et al., 1994). Melatonin synchronizes daily Figure 13.5) is the major e$erent pathway that projects activity/inactivity with daily changes in light/dark. It primarily to the nigral complex (ventral tegmental area also synchronizes other body functions and is respon- and substantia nigra; see Chapter 7) and to brainstem sible for maternal entrainment of fetus activity (Reppert nuclei, including the raphe nuclei and locus ceruleus et al., 1989). !e pain threshold is raised by melatonin. (Chapter 10). !e habenular nucleus is part of a dorsal Since this e$ect is blocked by naloxone, it appears that pathway connecting cortex with brainstem that paral- melatonin acts through opiate mechanisms (Golombek lels the ventral medial forebrain bundle. It is positioned et al., 1991). Melatonin has also been demonstrated to to link limbic structures with nuclei in the upper brain- have anticonvulsant properties and anxiolytic e$ects stem (Figure 8.9). in laboratory animals (Golombek et al., 1996). It increases the turnover of the inhibitory neurotrans- Lateral habenular nucleus mitter γ-aminobutyric acid (GABA) in the hypothal- !e lateral habenular nucleus has been described 150 amus, cerebral cortex, and cerebellum, suggesting that as the “crossroad between the basal ganglia and the Epithalamus

Frontal cortex of the dopaminergic mesocortical, mesolimbic, and Hypothalamus mesostriatal systems. !e animals exhibited impulsive Nucleus accumbens Septal nuclei responding, represented by a large increase in prema- Nucleus accumbens SNpc GPm ture responding and a decline in accuracy. Stria medullaris VTA Dopamine from the ventral tegmental area is important through the mesolimbic and mesocortical Pineal pathways for reward and cognition. Dopamine from the substantia nigra is important for motor activity. Dopamine is critical in its role for maximizing reward HABENULA potential resulting from anticipated motor behavior Medial Lateral (Matsumoto and Hikosaka, 2007). It is also import- nucleus nucleus ant in support of spatial memory (declarative mem- Fasciculus ory) and attention. !ese represent cognitive activity retroflexus Prefrontal cortex (Lecourtier et al., 2006). !e lateral habenula also inhibits serotonin neurons in the raphe nuclei and the dopamine neurons of Thalamus the ventral tegmental area (Park, 1987; Ji and Shepard, 2007). Lateral habenula neurons are strongly activated Hypothalamus in response to stress and food deprivation and in animal models of depression (Shumake et al., 2004; Yang et al., 2008), but this e$ect is reduced by antidepres- Brainstem Brainstem VTA VTA sant drugs or lesions of the lateral habenula (Yang et al., Raphe nuclei Raphe nuclei 2008). Hikosaka et al., 2008 hypothesize that increased SNpc SNpc activity in the habenula can result in depressed mood Figure 8.9. The medial habenula links the septal nuclei with the through its control of dopamine and serotonin (Geisler, thalamus. The lateral habenula links the frontal cortex, hypothal- 2008). !ere is some human evidence to support this amus, and dopaminergic nuclei to the brainstem and allows for hypothesis (Morris et al., 1999). !ese #ndings have feedback to the medial preoptic area of the hypothalamus and to the frontal cortex. GPm, medial segment of globus pallidus; SNpc, led to the suggestion that inactivation of the lateral substantia nigra pars compacta (dopamine); VTA, ventral tegmental habenula by deep brain stimulation may be e$ective in area (dopamine). treatment-resistant depression (Sartorius and Henn, 2007; Hauptman et al., 2008). limbic system” (Hikosaka et al., 2008). It receives #bers from the frontal cortex, the basal forebrain (substan- Medial habenular nucleus tia innominata and bed nucleus of the stria terminalis !e medial habenular nucleus shares many of the same of the extended amygdala), the preoptic area, and lat- incoming a$erent #bers with its lateral counterpart. It eral hypothalamus as well as the basal ganglia (medial also receives melatonin-containing axons from the pin- segment of the globus pallidus). It has reciprocal con- ealocytes of the pineal. !e septum is an especially rich nections (back-and-forth) with the raphe nuclei (sero- source of incoming #bers to the medial habenula. !e tonin) (Chapter 10) and the ventral tegmental area majority of outgoing #bers from the medial habenu- (dopamine). lar nucleus terminate in the interpeduncular nucleus Matsumoto and Hikosaka (2007) showed that in and median raphe of the midbrain where they regulate monkeys and humans activity in the lateral habenula sleep-wakefulness and food intake in response to stress increased in unrewarded trials and decreased in (Smith and Lonstein, 2008). rewarded trials. In another study, electrical stimulation !e habenular nucleus has been observed to be sig- of the lateral habenula in rats resulted in almost com- ni#cantly more calci#ed in schizophrenic patients than plete and long-lasting suppression of the dopamine in normal individuals. It is hypothesized that the calci- neurons of the ventral tegmental area and substantia #cation may be correlated with the enlargement of the nigra pars compacta (Ji and Shepard, 2007). In con- third ventricle. Calci#cation of the habenular nucleus may disrupt its role in providing a link between the lim- trast, Lecourtier and Kelly (2005) showed that lesions 151 of the habenula nuclei in rats resulted in an activation bic system and the upper brainstem (Ellison, 1994). Diencephalon: Hypothalamus and epithalamus

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Chapter 9 Diencephalon: Thalamus

Introduction medial subdivision lies medial to the internal medullary lamina and consists of the midline and medial !e thalamus functions as the principal relay station nuclear groups. !e lateral subdivision lies lateral to for sensory information destined for the cerebral cor- the internal medullary lamina and consists of the lat- tex. It is made up of a number of nuclei, which can be eral, ventral, and reticular nuclei, as well as the medial grouped into relay nuclei and di$use-projection nuclei and lateral geniculate bodies. !e intralaminar nuclei (Table 9.1). Each relay nucleus is associated with a sin- represent a fourth subdivision, and these nuclei are gle sensory modality or motor system and projects to a found encapsulated within the #bers of the internal speci#c region of the cerebral cortex with which it has medullary lamina. !e most prominent of the intral- reciprocal connections. !e di$use-projection group aminar nuclei is the centromedian nucleus (CM in of nuclei has more widespread connections with the Figure 9.3). cortex. !ey also interact with other thalamic nuclei. It is believed that the di$use-projection group is involved with regulating the level of arousal of the brain. !e Thalamic nuclei limbic thalamus consists of a number of the thalamic Anterior thalamic nuclei nuclei that project to the limbic cortex and includes both relay and di$use-projection nuclei. !e anterior group of thalamic nuclei consists of the anterodorsal, the anteroventral, and the anteromedial Anatomy and behavioral nuclei. !e anterior thalamic nuclei receive input from the mammillary body of the hypothalamus by way considerations of the mammillothalamic tract. !e anterior group !e thalamus consists of a symmetrical pair of ovoid projects to the cingulate gyrus. !e anterior thalamic structures located above (dorsal to) the hypothalamus. nuclear group is part of the limbic circuitry and con- !e le& thalamus and right thalamus are separated stitutes the original “limbic thalamus”. It is part of the medially by the third ventricle and bounded laterally by circuit of Papez (Figures 9.2 and 13.8). Disorientation the posterior limb of the internal capsule (Figures 9.1, has been seen following lesions of the anterior thalamic 9.2, and 9.3). !e massa intermedia (interthalamic nuclei (Gra$-Radford et al., 1984). Zubieta et al. (2002) adhesion) is a bridge of cells that spans the third ven- found that the anterior thalamus was activated during tricle and joins the le& with the right thalamus. !e pain processing, more so in men than in women. A thalamus is bounded in front (anteriorly) by the head decrease in volume has been reported in the anterior of the caudate nucleus and the genu of the internal cap- nucleus in patients with schizophrenia but this was not sule and behind (posteriorly) by the midbrain. !e signi#cant (Young et al., 2000; Byne et al., 2002, 2006). subthalamic nucleus (subthalamus) lies immediately Decreases in the number of projection neurons and below (ventral to) the thalamus and is sandwiched oligodendrocytes have also been reported in schizo- between the thalamus, internal capsule, and pretectal phrenia (Danos et al., 1998; Jakary et al., 2005; Byne area (Figures 9.2 and 9.3). et al., 2006). !e internal medullary lamina is a sheet of #bers that runs through the center of the thalamus, divid- Midline and medial nuclei ing it into three subdivisions (Figures 9.2 and 9.3). Two groups of thalamic nuclei lie medial to the internal !e anterior subdivision is embraced within the split medullary lamina. !ese are the medial nuclei and 156 anterior leaves of the internal medullary lamina and the midline nuclei (Figures 9.2 and 9.3). !e midline consists of the anterior group of thalamic nuclei. !e nuclei are continuous with the periaqueductal gray Anatomy and behavioral considerations

Table 9.1. Major connections of the thalamic nuclei that make up the four nuclear groups found in the human thalamus.

Nucleus Functional Major input from Major output to Function class Anterior group Anterior* Relay Hypothalamus Cingulate gyrus Learning, emotion, (mammillary body) memory Medial group Midline* Di#use- Reticular formation, Cerebral cortex Regulation forebrain projecting hypothalamus including cingulate excitability gyrus, amygdala Mediodorsal* Relay Basal ganglia, amygdala, Prefrontal cortex, Emotion, cognition, hypothalamus, nucleus cingulate gyrus, learning, memory accumbens, olfactory nucleus basalis system Lateral group Ventral Relay Basal ganglia Supplementary motor Movement planning anterior* cortex, cingulate gyrus Ventral lateral Relay Cerebellum Premotor and primary Movement planning motor cortex and control Ventral Relay Spinal cord, brainstem, Parietal cortex Touch, limb position posterior ascending discriminative sense touch systems Lateral dorsal* Relay Hippocampus Cingulate gyrus, ? parietal cortex Lateral Relay Superior colliculus, Posterior parietal Sensory integration posterior pretectum, occipital lobe cortex Pulvinar Relay Superior colliculus; Parietal, temporal, Sensory integration, parietal, temporal, and occipital association perception, eye occipital lobes cortex; cingulate gyrus movement control, language Lateral Relay Retina Primary visual cortex Vision geniculate Medial Relay Inferior colliculus Primary auditory Hearing geniculate cortex Reticular Di#use- Thalamus, cortex Thalamus Regulation of thalamic projecting activity Intralaminar* Di#use- Brainstem, spinal cord, Cerebral cortex, basal Regulation of cortical projecting basal ganglia ganglia activity

*Nuclei that are considered to be part of the limbic thalamus. of the midbrain reticular formation (Chapter 10). thalamic nuclei and is thought to decrease symptoms !ey are the target of dopaminergic #bers and express of obsessive-compulsive disorder (OCD) (Chapter 12; dopamine receptors. !ese are two criteria that qual- Martuza et al., 1990). ify them as part of the ascending dopaminergic system !e medial nuclear group is dominated by the med- (Chapter 7). Fibers from the midline nuclei project dif- iodorsal nucleus. It is a very large nucleus that occupies fusely. Targets include the amygdala and the anterior most of the space between the midline nuclei and the cingulate gyrus. !e midline nuclei provide an indirect internal medullary lamina and can be divided into as link from the brainstem to these limbic structures. many as seven subdivisions. !e most common div- A bilateral surgical lesion placed in the anterior ision describes a medially located magnocellular and portion of the internal capsule (anterior capsulotomy) laterally located parvocellular part. !e medial part 157 disconnects the orbital frontal cortex from the midline projects to medial prefrontal cortex and the lateral part Diencephalon: Thalamus

Anterior Figure 9.1. The brain section in this view is cut perpendicular to the long axis of the body and parallel to the horizontal Genu of corpus callosum limb of the neuraxis (see Figure 1.1). It is as Caudate nucleus if we are standing at the foot of the bed and looking at the patient. This diagram Lateral ventricle Putamen is identical to that of the insert on the left-hand side of Figure 9.2. Anterior Anterior thalamic nucleus refers to the front of the head, posterior Insular cortex to the back of the head. Lateral thalamic nuclei

Globus pallidus Medial thalamic nuclei

Internal capsule Internal medullary lamina

Lateral ventricle

Splenium of corpus callosum

Posterior

Third ventricle Stria medullaris Internal medullary AN lamina MD Reticular nucleus

Internal capsule A MI VL B

Subthalamic nucleus Hypothalamus Crus cerebri Mammillary body Third ventricle

Figure 9.2. The level of this cross section is indicated by A in the inset. The massa intermedia (MI) contains the midline nuclei. MD, mediodorsal nucleus; AN, anterior group of nuclei; VL, ventrolateral nuclei.

Habenular nucleus Third ventricle to lateral prefrontal cortex. Dopamine D2 receptors are Internal medullary Stria medullaris found concentrated in the magnocellular part (Alelú- lamina M Reticular nucleus Paz and Giménez-Amaya, 2008). LP !e mediodorsal nucleus is described as the thal- MD CM amic relay nucleus for association areas in the frontal VP Internal capsule lobe. It receives input from the amygdala, the nucleus Subthalamic accumbens, the olfactory region, the hypothalamus, nucleus and the basal ganglia. It projects to the nucleus basalis Hypothalamus Substantia nigra (of Meynert), the frontal eye #elds, the prefrontal cor-

Crus cerebri tex, and the cingulate gyrus (Baleydier and Mauguiere, Ventral tegmental area 1987). !e mediodorsal nucleus relays limbic system Figure 9.3. The level of this cross section is indicated by B in the information to the prefrontal cortex and to the cingu- inset in Figure 9.2. The centromedian nucleus (CM) lies within the 158 internal medullary lamina. M, midline nuclei; MD, mediodorsal late cortex. It has been subdivided into several regions. nucleus; LP, lateral posterior nucleus; VP, ventral posterior nuclei. !e magnocellular portion of the mediodorsal nucleus, Anatomy and behavioral considerations

Clinical vignette to that seen in the involuntary motor activity following A lesion of the ventral lateral nucleus along with the lesions in other parts of the basal ganglia responsible intralaminar nuclei and the mediodorsal nucleus on for Parkinson and Huntington diseases (Baxter, 1990). the right side was postulated to be the cause of a dis- !e mediodorsal nucleus has been implicated in inhibition syndrome that appeared in a 72-year-old schizophrenia. It has been reported to be reduced in woman (Bogousslavsky et al., 1988b). The patient, size in early-onset schizophrenia (Pakkenberg, 1992). who had no prior psychiatric history, developed a syn- However, a study of late-onset schizophrenia demon- drome of increased speech, jokes, laughing, inappro- strated that the thalamus was increased in size (Corey- priate comments, and confabulations. The authors Bloom et al., 1995), leading to the speculation that the suggested that this behavioral syndrome was pro- thalamus compensates for abnormalities and delays duced by interrupting the link provided by the medi- the onset of symptoms in some individuals (Jeste et al., odorsal nucleus between the limbic system and the prefrontal lobe. Mania following thalamic lesions is 1996). associated with damage to the right side (Cummings and Mendez, 1984). Ventral thalamic nuclei !e ventral thalamic group contains three major nuclei: the ventral anterior nucleus, the ventral lateral which lies medially, has close connections with the nucleus, and the ventral posterior nucleus. !e bor- pyriform cortex, the amygdala, and the neocortex of der between the ventral anterior and the ventral lat- the temporal lobe, as well as with the cingulate cortex. eral nucleus is indistinct, making it di%cult to clearly !e parvicellular portion is much larger and lies lat- separate the function of these two nuclei, which relay erally. It projects heavily to the prefrontal cortex. signals from the cerebellum and basal ganglia to the !alamic dementia presents with amnesia, speech cortex. A small number of cells in the ventral anterior disturbances, confusion, apathy, "attened a$ect, and nucleus project to the cingulate cortex. !ese cells are aspontaneity of motor acts. It o&en results from bilat- located in the region of the nucleus that receives input eral paramedian infarction of the thalamus (Clarke from the globus pallidus and substantia nigra. et al., 1994). !e lesion apparently interrupts recipro- !e ventral anterior nucleus is the most common cal connections between the thalamus and areas of the lesion site in the thalamus associated with aphasia frontal cortex. In contrast, some patients with bilateral (Nadeau et al., 1994). Mild transient hemiparesis and paramedian thalamic infarction exhibit thalamic pseu- hemiataxia may be present following damage to the ven- dodementia (robot syndrome), in which they act in a tral lateral nucleus (Bogousslavsky et al., 1986; Melo and manner similar to patients with thalamic dementia but Bogousslavsky, 1992). Hemineglect may be observed in can act normally if they are constantly stimulated by right-sided lesions (Gra$-Radford et al., 1985). other people who show them what to do. It is suggested Touch (somesthetic) signals are relayed from the that both syndromes result from damage to the medi- head and body to the somesthetic (parietal) cortex odorsal nucleus but that only the nonmagnocellular through the ventral posterior nucleus. !is nucleus is portions are involved in the robot syndrome. !e mag- frequently subdivided into the ventral posterolateral nocellular portion of the mediodorsal nucleus appears nucleus (VPL), which mediates touch from the body to be important in memory (Gra$-Radford et al., 1990; to the parietal cortex, and the ventral posteromedial Bogousslavsky, 1991; Bogousslavsky et al., 1991). nucleus (VPM), which mediates touch from the head In a report of eight patients with bilateral thalamic region to the parietal cortex (Chapter 4). tumors who exhibited personality change, memory A lesion of the ventral posterior nucleus produces loss, inattention, confusion, and hallucinations, in each sensory loss on the contralateral side without major case, the tumor involved the medial aspect of the le& cognitive de#cits. Paresthesias, including pain, may and right thalamus (Partlow et al., 1992). Personality be the #rst symptoms. !e patient may exhibit contra- changes o&en are severe enough to result in institu- lateral neglect. In some cases pain may develop only tional care. Most symptoms seen following an infarct a&er several weeks. !e thalamic pain syndrome is improve over time with the exception of amnesia. now more accurately called the central poststroke pain It has been hypothesized that the magnocellular syndrome. It can occur a&er thalamic lesions as well as portion of the mediodorsal nucleus may be released lesions in the spinal cord, brainstem, or cerebral hemi- 159 (disinhibited) in OCD. !e release in behavior is similar spheres (Bovie et al., 1989). Diencephalon: Thalamus

Neuropathic pain has been treated with varying Figure 9.4. A magnetic res- degrees of success with electrical stimulation of VPM/ onance image VPL. It is theorized that the pain results from lack of (T1-weighted) proprioceptive stimuli reaching the thalamus (Head and demonstrated a strategic stroke in Holmes, 1911). Stimulation correlates with increased the left thalamus blood "ow to the region including VPM/VPL contra- in a patient with lateral to the painful body site. Increased blood "ow has cognitive de"cits, particularly in also been reported in the anterior insula ipsilateral to working memory the thalamic stimulation (Duncan et al., 1998). and calculations. Lesions of the posterolateral thalamus can result (Reprinted with permission from in thalamic astasia, the inability to stand unsupported. Mendez et al., 2003.) !is is distinguished from pusher syndrome, in which patients actively push away from the nonparetic side (Karnath et al., 2000; Karnath 2007). Patients with pusher syndrome have a misperception of the body’s orientation. Pusher syndrome is seen following lesions involving the posterior thalamus and less frequently, the insula. !e lesion, which usually includes the ventral posterior and lateral posterior thalamic nuclei, may disrupt projections associated with somesthetic information (Pérennou et al., 2002). Lateral thalamic nuclei !e ventral intermediate (ventrointermedial) The lateral thalamic nuclear group makes up the nucleus forms the posterior and ventral portion of the largest of the thalamic nuclear groups. It consists ventrolateral nucleus. Deep brain stimulation of this of three nuclei. The lateral dorsal nucleus, the most nucleus is e$ective in treating essential tremor. While anterior of the group, is functionally related to the using electrodes to record tremors, Münte and Kutas anterior thalamic nuclear group and lies immedi- (2008) and Wahl et al. (2008) found that the thalamus ately behind the anterior nuclei. The major con- is sensitive to semantic and syntactic speech errors. nections of the lateral dorsal nucleus are with the !e authors suggested that the nearby centromedian cingulate and parietal cortex. The larger and more nucleus is the source of the signals representing speech posterior lateral posterior nucleus projects to the error detection. inferior parietal lobule. Clinical vignette !e pulvinar forms the most posterior portion of the thalamus and overhangs the dorsal surface of the A 61-year-old right-handed carpet salesman became midbrain. !e medial pulvinar has projections to the acutely unable to perform the calculations needed to determine the amount of carpet for a $oor area. He frontal lobe similar to those of the mediodorsal nucleus. underwent tests of his calculation ability. On 16 writ- Targets of #bers from the medial pulvinar include the ten problems, he made the following errors: 5 + 6 = dorsolateral and orbital prefrontal cortex as well as the 36, 26 + 17 = 53, 621 – 72 = 541, 5 × 13 = 75, 78/13 = insula and posterior cingulate gyrus (Romanski et al., 5.5. On a word problem (“18 books on 2 shelves, put 1997). !e mediodorsal nucleus and medial pulvinar twice as many on the top shelf), he stated, “18 on the may represent components of a single nuclear con- top and none on the bottom.” Further testing revealed tinuum (Romanski et al., 1997; Byne et al., 2009). In di!culties related to working memory, a frontal-ex- contrast, the lateral pulvinar has connections with the ecutive function.This patient had cognitive di!cul- visual cortex and is believed to be involved in the con- ties from a thalamic stroke (Figure 9.4). On magnetic trol of eye movements. !e pulvinar contains several resonance imaging, he had a new lacunar infarct in nuclei that are retinotopically organized and impli- the left thalamus. Infarction in the territory of the left tuberothalamic artery, with injury to the medial group cated in processing behaviorally salient visual targets. of thalamic nuclei and their prefrontal connections, It has direct projections to the lateral amygdala and is can produce di!culty in the working memory neces- proposed to form part of a secondary extrageniculos- 160 sary to perform calculations. triate visual system (Morris et al., 2001; Vuilleumier et al., 2003). Anatomy and behavioral considerations

Signi#cant volume reductions in autopsy material reticular nucleus is believed to mediate the inhibitory from schizophrenia patients have been reported for the in"uences from the frontal lobes as well as excitatory pulvinar bilaterally (Danos et al., 2003) and on the right impact of the brainstem reticular formation. It provides side (Highley et al., 2003). A volume reduction in the a possible mechanism for autohypnosis and voluntary pulvinar but not the mediodorsal nucleus was reported pain control (Mesulam, 1985; Scheibel, 1997). in schizotypal personality disorder (Byne et al., 2001). !e pulvinar has been implicated in “blindsight” Intralaminar nuclei (Chapter 4). An increase in bilateral pulvinar relative !e intralaminar nuclei represent an anterior continu- cerebral blood "ow (rCBF) has been reported following ation of the brainstem reticular formation (Chapter 10). alleviation of chronic pain by anesthetic blocks and by In addition to reticular a$erents, projections from spi- direct thalamic stimulation (Kupers et al., 2000) and an nal and brainstem pain systems are important inputs to increase in rCBF in the le& pulvinar in response to sub- the intralaminar nuclei. !e pattern of projection from occipital stimulation for relief of the pain of migraine the intralaminar nuclei is di$use and widespread, and headache (Matharu et al., 2003). Pulvinotomy and reaches all areas of the cerebral cortex. !e intralami- electrical stimulation of the pulvinar have been used nar nuclei provide signi#cant input to the basal ganglia successfully in the past for the control of chronic pain as well as to cells located in the thalamus itself. (Yoshii et al., 1980). !e pulvinar receives nociceptive !e centromedian nucleus is the largest of the input and projects to the superior parietal lobule but it intralaminar nuclei. It receives #bers from the basal is unknown whether the pulvinar mediates pain or is ganglia, brainstem reticular formation, vestibu- just associated with it (Matharu et al., 2003). lar nuclei, and superior colliculus. It projects di$use excitatory projections to broad cortical areas. It has Medial and lateral geniculate bodies connections with the basal ganglia, primarily the puta- !e medial geniculate body relays auditory signals men, and is part of sensorimotor and limbic loops. !e from the inferior colliculus to the temporal cortex. centromedian and parafascicular nuclei make up the !e lateral geniculate body relays visual signals from caudal group of intralaminar nuclei. !e two are some- the retina to the occipital cortex. Damage to the lateral times grouped together as the centromedian–parafas- geniculate body can result in visual #eld disturbances cicular complex. (Bogousslavsky et al., 1988a). !e di$usely projecting intralaminar nuclei are part of a system that governs the level of arousal of the Reticular nucleus brain. !e system is believed to play a role in select- A sheet of myelinated #bers called the external medul- ive attention. It becomes activated when going from a lary lamina covers the lateral, anterolateral, and relaxed to an attention-demanding state (Kinomura ventrolateral surfaces of the thalamus and lies between et al., 1996). the thalamus and the internal capsule. Embedded Lesions placed in the medial portion of the cen- within the external medullary lamina is a group of tromedian nucleus produce a reduction in aggression. small nuclei, collectively called the reticular nuclei, Lesions located laterally in this nucleus are less e$ective or more simply the reticular nucleus. Neurons of the in reducing aggression (Andy et al., 1975). Transient reticular nucleus are γ-aminobutyric acid (GABA) loss of consciousness usually seen a&er a paramedian ergic and make extensive reciprocal connections with infarction may be due to involvement of the intralami- all the nuclei of the dorsal thalamus. !ey receive #bers nar nuclei (Karabelas et al., 1985). from, but do not project #bers to, the cerebral cortex. Signi#cant centromedian volume reduction has !e reticular nucleus receives collateral input from the been reported in autopsy studies in schizophrenia. One thalamocortical, corticothalamic, thalamostriate, and study reported a nonsigni#cant 13.5% reduction and a pallidothalamic #bers. second found a signi#cant reduction when corrected !e reticular nucleus is believed to serve as an for brain weight (Byne et al., 2002). Findings suggested attentional valve or gate for thalamocortical transmis- that volume is increased by exposure to neuroleptic sion. !ere appear to be as many gates as there are sen- drugs (Kemether et al., 2003). It was speculated that sory modalities with individual cell groups within the this is due to the high density of D2-like receptors in the reticular nucleus that are sensitive to speci#c sensory centromedian nucleus (Rieck, et al., 2004; Lieberman modalities or to portions of sensory modalities. !e et al., 2005; Byne et al., 2009). 161 Diencephalon: Thalamus

!e centromedian–parafascicular complex exhibits a has been proposed between thalamus volume and clin- marked decrease in cell numbers in Huntington disease. ical response to drugs (Strungas et al., 2003). Because of the suspected role played by the centromedian One of the primary functions of the thalamus is to nucleus in oculomotor control, it is speculated that the #lter or gate sensory input. A defect in this function cell loss is the basis of abnormal saccadic eye movement could explain di%culties in the interpretation of sen- seen in Huntington disease (Heinsen et al., 1999). sory input, which may include some of the symptoms of schizophrenia. Limbic thalamus Distractibility, loss of associations, and shi&ing !e limbic thalamus is de#ned as that portion of the attentional focus commonly seen in schizophrenia thalamus that serves the limbic cortex (Bentivoglio patients may result from sensory overload. !e inabil- et al., 1993). Based on this de#nition, the limbic thal- ity to screen out irrelevant stimuli may be a failure amus originally was made up of only the anterior thal- of the gating function of the thalamus (Bra$, 1993). amic nuclear group. Results of more recent studies Regional blood "ow to the thalamus increases bilat- have broadened the content of the limbic thalamus to erally during auditory hallucinations (but not during include parts of a number of thalamic nuclei (Table visual hallucinations) experienced by schizophrenia 9.1). !e lateral dorsal nucleus projects to the cingu- patients (Silversweig et al., 1995). late cortex. In addition, the di$use group of nuclei One hypothesis advanced to explain the variety of that project to many areas of the cortex include cell symptoms of schizophrenia is that the midline neural groups that project to the cingulate cortex. !e mid- circuits which mediate attention and information pro- line and intralaminar nuclei, in particular, contain cessing are dysfunctional. When magnetic resonance cells that project to the cingulate cortex. !e ventral (MR) images of normal individuals were averaged anterior nucleus is generally considered one of the together and then compared with the averaged MR motor nuclei and is associated with the basal ganglia images of schizophrenia patients, speci#c regional and cerebellum. However, the ventral anterior nucleus abnormalities were observed in the thalamus and adja- also projects to the cingulate cortex, thus establishing a cent white matter. !e lateral and ventrolateral areas close link between motor systems and the limbic cortex of the thalamus, which project to the cingulate gyrus, (Vogt et al., 1987). !e mediodorsal nucleus projects parietal cortex, and temporal cortex, were seen to be heavily to the prefrontal cortex. It also sends #bers to most involved (Andreasen et al., 1994). !e reduction the cingulate cortex and is included by some as part of in size of the thalamus may produce an abnormality the limbic thalamus (Bentivoglio et al., 1993). !e cin- in the normal gating and #ltering function of the thal- gulate cortex projects back to all of the components of amus and allow a bombardment of the cortex by sen- the limbic thalamus. Anterior, mediodorsal, and mid- sory stimuli, resulting in di%culty in distinguishing line nuclei project to the ventral anterior portion of the “self” from “nonself.” Figure 9.5 illustrates a decrease cingulate cortex. !ese thalamic nuclei receive much in blood "ow in the thalamus seen in schizophrenia of their information from brainstem and hypothalamic (Andreasen, 1997). nuclei that are recognized as autonomic centers. !e !e thalamus is involved in many functions, includ- regulation of visceral and autonomic function is one ing the storage and retrieval of memory. As stated by of the prominent roles of the ventral anterior cingulate Silversweig and associates (1995), “!e thalamus is cortex (Chapter 12). believed to generate an internal representation of reality, in the presence or absence of sensory input.” !e Other behavioral considerations anterior nuclei and the lateral dorsal nucleus in par- A number of studies have shown decreased thalamic ticular are involved in memory. Memory disturbance volume in schizophrenia. Several have compared it with in Korsako$ disease corresponds with loss of cells in total brain volume, which is known to be decreased in the medial portion of the dorsal medial nucleus as well schizophrenia, and found the thalamic decrease sig- as cells in the nearby midline nuclei. ni#cant (Konick and Friedman, 2001; Kemether et al., It has been hypothesized that there exists a medial 2003). !alamic volume may be sensitive to neurolep- and a lateral pain system (Albe-Fessard et al., 1985). tics. Several studies have reported that thalamic vol- !e medial pain system includes the periaqueductal ume correlates positively with dosage of neuroleptic gray of the midbrain and the intralaminar and mid- 162 drugs (Gur et al., 1998; Khorram et al., 2006). A link line thalamic nuclei, which project to the cingulate References

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CChapterhapter 10 Brainstem

Introduction !e brainstem is the connection between the spinal cord, the cerebellum, and the cerebrum. It has only Fourth Solitary tract ventricle recently been implicated in behavior. !e brainstem PrH and nucleus Dorsal vagal Cerebellar anatomically comprises three areas: the medulla, the nucleus peduncle pons, and the midbrain (Figure 2.1). !e medulla, the most inferior segment of the brainstem, represents a MLF conical, expanded continuation of the upper cervical spinal cord. !e pons lies between the medulla and the midbrain. !e midbrain is the smallest and least Trigeminal di$erentiated division of the brainstem. !e nuclei nucleus of cranial nerves III through XII are located in the Raphe and tract brainstem along with long sensory and motor tracts nuclei LPGi that pass between the brain and spinal cord. Several regions of the brainstem, however, seem to be signi#- Reticular Inferior olive formation cantly involved in behavior. !ese behaviorally active Sensory tract Pyramidal regions include: the reticular formation, the parabra- motor tract chial nucleus, the raphe nuclei, the periaqueductal gray Figure 10.1. A cross section typical of the medulla. The brainstem (PAG), the nucleus locus ceruleus, the lateral tegmen- inset in the upper left indicates the level of the cross section. PrH, tal nucleus, the ventral tegmental area (VTA), and the nucleus prepositus hypoglossi; LPGi, caudal extent of nucleus inferior olive. !e VTA is considered to be one of the paragigantocellularis lateralis (positions approximate); MLF, medial longitudinal fasciculus. basal ganglia (Chapter 7). Anatomy and behavioral intralaminar nuclei of the thalamus (Table 9.1, Chapter considerations 9). !e reticular formation extends rostrally from the brainstem into the hypothalamus. Ascending reticular Reticular formation #bers to the hypothalamus are distinct from those that !e reticular formation is one of the oldest portions of go to the thalamus. the brain and represents the core of the brainstem. It is !e continuous bottom-up sensory input into the composed of complex collections of cells that form both ARAS plays an important role in wakefulness, alertness, di$use cellular aggregations and more de#ned nuclei. and arousal. Lesions in the rostromedial midbrain teg- !e ascending reticular activating system (ARAS) mentum abolish the electroencephalographic (EEG) is a physiological concept. It is represented anatomic- arousal reaction elicited by sensory stimulation even ally by the central core region of the brainstem (Figure though the long ascending sensory pathways remain 10.1), including the raphe nuclei (Figure 10.2). !is intact. !e cerebral cortex acts in a top-down man- region contains a number of nuclei. !e ARAS receives ner to alter the state of consciousness by in"uencing collateral #bers from the surrounding speci#c sen- the reticular neurons. Such a role has been suggested sory systems. !e main long ascending pathway of by the well-known arousing e$ect of psychic stimuli. the brainstem reticular formation is the central teg- Areas of the cerebral cortex from which the arousing 167 mental tract (Figure 10.3). !is tract projects to the e$ect can be obtained by electrical stimulation include Brainstem

in sleep mechanisms (Figure 10.3). It is recognized as important in the induction and maintenance of rapid eye movement (REM) sleep (Semba, 1993). It is consid- Fourth ventricle Locus ceruleus Parabrachial ered to be a striatal output station and is a component nucleus Cerebellar of the “mesencephalic locomotor region” (Mogenson peduncles et al., 1989; Winn et al., 1997). A decrease in choline Tegmentum acetyltransferase has been reported in this nucleus in schizophrenia patients, which suggests a reduction MLF in brainstem acetylcholine activity in this disorder (Karson et al., 1993). See Chapter 7 for a more complete Basilar pons discussion of the importance of the pedunculopontine Sensory tegmental nucleus in the regulation of behavior. tracts Raphe nuclei Parabrachial nucleus !e parabrachial nucleus lies medial to the superior Figure 10.2. A cross section typical of the pons. The sensory tracts from medial to lateral are the medial lemniscus, the spinal cerebellar peduncle and medial to the sensory (lemnis- lemniscus, and the lateral lemniscus. MLF, medial longitudinal cal) tracts in the pons and midbrain (Figure 10.3). It fasciculus. receives visceral sensory information from the spinal cord and brainstem. It gives rise to ascending #bers that project to the hypothalamus (Chapter 8) and amygdala (Chapter 11) and to the raphe nuclei (Holstege, 1988). Cerebral aqueduct Inferior colliculus !e parabrachial nucleus is a general integrative Periaqueductal gray Oculomotor site for visceral information, including taste, cardio- nuclei Central respiratory signals, and visceral pain (Craig, 1996; tegmental Chamberlin, 2004). It links these sensations with the tract Sensory central nucleus of the amygdala and the hypothalamus pathway (see “autonomic sensory nuclei” in Figure 11.5 and R 11.6). It is proposed that the parabrachial nucleus is Cerebellar peduncle PPTg Clinical vignette Motor pathway A 15-year-old boy underwent resection of a cerebellar astrocytoma arising from the fourth ventricle and Substantia nigra adherent to the brainstem. Post operatively he devel- Ventral tegmental area oped a sleep disorder where he suddenly sat up in bed, screamed, and appeared to be staring in fright. During Figure 10.3. A cross section typical of the caudal midbrain at the these episodes he was agitated and would try going level of the inferior colliculus. PPTg, pedunculopontine tegmental over the rails or would thrash about in bed scream- nucleus; R, raphe nucleus. ing. After one to two minutes, he promptly fell back to sleep. The patient had incomplete recollections the orbital prefrontal cortex, the lateral surface of the of these episodes. Sometimes the only evidence of frontal lobe, the sensory motor cortex, the superior an episode was injury or blood on the $oor. At other temporal gyrus, and the cingulate gyrus. !e reticular times, he recalled being frightened by images of parts formation has three more important functions: regu- of people sticking out of walls or by the belief that the lation of muscle re"exes, coordination of autonomic bedposts were his roommates restraining him. functions, and modulation of pain sensation. It is of The patient’s evaluation was consistent with night interest that reticular formation neurons involved in terrors, or pavor nocturnus, associated with his brainstem lesion. Polysomnography documented his night the control of breathing and cardiac function are in"u- terrors with spontaneous arousals punctuating all enced by higher centers, including the hypothalamus stages of sleep, particularly stage 3 and 4 sleep. His and prefrontal association areas. episodes of night terrors decreased after he started to 168 !e pedunculopontine tegmental nucleus (PPTg) take clonazepam at bedtime (Mendez, 1992). is a cholinergic nucleus of the ARAS that is involved Anatomy and behavioral considerations important in the emotional and autonomic responses to incoming visceral signals, especially visceral pain (Bernard et al., 1996; Norgren et al., 2006). Superior Cerebral colliculus aqueduct Periaqueductal gray Oculomotor Thalamus Raphe nuclei nuclei Several groups of cells that are situated along the midline of the medulla, pons, and midbrain are collectively called the raphe nuclei (Figures 10.1, 10.2, 10.3, and 10.4). !ey are part of the brainstem reticular forma- R tion, but produce a particular neurotransmitter, sero- Motor nucleus tonin [5-hydroxytryptamine (5-HT)]. Neurons from di$erent raphe nuclei contain speci#c cotransmitters Motor pathway (peptides). Areas that project #bers to the raphe nuclei Substantia nigra Ventral tegmental include the amygdala, hypothalamus, and PAG, as well area as other brainstem nuclei (Figure 10.5). Figure 10.4. A cross section typical of the rostral midbrain at the Rostral pontine and midbrain raphe nuclei project level of the superior colliculus. R, raphe nucleus. to the PAG and to structures in the cerebrum. Most pontine raphe nuclei have long ascending projections that are located in the medial forebrain bundle. Fibers pro- Cerebral cortex ject to the hypothalamus, nigral complex, intralaminar Frontal lobe thalamic nuclei, stria terminalis, septum, hippocam- Limbic structures pus, amygdala, and cerebral cortex. Of particular interest are raphe projections to the ventral tegmental area Periaqueductal and to the nucleus accumbens. Cortical projections are gray con#ned largely to the frontal lobe, although #bers to Reticular formation other neocortical areas have been demonstrated. Raphe nuclei Limbic Medullary and caudal pontine raphe nuclei project structures to other parts of the brainstem and to all levels of the cord. Targets include the trigeminal nuclei and the dor- Brainstem sensory nuclei sal and ventral spinal cord gray matter. !ese descending projections of the raphe nuclei are ideally situated Spinal cord to regulate incoming sensory stimuli. !e raphe spinal Dorsal horn tract, which terminates in the spinal trigeminal nucleus Ventral horn and in the spinal cord dorsal horn, regulates (inhibits) Figure 10.5. The raphe nuclei are a major source of serotonin. incoming pain signals (Mason and Leung, 1996). !e Descending in!uences can block pain stimuli (dorsal horn) and nucleus raphe magnus, which gives rise to the raphe facilitate motor activity (ventral horn). Ascending projections inhibit spinal tract, is controlled by neurons in the PAG. !ey, nonmeaningful stimuli and facilitate meaningful signals. in turn, receive input from the limbic system, thus providing a link between emotion, pain, and defense hypersensitive to virtually all environmental stimuli behaviors (see the following section on PAG). Other and is hyperactive in all situations. Serotonin inhib- raphe spinal projections that terminate in the ventral its sensory stimuli that have a waking e$ect (see the horn are thought to function in a neuromodulatory section later on locus ceruleus and lateral tegmental role to facilitate locomotion. nucleus). It may help to facilitate meaningful sensory Serotonin and the raphe nuclei have been impli- stimuli and to inhibit nonmeaningful sensory stimuli. cated in the regulation of sleep, aggressive behavior, Serotonin in this way aids in maintaining behavior pain, and a variety of visceral and neuroendocrine within speci#c limits. functions. Raphe neurons decrease their #ring rate Serotonergic neurons may have a priming e$ect on from waking to sleep and cease #ring during REM the cells of the nucleus locus ceruleus, which are respon- sleep. Destruction of serotonin neurons or block- sible for triggering the REM sleep stage (Jacobs, 1994). 169 ade of serotonin receptors produces an animal that is In contrast to locus ceruleus neurons, which increase Brainstem

their #ring rate during periods of intense environmen- Clinical vignette tal stimuli, the serotonergic neurons #re more rapidly A 59-year-old man was found dead from a self-in$icted during periods of quiet, rhythmical behaviors such gunshot wound. Three years before his death he had as grooming or chewing, behaviors associated with a developed left-sided hemianesthesia. A computed relaxed state (Jacobs and Fornal, 1993). tomographic (CT) scan taken at the time showed a Activity in the dorsal raphe nuclei raises the thresh- lesion in the tegmentum of the upper pons on the right old that activates defensive behaviors controlled by side. Over the following few months other neurological the PAG of the midbrain. Medullary raphe nuclei de"cits developed but he was not incapacitated. Five play a similar role in the modulation of cardiovascu- months after the initial episode he developed severe lar responses to stress (Lovick, 1996). Projections from depression with paranoid ideations. The patient had no past or family history of a#ective disorders. He failed to the raphe nuclei to the mesolimbic structures (ventral respond to a number of antidepressants that were tried tegmental area and nucleus accumbens) provide a link over a period of two years. Postmortem examination between serotonin and dopamine. It is hypothesized revealed a cavernous hemangioma impinging on the that the raphe nuclei play an important regulatory role upper pontine region of the raphe nuclei on the right in the control of dopamine release. Because of this rela- side and extending to partially involve the raphe on the tionship the raphe nuclei may play a role in schizophre- left side. It was believed that the lesion caused deple- nia (Mylecharane, 1996). tion of the ascending serotonergic system to the fore- A loss of the serotonergic neurons of the raphe brain (Kline and Oertel, 1997). nuclei has been documented in Alzheimer disease (Aletrino et al., 1992). However, the concentration of cortical serotonin was found to be in the normal range, Clinical vignette suggesting that sprouting of raphe axon terminals in A 55-year-old right-handed man presented with the cortex makes up for the de#ciency of serotonin due acute, uncontrolled crying spells and numbness over to raphe neuron loss (Chen et al., 1996). his left face and arm. Around 6:00 am he awoke with a di#use pressure headache and suddenly started Blood levels of serotonin are elevated in autistic crying for no apparent reason. After "ve minutes, the and in some mentally retarded individuals. !e sig- crying abruptly ceased. Over the next two to three ni#cance of this #nding is obscure since cerebrospinal hours, he had "ve more crying spells, each lasting "ve "uid levels do not correlate with blood levels. It has to ten minutes, occurring out of context, without pre- been suggested that the abnormal serotonin levels may cipitating factors or sadness, with an acute onset and re"ect a role played by serotonin in brain development o#set, and without alteration of consciousness. The (McNamara et al., 2008). patient’s left face and arm numbness persisted during Uncontrolled crying is a behavior commonly seen and between these crying spells but abruptly resolved a&er stroke (one-year incidence is 20%). Successful shortly after his last crying spell. treatment by selective serotonin reuptake inhibi- After an extensive neurological evaluation, a diag- tor drugs has led to the suggestion that this behavior nosis of transient ischemic attacks with crying spells was made. The transient ischemic attacks could have results from stroke-induced partial destruction of involved the right brainstem and the raphe nuclei. This raphe nuclei or of their ascending projections to the patient may have had a temporary activation or stimu- cerebral hemispheres (Andersen, 1995). lation of ischemic areas or alterations in serotonergic neurons (Mendez and Bronstein, 1999). Periaqueductal gray !e PAG surrounds the cerebral aqueduct in the mid- system is also an important source of #bers to the PAG brain (Figures 10.2 and 10.4). It is connected with (Chapter 11, Figure 11.5). many forebrain structures above as well as with brain- !e PAG is important in eliciting many somatic stem structures below. It has reciprocal connections and visceral stereotypical behaviors. It is the major with the central nucleus of the amygdala. Descending center through which the hypothalamus enacts behav- #bers from the PAG include those to the raphe nuclei iors critical to the survival of the self and of the species. involved in the suppression of incoming pain sig- !ese behaviors include regulation of heart rate and nals. !e PAG is centrally located between the limbic respiration, urination, grooming, and basic elements 170 system and somatic and visceral motor control cent- of defensive and reproductive behaviors (Craig, 1996). ers. !e central nucleus of the amygdala of the limbic Other behaviors elicited by stimulating the PAG include Anatomy and behavioral considerations

threat, freezing, escape, and vocalization (Bandler and Cerebral cortex Keay, 1996; Schenberg et al., 2005). Amygdala Nashold et al. (1974) found that stimulation of the PAG evoked “feelings of fear and death”. Facial blushing, Hippocampus sweating, and other autonomic responses were noted. Cerebellum It has been suggested that the PAG plays a key role in triggering panic (Gorman et al., 1989: Chapter 11). Reticular Locus ceruleus Locus ceruleus and lateral formation Lateral tegmental nucleus tegmental nucleus !e locus ceruleus is represented by a group of dis- Brainstem sensory nuclei tinct nerve cell bodies that make up a nucleus near the ventrolateral corner of the fourth ventricle in the pon- Spinal cord tine tegmentum (Figure 10.3). It extends rostrally into Figure 10.6. The locus ceruleus and lateral tegmental nucleus the PAG of the midbrain. Cells of the locus ceruleus provide norepinephric projections to the entire neuraxis. Novel are rich in norepinephrine (NE), and the locus ceruleus environmental stimuli act through norepinephrine to direct the contains half the NE neurons found in the brain. brain to alert, orient, and attend to selective stimuli. The two speci"c reticular nuclei that contact the locus ceruleus are nucleus Input to the LC is provided largely by two reticu- hypoglossi prepositus and nucleus paragigantocellularis. lar nuclei, the nucleus prepositus hypoglossi and the nucleus paragigantocellularis (see PrH and LPGi, the hippocampal formation and as a component of Figures 10.1 and 10.6; Aston-Jones et al., 1995). !e the cingulum to the cingulate cortex. A contingent of nucleus prepositus hypoglossi provides inhibitory #bers even terminates in the cerebellum (Chapter 2). input whereas the nucleus paragigantocellularis pro- Descending #bers from the locus ceruleus are rela- vides strong excitatory input (Aston-Jones et al., 1990, tively sparse. E$erent #bers from the locus ceruleus 1991a). !e prepositus hypoglossi nucleus receives to the caudal brainstem terminate on sensory nuclei. input from the nucleus of the solitary tract, which Fibers to the spinal cord end in both the dorsal and the conveys information about the vegetative state of the ventral horns (Holets, 1988). body. !e prepositus also receives input from other One of the most profuse projections of the locus brainstem sensory nuclei and from the spinal cord ceruleus is to the thalamus, where terminals are found (Aston-Jones et al., 1991a). !e nucleus paragiganto- in the intralaminar and anterior nuclei (Table 9.1). cellularis receives signals from diverse sites throughout !ese thalamic nuclei are included as part of the lim- the brainstem and spinal cord that are associated with bic thalamus. !e limbic thalamus projects to all cor- autonomic and integrative functions (Aston-Jones tical areas and has been linked to arousal and selective et al., 1991b). Other #bers to the locus ceruleus arrive attention. !e norepinephrine system that arises in the from the parabrachial nucleus, the PAG, and the hypo- LC “is unique in the brain in that it innervates more thalamus. It has been suggested that one or more of CNS areas than any other single nucleus” (Aston-Jones these sources are important in the inhibition of neuron et al., 1995). !e remarkable feature of the locus ceru- discharge seen in the locus ceruleus during paradox- leus projection is its wide distribution throughout the ical sleep (Luppi et al., 1995). brain. Each locus ceruleus neuron may contact thou- !e ascending projection from the locus ceruleus sands of cortical neurons. !e most rostrally project- represents the majority of its output. !is group of #b- ing #bers of the locus ceruleus exit from the medial ers passes rostrally through the midbrain, lateral to the forebrain bundle and distribute to the rostral, dorsal, medial longitudinal fasciculus. !e #bers accompany and lateral cortex of the frontal lobe, where they ter- the medial forebrain bundle to and through the lat- minate in the most super#cial cortical layer, which is eral hypothalamus. !is ascending pathway continues considered an important site for cortical integration. rostrally to levels of the anterior commissure, where it !e lateral tegmental nucleus is represented by scat- divides into #bers that innervate midline portions of tered NE neurons that extend ventrolaterally from the the thalamus, the amygdala, the hippocampus, and locus ceruleus to the ventral aspect of the brainstem. vast regions of the cortex (Foote et al., 1983). Other Although these cells may appear to be only a ventro- 171 #bers from the locus ceruleus pass via the fornix to lateral extension of the locus ceruleus, the connections Brainstem

of the lateral tegmental nucleus di$er from those of the A relatively low tonic level of locus ceruleus activity is locus ceruleus. Targets of the #bers from the lateral teg- associated with inattention. mental nucleus generally do not overlap those of the Norepinephrine facilitates long-term potentiation locus ceruleus, thus justifying the recognition of the of hippocampal neurons, indicting that it can in"u- lateral tegmental nucleus as more than just an exten- ence memory. NE functions in the cortex to inhibit sion of the locus ceruleus. Major projections descend ongoing random neuron activity and to potentiate and terminate in the spinal cord and brainstem. More neuron response to selective stimuli, thus increasing di$use projections terminate in the thalamus, hypo- the signal-to-noise ratio for incoming sensory signals. thalamus, amygdala, and cerebellar cortex (Burstein, Actions of NE on the thalamus and cortex enhance the 1996). Like the NE neurons of the locus ceruleus, the signal processing ability of the forebrain (Berridge, lateral tegmental nucleus neurons also cease #ring dur- 1993). Norepinephrine produces a slow excitatory ing sleep. postsynaptic potential (EPSP) in neurons of the hippo- !e LC operates in a bimodal fashion: phasic and campus and over a wide area of the cerebral cortex tonic. In the phasic mode it produces a short lasting, (Nicoll et al., 1987). widespread release of norepinephrine. !is functions !e locus ceruleus is believed to play an important to increase gain of cortical processing to enhance focus role in the initiation of REM sleep. Locus ceruleus neu- on task-appropriate behavior while at the same time rons are inactive during sleep, and electrical stimula- inhibiting attention to distracting stimuli. !e phasic tion of the locus ceruleus and subsequent release of NE response is believed to be driven by activity in the produce an increase in the state of arousal (Aston-Jones orbital prefrontal cortex and anterior cingulate gyrus and Bloom, 1981). !e administration of NE is known (Rajkowski et al., 2000, 2004; Aston-Jones et al., 2002). to increase the state of arousal and also to increase the !e orbital prefrontal cortex and anterior cingulate level of anxiety. Both arousal and anxiety, therefore, are also responsible for transitions between tonic and may be linked to the locus ceruleus. Monoamine oxi- phasic modes (Corbetta et al., 2008). dase (MOA) inhibitors and tricyclic agents, which are Locus ceruleus neurons in the tonic mode increase clinically e$ective in treating depression in humans, baseline activity and at the same time decrease phasic inhibit the #ring of locus ceruleus neurons in experi- activity. !e tonic mode allows the brain when not mental animals. !e high level of anxiety and loss engaged in a speci#c task, to operate in a search mode of pleasure reported by depressed patients may be to explore alternative behaviors (Aston-Jones and related to the loss of regulation of NE by locus ceruleus Cohen, 2005). In contrast, abnormally elevated tonic neurons. baseline activity of the locus ceruleus is believed to be Acute exposure to opiates inhibits the action of associated with high distractibility. A high tonic level locus ceruleus neurons by binding µ receptors that of locus ceruleus activity is associated with labile atten- are coupled to G-protein (Chapter 3) (Williams tion and poor task performance –behavior o&en seen et al., 2001). In contrast, chronic exposure to opiates in attention-de#cit hyperactivity disorder (Aston- increases the excitability of the locus ceruleus neu- Jones and Gold, 2009). rons by upregulation of the intracellular cyclic adeno- Operation in either tonic or phasic mode has been sine monophosphate (cAMP) pathway (Nestler and recognized in the regulation of arousal, attention, Aghajanian, 1997). !is is an expected response that and related autonomic tone. Locus ceruleus neurons brings the locus ceruleus #ring rate back toward a nor- respond with increased rates of #ring to novel envir- mal level. When opiates are withdrawn, the locus ceru- onmental stimuli but not to routine environmental leus is activated. !is activation is responsible for some stimuli (Jacobs, 1990). Stimuli that are e$ective in pro- of the behavioral signs of withdrawal. ducing a response in the neurons of the locus ceruleus A loss of cells is seen in the locus ceruleus of patients are stimuli that disrupt ongoing behavior and elicit an with Parkinson disease or Alzheimer disease (Zweig orienting response. !e largest response in locus ceru- et al., 1993). !ese individuals are o&en diagnosed with leus activity occurs during an abrupt transition from depression, and cell loss in the locus ceruleus correlates sleep to waking (Aston-Jones et al., 1996). with depressive signs and symptoms (Forstl et al., 1992). !e ascending locus ceruleus system is believed to One model of depression recognizes the degeneration function in arousal. It determines the salience of a tar- or retraction, or both, of locus ceruleus neurons as 172 get and is speculated to facilitate some types of learning. part of the pathophysiology of this disorder (Kitayama References et al., 1994). Locus ceruleus neurons are sensitive to activated. !eir action is modulated through GABA- corticotropin-releasing factor (CRF), and the hypoth- receptor-controlled gap junctions. Animal models alamic-pituitary-adrenal (HPA) axis is activated in indicate that inferior olive neurons may be involved in depression and altered in panic disorder (Chapter 8). essential tremor (Miwa, 2007). Patients with essential !e increase in CRF production during activation of tremor are reported to exhibit hypermetabolism in the the HPA axis may involve the LC in these disorders. inferior olive (Hallett and Dubinsky, 1993; Wills et al., Some antidepressant drugs may act by blocking CRF 1994). It is hypothesized that sub-threshold oscillations activation of the locus ceruleus (Curtis and Valentino, in the inferior olive form the basis of essential tremor 1994). In contrast, loss of cells in the locus ceruleus has (Loewenstein, 2002). been reported in patients with Alzheimer disease, but with no additional loss of locus ceruleus neurons in patients with both Alzheimer disease and depression Select bibliography (Hoogendijk et al., 1999). Arango, V., Underwood, M.D., and Mann, J.J. Biological Alcohol activates the norepinephrine system alterations in the brainstem of suicides. In: J.J.Mann (ed.) Suicide. Psychiatric Clinics of North America (vol. through a system that involves serotonin (Blum and 20). (Philadelphia: Saunders, 1997, pp. 581–594.) Kozlowski, 1990). !e number of locus ceruleus neu- Carpenter, M.B., and Sutin, J. Human Neuroanatomy. rons is reduced in alcoholics (Halliday and Baker, 1996). (Baltimore: Williams & Wilkins, 1983.) !e mechanism remains in question (Karolewicz et al., Hales, R.E., and Ydofsky, S.C. Textbook of Neuropsychiatry. 2008). Locus ceruleus neurons increase their #ring (Washington D.C.: American Psychiatric Association rate during opiate withdrawal (Self and Nestler, 1995). Press, 1987.) Karson et al. (1991) reported no change in the number Holstege, G., Bandler, R., and Saper, C.B. !e emotional of locus ceruleus neurons in patients with schizophre- motor system. Progress in Brain Research (vol 107). nia, but they found a signi#cant reduction in neuron (Amsterdam: Elsevier, 1996.) size. A model has been proposed that an increase in LC References activity is involved in attention-de#cit hyperactivity Aletrino, M.A., Vogels, D.J.M., Van Doinburg, P.H.M.F., disorder. !e model proposes that LC neurons #re at and Ten Donkelaar, H.J. 1992. Cell loss in the nucleus an abnormally high level as a result of a biochemical raphe dorsalis in Alzheimer’s disease. 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175

Chapter 11Limbic system: Temporal lobe

Anatomy parahippocampal gyrus rolls medially deep to the sur- !e temporal lobe can be divided into two parts. !e face to produce the parahippocampal sulcus. !e cortex newer lateral portion (neocortical) is responsible for transitions from six layers to three from the entorhinal audition, speech, and for the integration of sensory area to the hippocampal formation. !e hippocampal information from a variety of sensory modalities. !e neocortical division is the topic of Chapter 5. !e other division of the temporal lobe is the ventromedial portion, which is older cortex (archicortex and paleocortex) and consists of regions that have become recognized as components of the limbic system. !e limbic system structures that are part of the temporal lobe include the parahippocampal gyrus (Figures 5.4 and 13.1), the entorhinal cortex, the hippocampal formation (Figure 11.1), the uncus (Figure 13.2), and the H amygdala (Martin, 1996). !e cortex of the temporal A pole is sometimes considered limbic but is covered in Chapter 5. All sensory information from the external world passes through unimodal and multimodal association areas before #nally converging on the Figure 11.1. The approximate location of the amygdala (A) and hippocampus and amygdala. !ese structures can be hippocampus (H) in the temporal lobe is indicated. Compare with considered to be supramodal centers. Chapter 13 pro- Figure 2.2. vides an overall picture of the limbic system. !e hippocampus is important in declarative memory and for learning the importance of speci#c external stimuli. !e amygdala appears to be important in Lateral ventricle

assigning emotions to stimuli. !is includes emotional Pyramidal cell CA2 Fimbria of fornix conditioning and learning the relationship between CA3 internal and external cues related to emotion and a$ect Dentate gyrus CA1 Parahippocampal (Bechara et al., 1995). sulcus Subiculum Hippocampal formation !e hippocampal formation occupies a central pos- x ition in the limbic system (Figures 11.1, 11.2, and 11.3). te or al c !e hippocampal formation consists of the subicu- Entorhin lum, the hippocampus proper, and the dentate gyrus. Figure 11.2. A diagrammatic cross section through the ventro- Viewed from the ventral surface, the cortex medial medial temporal lobe and the entorhinal cortex of the parahippoc- to the collateral sulcus is the parahippocampal gyrus ampal gyrus. The hippocampal formation consists of the subiculum, (Figure 5.4). !e anterior end of the parahippocampal the dentate gyrus, and the hippocampus proper. The hippocampus proper is made up of four longitudinal zones, CA1–CA3. Information 176 gyrus is the entorhinal cortex and corresponds with enters the hippocampal formation via the entorhinal cortex and Brodmann’s area (BA) 28 (Figures 13.1 and 13.2). !e exits via the fornix. Anatomy

Visual associaton cortex described as the “single most vulnerable circuit in the Auditory association cortex cerebral cortex” (Morrison and Hof, 1997). Although Somatosensory association cortex these two pathways supply input to the hippocampus they also contain a signi#cant number of e$erent Entorhinal cortex Brainstem #bers. Locus ceruleus !e hippocampus is more primitive than the Raphe nuclei Ventral tegmental entorhinal cortex and consists of only three cell layers. Amygdala Hippocampus area !e pyramidal cell is the most distinctive cell of the hip- Fornix pocampal formation. Moderate amounts of dopamine, norepinephrine, and acetylcholine are present in the hippocampal formation. In addition to the entorhinal Hypothalamus Septum cortex, other sources of input to the hippocampal formation include the septal nuclei, hypothalamus, and Figure 11.3. A diagram of the major connections of the hippocampus. Processed sensory information arrives at the hippocampus thalamus as well as the brainstem (Figure 11.3). via the entorhinal cortex. Major hippocampal e#erents project to Two functionally separate circuits involve the three the amygdala, hypothalamus, and the septum. hippocampal sectors. A direct entorhinal-CA1 circuit is important for recollection-based recognition formation lies deep within the parahippocampal sul- memory. !e CA3 sector coupled with CA1 is neces- cus and forms a portion of the medial wall of the tem- sary for recall (Brun et al., 2002). Pyramidal cells in poral horn of the lateral ventricle (Figure 11.2). !e CA1 (Sommer’s sector) are highly sensitive to anoxia subiculum is three-layered cortex that lies between and ischemia, including epileptic seizure-induced the entorhinal cortex and the hippocampus proper. damage. !e presubiculum and parasubiculum are anteropos- Signals leave the hippocampus by way of the axons terior columns that lie between the parahippocampal of the pyramidal cells (Figure 11.2). !ese axons accu- cortex and the subiculum proper. !e hippocampus mulate medially to form the #mbria of the fornix proper is divided into four major #elds represented by (Figures 11.2 and 11.3). E$erent #bers from the hippo- cell columns CA1–4 (Figure 11.2). !ese longitudin- campus project to the septal area and to the hypothal- ally oriented sectors are referred to as CA1, CA2, and amus. Reciprocal (back-and-forth) connections exist CA4. CA refers to cornu ammonis, or Ammon’s horn, between the hippocampus and the amygdala. an early name for the hippocampus. CA1 lies ventrolat- !e hippocampal formation is well known for its erally, and CA4 lies medially near the origin of the for- role in declarative memory. Declarative memory is the nix. CA1 borders the subiculum and CA4 borders the memory of facts, experiences, and information about dentate gyrus. !e principal layer of the dentate gyrus events. !e hippocampus will retain the memory for is populated by granular cells. It also contains a small weeks to months before it is consolidated elsewhere population of stem cells. in the cortex. One hypothesis of memory involving !e entorhinal cortex is the gateway to the hip- the hippocampal formation is based on the concept pocampal formation (Figure 11.3). It receives input of a “cognitive map” (Jacobs and Schenk, 2003). !is from the olfactory bulb, prepyriform area, amygdala, hypothesis proposes that the original need for mem- and multimodal association areas of the temporal and ory was for a mechanism that provides for the ability frontal lobes. !e entorhinal cortex di$ers signi#cantly to return home. !e hippocampus appears to contain from that of other six-layered neocortical regions, and a world-centered map as opposed to the egocentric it is probably a form of transitional cortex. Two path- map found in the posterior parietal lobe (see page 40). ways conduct signals from the entorhinal cortex to the Declarative memory grew from the map mechanism hippocampal formation. Axons pass from the medial and much of declarative memory is based on a stepwise entorhinal cortex to the hippocampal formation form- sequence of events similar to those experienced as one ing the alvear pathway. !is pathway terminates in the journeys away from home. Wilson and McNaughton subiculum and CA1. Axons from the lateral entorhinal (1993) reported recording large ensembles of neurons cortex make up the perforant pathway. !e perforant from the CA1 region of the rat during spatial explor- pathway terminates in the dentate gyrus and all sectors ation. !e investigators could determine the location of the hippocampus. !e perforant pathway has been of the rat by analyzing the pattern of ensemble #ring 177 Limbic system: Temporal lobe

(Kjelstrup et al., 2008). Sleep is important in consoli- Figure 11.4. A. A coronal cut dating memories. !e hippocampus is activated during showed an area rapid eye movement (REM) sleep, and is likely to con- of hyperintensity tribute signi#cantly to the REM sleep phenomenon. in the left medial temporal lobe Changes seen between training sessions are believed to on T2-weighted be due to increased synaptic connections formed when magnetic reson- sessions were replayed in the hippocampus when the ance imaging. B. A horizontal view animals slept (Skaggs and McNaughton, 1996). revealed mass e#ect from the left Clinical vignette medial temporal A 40 year-old right-handed man was hospitalized for in!ammation. (Reprinted with delirium and generalized seizures. On examination, he permission from was confused, disoriented, and febrile. He was treated Mendez and for presumed herpes simplex encephalitis with aci- Cummings, 2003.) clovir and phenytoin. Magnetic resonance imaging showed hyperintense lesions in the left mesial temporal lobe with signi"cant swelling consistent with herpes encephalitis (Figure 11.4). After recovery, the patient was left with a severe amnestic disorder from damage to the left hippocampal formation and parahippocampal gyrus. He had di!culty learning any new information and inability to recall any items on delayed recall tests. His remote memory, however, remained intact.

Maguire et al. (2000) found that the posterior hippocampal gray matter volume was greater in experienced London taxi drivers compared with control subjects. !e gray matter volume of the right posterior hippocampus volume varied positively with the time driving. !is di$erence appeared to be the result of experience and not innate navigational expertise (Maguire et al., 2003). produce de#cits in declarative memory (Squire et al., Hippocampal structures have been implicated in 1990). None of these restricted lesions is as disruptive both cognitive and emotional processes. !e hippoc- to memory as is a lesion that involves all of the hip- ampal formation deals with two forms of information. pocampal formation plus the surrounding temporal One form arrives from other areas of the cortex, is cog- cortex (Delis and Lucas, 1996). In addition to temporal nitive in nature, and enters by way of the entorhinal lobe structures, lesions involving the fornix, the mam- cortex. !e other form arrives from the septum, amyg- millary body, and the medial thalamus can produce dala, hypothalamus, and brainstem, and is related to the amnesia. Patients who present with severe amnesia behavioral/emotional state. !e hippocampal–septal without dementia typically have lesions in the med- “corridor” is believed to have an important modulatory ial temporal lobe. !e amnesia is anterograde; that is, e$ect on hypothalamic–brainstem structures involved the ability to store and recall information is lost sub- in various endocrine, autonomic, and somatomotor sequent to the date of damage to the medial temporal aspects of emotional behavior (Alheid and Heimer, lobe. Events that took place up to several years before 1996). Limbic activation may be necessary to bring the date of the lesion may be hazy. Childhood memor- percepts to a conscious level before they are processed ies remain intact. in the temporal lobe. Decreased hippocampal volume has also been Lesions restricted to the hippocampus proper, reported in other psychiatric disorders such as uni- 178 the fornix, the subiculum, or the dentate gyrus each polar depression (Sheline et al., 1996), posttraumatic Anatomy

Clinical vignette being greatest during the early stages of acquisition. A 68-year-old lifelong housewife and mother of four Simultaneous activation of the amygdala and hippo- had no psychiatric or neurological problems until campus is important in memory formation and recall approximately three years prior to hospitalization. At and inhibits activity in the amygdala (Milad et al., that time she noted progressive di!culty with remem- 2007). It is believed that the action of the medial pre- bering things. On presentation for hospitalization she frontal cortex suppresses the emotion assigned to the demonstrated profound memory loss, particularly for current situation if it is determined that the chosen recent events. She was unable to care for herself and emotion is incorrect. became agitated at times. A computed tomographic (CT) examination showed a large, left-sided sphen- Clinical vignette oidal wing meningioma. Amnestic periods resulted from decreased blood $ow to the medial temporal A 30-year-old woman with normal IQ had bilateral loss regions during a transient ischemic attack. Epileptic of the amygdala due to calci"cation resulting from the activity in this area may also result in similar symptom- rare genetic Urbach–Wiethe disease. Testing revealed atology (Pritchard et al., 1985). that she was able to recognize the personal identity of faces and could learn the identity of new faces (Adolphs et al., 1995). She was able to recognize proto- stress disorder (PTSD) (Gurvits et al., 1996), bipolar typical fear from facial expression but was unable to disorder (Hirayasu et al., 1998), and alcohol depend- assess the intensity of the fear expressed. She had ence (DeBellis et al., 2000). experienced failure in social and marital relations and Acetylcholine is important in the operation of the was unable to hold a job but was not a social outcast, hippocampus. During high cholinergic activity, old as is the case with monkeys with loss of the amygdala memory is recalled. During low cholinergic activity, (Adolphs et al., 1995). new memory is formed (Hasselmo et al., 1995). It is proposed that a defect in a cholinergic receptor could result in perceptual di%culties such as those seen in Connections with the prefrontal cortex and cin- schizophrenia (Adler et al., 1998). gulate gyrus allow for appreciation of the emotion, for memory of the emotional situation and for the Amygdala formulation of appropriate somatic and autonomic !e amygdala is a nuclear complex located inside the responses. Connections with the central nucleus pro- temporal lobe, deep to the uncus (Figures 5.4 and 11.1). vide the basis of direct control of brainstem motor and It is one of the most studied limbic structures, and such autonomic nuclei. a mountain of evidence has accumulated implicating It is convenient to recognize three nuclear areas its role in our emotional life that it has been dubbed within the amygdala, although each of these three may “the heart and soul of the brain’s emotional network” be subdivided (Price et al., 1987). !ese areas are the (LeDoux, 1992). lateral (basolateral) nuclei, the central nucleus, and the Input to the amygdala allows it to monitor current medial (corticomedial) nuclei (11.5). internal and external sensory cues. It is particularly sensitive to cues that are of a social nature. !e amyg- Lateral (basolateral) nuclei dala matches sensory input with emotions. Its close ties Sensory input to the lateral nuclei of the amygdala with the hippocampus help form memory match-ups arises from third-order unimodal sensory cortex, espe- between particular sensory cues and particular emo- cially the visual association cortex of the temporal lobe. tions. Although the amygdala has been associated Other sensory areas that project to the amygdala include with anxiety and fear we now recognize it is activated the multimodal sensory areas of the frontal lobe, with equally by positive and negative emotions (Fitzgerald those from the temporal lobe being particularly dense et al., 2006). For example when presented with the face (Amaral et al., 1992; Figures 5.2, 11.5 and 11.6). It is via of a new individual the amygdala matches the new indi- these routes that sensory information from the external vidual’s facial characteristics with those experienced in environment reaches the amygdala. Other #bers arrive the past and assigns an emotion. In this way we pre- from the insular cortex which provides sensory infor- judge the individual (Figure 6.9). mation from the internal environment (Chapter 5). It is activated in humans during the acquisition Sensory #bers from the vagus nerve relay in the soli- 179 of conditioned fear with the magnitude of activation tary nucleus. !e solitary nucleus projects directly to Limbic system: Temporal lobe

Prefrontal cortex Orbital cortex

Mediodorsal thalamic nucleus Olfactory bulb Ventral striatum Cingulate gyrus

Hypothalamus

Medial nuclei Lateral nuclei

External and Central nucleus Pain, taste internal sensory signals

Brainstem Uni- and multimodal PAG sensory areas Autonomic motor nuclei and insular cortex Brainstem Autonomic sensory nuclei

Figure 11.5. The major connections of the individual nuclei of the amygdala (lateral nuclei, central nucleus, and medial nuclei). Behaviorally preeminent pathways are shown with bold lines. The lateral nuclei evaluate integrated sensory information with regard to emotional content and interconnect with the prefrontal cortex, cingulate gyrus, and ventral striatum for somatic response and emotional appreciation. The medial nuclei associate taste and pain signals with emotions. The central nucleus connects with brainstem autonomic centers for motor and autonomic response to emotional stimuli. All three nuclei of the amygdala have connections with the hypothalamus for expression of emotion by way of the autonomic and endocrine systems. PAG, periaqueductal gray.

Figure 11.6. Neuroanatomical Phobic avoidance structures related to panic disorder. The and cognitive generated amygdala is believed to play a central role in panic disorder. Sensory cues that trigger panic Prefrontal cortex Stimuli that elicit panic may originate internally or externally situational panic Anxiety (right side of "gure). Anxiety is the result of Hypothalamus MD excitation of the amygdala. Phobic avoid- Flight, fight, Multimodal ance may originate in the prefrontal lobes. hand wringing Amygdala sensory convergence PAG area Somatic and motor behaviors typical of panic are e#ected by the periaqueductal Raphe nuclei gray (PAG) and brainstem autonomic nuclei. LC, locus ceruleus; MD, medi- LC odorsal thalamic nucleus; PB, parabrachial nucleus; LPGi, nucleus paragigantocel- Brainstem Peripheral lularis lateralis; PrH, nucleus prepositus LPGi PB visceral autonomic PrH Sol hypoglossi, Sol, solitary nucleus. Change in: nuclei receptors respiration, heart rate, etc.

the lateral amygdala providing norepinephrine input. humans) from the adrenal cortex enters the brain and Locus ceruleus also provides norepinephrine projec- in"uences activity in the lateral amygdala. tions to the lateral amygdala. Nucleus basalis provides Two major routes exit the lateral amygdala. !e 180 a source of acetylcholine. Corticosterone (cortisol in stria terminalis projects to the septal nuclei and Anatomy hypothalamus. !e ventral amygdalofugal pathway Central nucleus projects to the hypothalamus, hippocampus, medio- !e central nucleus of the amygdala receives input dorsal thalamus, anterior insula, and ventral striatum, from the lateral and medial amygdala nuclei as well which includes the nucleus accumbens. !e ventral as from brainstem autonomic sensory nuclei (soli- amygdalofugal pathway also contains direct recipro- tary and parabrachial nuclei; Chapter 10). !e cen- cal connections with the orbital and medial prefrontal tral nucleus is the predominant output channel for cortex as well as the anterior cingulate gyrus. the amygdala (Bohus et al., 1996). E$erents from the !e lateral amygdala is important in the acquisi- central nucleus terminate in the dorsal nucleus of the tion and retention of memories of emotional experi- vagus as well as other brainstem parasympathetic ences (Chavez et al., 2009; McGaugh, 2004). Evidence motor nuclei and in the brainstem reticular forma- indicates that memory is not stored in the amygdala tion, including the periaqueductal gray (Chapter 10; but that activity within the amygdala consolidates Figure 10.3). Other e$erents also control autonomic memory elsewhere in the brain. Norepinephrine activity by way of e$erent #bers to the hypothalamus release within the amygdala appears to be critical for (Figure 11.5). memory formation. Norepinephrine from the adrenal Signals are processed over parallel pathways medulla activates vagus nerve receptors, which through the amygdala. !ese pathways converge in send signals to the solitary nucleus in the brainstem the central nucleus (Pitkanen et al., 1997). !e central (Figure 10.1). !e solitary nucleus projects noradren- nucleus is closely tied with the emotional responsive- ergic #bers to the lateral nuclei of the amygdala. !e ness of parasympathetic tone. It copes with environ- solitary nucleus also projects to the locus ceruleus mental challenges by promoting responses that have which projects its own norepinephrinergic #bers to been successful in the past and by assigning emo- the amygdala (Williams and Clayton, 2001; Chang tional signi#cance to current events (Hat#eld et al., et al., 2005; Miyashita and Williams, 2006). !e basal 1996). Fight or "ight responses or defensive freezing nucleus provides cholinergic input. Although cho- behaviors can be elicited by the central nucleus and linergic input may not produce memory consolida- its connections with the periaqueductal gray (Chapter tion it acts in a modulatory role to enhance memory 10; Figure 10.3). !e central nucleus plays a key role consolidation initiated by norepinephrinergic activ- in monitoring the level of autonomic tone by way ity. Cortisol also plays a role by activating brainstem of feedback from the viscera. Connections with the nuclei such as the solitary nucleus. Cortisol may also brainstem autonomic motor nuclei provide a route act directly on the lateral amygdala (Buchanan and by which the amygdala directly modi#es the auto- Adolphs, 2003). nomic nervous system. Kreindler and Steriade (1964) Brain regions in"uenced by the lateral amygdala found that stimulation of the central nucleus in the for memory consolidation include the hippocampus, cat produced electroencephalographic (EEG) changes nucleus accumbens, and caudate nucleus. E$erents indicative of arousal. Rats with a lesion in the central from the amygdala in"uence memory in the caudate nucleus fail to bene#t from procedures that normally nucleus related to visual cues (Packard et al., 1994; improve response to conditioned stimuli (Holland Grahn et al., 2009). and Gallagher, 1993).

Medial nuclei !e most prominent source of #bers that enter into the Uncus medial division of the amygdala is the olfactory bulb !e uncus is found super#cial to the amygdala on the (Figure 11.5). Other a$erents arise from brainstem ventromedial aspect of the temporal lobe (Figure 5.4). areas that are related to visceral sensations, taste, and It is continuous posteriorly with the entorhinal area pain. !ese connections may contribute to the emo- and is continuous anteriorly with the periamygdaloid tional aspects of smell, taste, and pain. area and the prepyriform area. Its dorsal surface is E$erents from the medial nuclei terminate in the the amygdaloid (semilunar) gyrus. !e amygdala lies hypothalamus, especially in the ventromedial nucleus deep to the surface of the uncus (Figures 11.1 and which is related to feeding behavior. Hypothalamic 13.2). !e uncus represents the bulk of the body of the e$erents in"uenced by the medial amygdala include “pear” a&er which the pyriform (pear-shaped) lobe is 181 those that regulate the anterior pituitary (Chapter 8). named. Limbic system: Temporal lobe

Functional and behavioral sensory signals reach the amygdala. A cortical route involves initial processing in the striate visual cortex. considerations A more direct route involves a subcortical extrastri- !e overall function of the amygdala is to assign emo- ate pathway that includes the superior colliculus and tional signi#cance to a current experience (Deakin and pulvinar (Chapter 9) (Morris et al., 1999). !e direct Grae$, 1991). It helps focus attention on the critical route allows the amygdala to discriminate between stimulus at the expense of irrelevant stimuli. !e loss of emotional and nonemotional visual targets, even if fear seen in the Kluver-Bucy syndrome is attributed to the image is viewed so quickly that the subject is not bilateral destruction of the amygdala (see below). !e consciously aware of having viewed it (Morris et al., sensation of anxiety is appreciated in the orbital pre- 1998; Whalen et al., 1998; Killgore and Yurgelun-Todd, frontal cortex and possibly the cingulate gyrus by way 2004). Activation of the amygdala provides evidence for of projections from the amygdala. Projections from context enhancement of emotionally important visual the amygdala to the hypothalamus as well as recipro- targets. It sends feedback projections to the visual path- cal hypothalamic-prefrontal connections are the basis way that can draw attention to emotionally important of the endocrine, autonomic, and behavioral reactions targets (Figure 4.6). !e le& amygdala more than the to emotional situations. !e location of the amygdala right responds when sexually explicit visual images are with respect to the prefrontal cortex and autonomic seen and more activation is seen in men than in women centers is consistent with the role it plays in learning (Hamann et al., 2004). !e amygdala in cooperation relationships between stimuli and socially important with the hippocampus is responsible for fear condi- behavior (Aggleton, 1993). tioning that is the coupling of a neutral stimulus with !e #&h to the seventh year of age is a critical period one that evokes fear (Dolan, 2002). !e amygdala for the development of emotion-related facial recogni- does not appear to be critical for species- typical social tion (Tremblay et al., 2001). As adults age, they pay less behavior, but is important in inhibiting social behav- attention to negative emotional stimuli than to posi- ior when evaluating new individuals for signs of threat tive emotional stimuli. Collaborating evidence showed (Amaral, 2003). It is lateralized based on sex. In one the amygdala of both younger and older adults is acti- experimental setting, enhanced memory for emotional vated when viewing emotional images. But compared #lms viewed correlated with increased activity in the with younger adults, Mather et al. (2004) reported that right amygdala for men. !e same situation correlated activation in older adults was greater for positive than with increased activity in the le& amygdala for women for negative emotional pictures. In contrast, Schwartz (Cahill et al., 2001). et al. (2003) have shown that infants with an inhibited Morris et al. (1998) speculated that the right amyg- social temperament tend to mature into adults with a dala is more involved in the nonconscious detection of similar personality. As adults these socially inhibited meaningful emotional stimuli, whereas the le& amyg- individuals showed signi#cantly greater activation of dala is related to the conscious processing of emotional the amygdala bilaterally to novel faces than do unin- stimuli. !ere is evidence that the right amygdala is hibited individuals. Although the amygdala appears to critical in processing inherent emotional content of respond preferentially to fearful expressions, le& amyg- stimuli (Phelphs et al., 2001; Nomura et al., 2004). In dala activation correlated positively with the degree one study, the right showed more rapid habituation to of extraversion of the subject (Canli et al., 2002). !e fearful stimuli than did the le& amygdala, especially results suggest that the personality of extraversion may during processing facial expressions (Hariri et al., in"uence the brain response to emotionally important 2002). stimuli. Electrical stimulation of the amygdala in humans !e amygdala responds to emotionally expressive elicits feelings of fear and anxiety as well as autonomic faces and other emotionally important images inde- reactions consistent with fear (Gloor et al., 1981). pendent of the current focus of attention (Figure 11.7) Electrical stimulation of the medial division of the (Vuilleumier et al., 2001, 2002; Morris et al., 2002). amygdala in female mammals results in ovulation and Evidence indicates that it not only detects facially uterine contraction. It induces penile erection in the communicated threat, but determines if the threat male. Exaggerated and indiscriminate sexual activ- is directed at the subject or elsewhere (Adams et al., ity may result from bilateral damage to the amygdala 182 2003). !ere appear to be at least two routes by which (Sachs and Meisel, 1994). !e descending raphe spinal Functional and behavioral considerations

Figure 11.7. Functional magnetic resonance imaging demonstrates activation of both the left and right amygdalae when processing facial expressions of fright (green –see color plate) as well as during conditioned fear (red). Expressions of fright produce activity more in the left side of the upper amygdala than in the right side, whereas the response to conditioned fear is more evenly distributed. (Reproduced with permission from Vass, 2004.) See also color plate.

pathway that regulates incoming pain signals is also a multiple personalities, panic-like attacks, and delu- target of #bers from the amygdala. sions of possession. In most of the cases, structural Projections from the amygdala to brainstem motor imaging [computed tomography (CT) or magnetic res- and autonomic nuclei mediate the autonomic and facial onance imaging (MRI)] was normal and EEG revealed reactions to emotionally evocative stimuli. Electrical the abnormal electrical activity. stimulation of the central nucleus of the amygdala in Since the highest incidence of psychiatric compli- cats results in behavioral and autonomic changes that cations among patients with temporal lobe epilepsy is resemble a state of fear, including an increase in heart in those with spike foci in the anterior temporal area, it and respiration rate and an increase in blood pressure. is assumed that these spikes cause abnormal activation Chronic stimulation produces stomach ulcers in rats. in the amygdaloid complex. It should be noted, how- Electrical stimulation of the medial division also pro- ever, that the evidence does not support the notion that duces an increase in plasma levels of corticosterone, directed or organized aggression can be a direct conse- possibly by way of projections to the hypothalamus. quence or a manifestation of ongoing seizure activity. Dopaminergic #bers that project from the amygdala to Surgical amygdalectomy has been performed to allevi- the hippocampus are part of a behaviorally signi#cant ate severe and intractable aggression. reward system (Blum et al., 1996). Bilateral destruction of the amygdala and sur- Hermann et al. (1992) reported that in 13 of 15 rounding structures in the monkey produces the patients with ictal (epileptic) fear, the abnormal EEG Kluver–Bucy syndrome (Chapter 13). !is disorder activity originated from the right temporal lobe lim- is characterized by excessive docility, lack of fear bic structures, especially the amygdala. It is easy to response, and hypersexuality (Delis and Lucas, 1996). speculate how ictal activity in this region can lead to an Bilateral temporolimbic damage in humans produces a increase in anxiety and psychiatric manifestations such similar behavioral pattern, frequently accompanied by as are seen in panic attacks or pathological aggression. amnesia, aphasia, and visual agnosia (Aggleton, 1992). Hallucinations have been experienced during tem- Patients show few strong responses to provocative poral lobe stimulation. !e most complex forms of stimuli, and aggression is rare (Saver et al., 1996). hallucinations are associated with lesions in the anterior portion of the temporal lobe, which contains the Clinical vignette amygdala, the uncus, and the anterior hippocampus. A 40 year-old man with a history of posttraumatic Epileptic activity in the di$erent temporal-limbic epilepsy developed hyperoral and other behavioral regions can result in the generation of syndromes that changes after a period of status epilepticus. On reso- are very similar to many “functional” psychiatric disor- lution of the abnormal epileptiform activity, he dem- ders. A “must read” paper by Mesulam (1981) describes onstrated a voracious appetite and indiscriminate eating habits, which included eating paper towels, 12 such cases in detail. In this series, patients exhibited 183 Limbic system: Temporal lobe

Clinical vignette (cont.) subventricular zone which lies just deep to the cavity of the lateral ventricle. As the cells mature they migrate to plants, Styrofoam cups, and feces. At one point, he the olfactory lobe where they di$erentiate into granule drank urine from a catheter bag. The patient would also wander about the ward and touch many objects. or periglomerular inhibitory neurons (Doetsch et al., He frequently wandered into the rooms of other 1999). !e second neurogenic region is the subgranu- patients and touched them inappropriately. Although lar zone of the dentate gyrus. !is is a thin layer of the initially aggressive, he became quite agreeable and dentate gyrus that measures only about three cells deep docile. The patient had Kluver–Bucy syndrome from (Seri et al., 2004). As these cells mature they migrate damage to both amygdalae. His hyperoral behavior into the granular cell zone where they di$erentiate resulted in death from asphyxiation. The patient had into excitatory granular neurons as well as glia cells in a respiratory arrest after stu!ng his mouth with surgi- the dentate gyrus as well as CA1 of the hippocampus cal gauze. Neuropathology revealed virtual absence of (Ambrogini et al., 2004; Jin et al., 2004; Verwer et al., the left amygdaloid complex and atrophy of the right 2007). Other areas suspected of supporting neurogen- amygdala (Mendez and Foti, 1997). esis include the neocortex (Gould et al., 2001; Dayer et al., 2005), striatum (Bedard et al., 2006; Luzzati et al., !e degree of craving of cocaine addicts has been 2006), amygdala (Fowler et al., 2002), and hypothal- shown to parallel an increase in cerebral glucose metab- amus (Fowler et al., 2002). Neurogenesis is well estab- olism in the frontal cortex and the amygdala (London lished in humans as well as animals (Ericksson, et al., et al., 1996). It is proposed that increased levels of glu- 1998; Manganas et al., 2007). tamate in the amygdala mediates the craving experi- Jacobs (2002) suggests the new cells may be main- enced by cocaine addicts (Kalivas et al., 1998). tained following a process termed “use it or lose it.” It Drevets et al. (1992) reported that blood "ow to the has been estimated that upwards of 10 000 new cells le& amygdala was increased signi#cantly in patients are added each day to the dentate gyrus in the adult with unipolar major depression. A circuit involving the rat (Cameron and McKay, 2001). !e nascent neurons prefrontal cortex, the amygdala, and related parts of the are excited by γ-aminobutyric acid (GABA) to activate basal ganglia and medial thalamus has been proposed GABAergic receptors that control growth and di$eren- to describe the functional neuroanatomy of depres- tiation of dendrites and synapses (Overstreet-Wadiche sion. In another study, the amygdala was found to be et al., 2005; Ge et al., 2006, 2007). A surplus of neurons signi#cantly larger in patients with bipolar disorder is produced. !ose not used a&er two to three weeks are than in control subjects. Other structures (thalamus, lost through programmed cell death (apoptosis) (Biebl pallidum, and striatum) showed modest enlargement et al., 2000; Kempermann et al., 2003). Neurogenesis (Strakowski et al., 1999). occurs throughout life as seen in rodents, but decreases Atrophy of regions of the amygdala containing signi#cantly with age (Kempermann, 2005). Age- large neurons which have reciprocal connections with related decline in production has been documented in the basal nucleus of Meynert has been reported in humans (Manganas et al., 2007). Alzheimer disease (Scott et al., 1991). !is is consist- Several growth factors are associated at di$erent ent with reduced acetylcholine esterase activity in the stages of adult neurogenesis. Proliferation, di$eren- amygdala in Alzheimer disease (Shinotoh et al., 2000). tiation, and survival of the new neurons is supported It is hypothesized that functional changes in the neo- by growth factors including #broblast-growth factor-2 cortex and amygdala are early and leading events in (FGF-2) (Rai et al., 2007), insulin-like growth factor-1 Alzheimer disease rather than a consequence of degen- (IGF-1) (Aberg et al., 2003; Trejo et al., 2008), and vas- eration elsewhere (Herholz et al., 2004). cular endothelial growth factor (VEGF) (Jin et al., 2002; Schanzer et al., 2004). Successful neurogenesis also Neurogenesis depends on neurotropic factors such as brain-derived Mitotic #gures re"ecting neuron cell division have neurotropic factor (BDNF) (Scharfman et al., 2005) been observed in the wall of the lateral ventricle of the and nerve growth factor (NGF) (Frielingsdorf et al., rat (Allen, 1912). It is now generally accepted that new 2007). Even electroconvulsive shock has been shown neurons (neurogenesis) occur in two regions of the to promote neurogenesis (Madsen et al., 2000). adult brain. One is in the olfactory system. Neurons Neurogenesis in the hippocampus is regulated by 184 form in the wall of the anterior forebrain in the glutamatergic #bers that arise in the entorhinal cortex, Functional and behavioral considerations pass through the perforant path, and terminate in the compared with normal control subjects. Compared dentate gyrus. Excitatory input acting on N-methyl-*- longitudinally over an average of 15 months (schizo- aspartate (NMDA) receptors has been shown to inhibit phrenic patients) and 68 months (controls), the tem- neurogenesis (Bursztain et al., 2007; Nacher et al., poral lobe volumes of both groups declined. !is 2007). However, stimulation of α-amino-5-hydroxy-3- decline in volume was viewed as age related and cor- methyl-4-isoxazole propionic acid (AMPA) and kainite related with a decline in neurocognitive performance receptors enhances hippocampal neurogenesis (Bai et in the control subjects. Interestingly, the decline in al., 2003; Jessberger et al., 2007). !e e$ect of activation temporal lobe volume in the schizophrenia group cor- of other neurotransmitter pathways is being examined related with an improvement in delusions and thought and the results of published studies have been compre- disorder (Gur et al., 1998). hensively reviewed by Balu and Lucki (2009). !e organization of pyramidal cells in the hippo- Stress is documented to a$ect learning and mem- campus is thought to be disturbed in schizophrenia. ory (Stranahan et al., 2008). It may operate through Guze and Gitlin (1994) reported that the degree of several mechanisms, but stress is also shown to have reduction of the tissue volume of both the hippocam- a strong negative a$ect on adult hippocampal neuro- pus and the amygdala in patients with schizophrenia as genesis (Mirescu and Gould, 2006; Airan et al., 2007). compared with normal control subjects correlates with Several experimental studies have found that volun- the severity of positive psychotic symptoms. Delusions, tary exercise and an enriched environment increased hallucinations, and paranoid ideas (positive symptoms hippocampal neurogenesis in animals (van Praag et of schizophrenia) are associated with temporolimbic al., 1999; Brown et al., 2003; Bruel-Jungerman et al., dysfunctions (Bogerts, 1998). Reality distortion (delu- 2005, 2007). sions and hallucinations) has been shown to correlate Learning and memory are impaired in patients with with increased blood "ow in the le& mesiotemporal depression (Austin et al., 2001; Fossati et al., 2002). lobe structures (Liddle et al., 1992). Depressed patients exhibit reduced hippocampal vol- !e glutamatergic hypothesis of schizophrenia ume (Bremner et al., 2000; Sheline et al., 2003). Evidence proposes that there is a disruption of glutamate-me- indicates that the reduction is due to reduced dendritic diated transmission within the hippocampus. Krystal arborization and glial cell number rather than neuron et al. (1999) showed that antagonism of the glutamater- loss (Reif et al., 2006). Neuron loss may not contrib- gic NMDA receptor produced behavioral and cogni- ute to depression, but neurogenesis corresponds with tive e$ects in normal subjects similar to schizophrenia. the bene#cial e$ects of a$ective antidepressant drug A reduction in excitatory transmission, especially in therapy. !e time course of action of antidepressant CA1, is proposed to result in decreased glutamatergic drugs corresponds with the time required for increase stimulation of the anterior cingulate cortex, nucleus of neurogenesis in mice (Nakagawa et al., 2002). accumbens, and the temporal cortex (Tamminga, Neurogenesis is decreased in patients with schizo- 1998, 1999). Hippocampal neurons appear to be par- phrenia (Reif et al., 2006. !e administration of anti- ticularly vulnerable following traumatic brain injury psychotic drugs shows mixed e$ects on enhancing (McCarthy, 2003). neurogenesis (Halim et al., 2004; Kodama et al., 2004; Imaging studies have revealed di$erences between Schmitt et al., 2004; Wang et al., 2004). control subjects and schizophrenia patients in a number of cortical regions. !e most consistent #ndings Schizophrenia are in the region of the medial temporal lobe (Kotrla Ventricular enlargement of up to 33% has been reported and Weinberger, 1995). Abnormalities in the histology in schizophrenia (Pakkenberg, 1987). !e greatest of the entorhinal cortex have played an important role enlargement is seen in the temporal horn of the lateral in discussions of the neuroanatomical substrates of ventricle (Brown et al., 1986). Ventricular enlargement schizophrenia. A bilateral reduction in overall volume is a re"ection of brain tissue loss. !e greatest loss of of the hippocampus is reported in patients with schizo- tissue in schizophrenia is seen in the hippocampal for- phrenia (Nelson et al., 1998). Decreases in mean hip- mation, the amygdala, and the parahippocampal gyrus pocampal neuron density have been reported (Krimer (Bogerts et al., 1985; Nelson et al., 1998; Velakoulis et et al., 1997) along with disruption of cortical layers and al., 1999). Lower volumes have been reported in the a decrease in mean neuronal size (Heckers and Heinsen, temporal lobes of patients with schizophrenia when 1991; Jakob and Beckman, 1994). If it is true that the 185 Limbic system: Temporal lobe

numbers of neurons remain constant while the volume believed to re"ect dysfunction of entire circuits rather of tissue is reduced, this suggests that there is abnor- than one single brain structure (Drevets et al., 2004). mal connectivity (“wiring”). !e areas most a$ected One of these is the limbic-cortical-striatal-pallidal-tha- include the entorhinal area, the subiculum, and the lamic circuit. Limbic structures in this circuit include le& anterior and mid-regions of CA1 and CA2 in the the amygdala and hippocampal subiculum (Ongür hippocampus (Arnold et al., 1995; Narr et al., 2004). et al., 2003). !ese abnormalities are compatible with neurode- Neuroanatomical abnormalities have been seen velopmental models of schizophrenia that describe in limbic structures for early-onset, recurrent major abnormal synaptic pruning (Figure 6.11) and abnor- depressive disorder and/or bipolar disorder. Reductions mal embryological migration of neurons (Arnold et al., in volume, cell counts, metabolism, and blood "ow have 1997). However, there is also reported to be a selective all been reported for the amygdala and hippocampus decrease in the actual number of nonpyramidal cells of (Ongür et al., 2003; Drevets, 2007; Drevets et al., 2008). CA2 in schizophrenia and manic depression patients. Volume reduction in the hippocampus of as much as !is indicates that cell loss in the hippocampus may be 19% has been reported and the loss appeared to cor- a contributing factor in the pathophysiology of major relate with time spent depressed (Sheline et al., 2003; psychoses (Benes et al., 1998). Neumeister et al., 2005). Drevets and Price (2005) and Heckers (2001) summarized hippocampal #nd- Hasler et al. (2008) found that the activity of the amyg- ings in schizophrenia in three points. First, most dala as well as that of the subgenual anterior cingulate studies have found a decrease in hippocampal vol- cortex and ventromedial prefrontal cortex increased ume in schizophrenia patients. !is reduction is sub- proportional to the severity of depression. Hasler tle and is in the order of 4% as compared with healthy et al. (2008, 2009), as well as Neumeister et al. (2004), controls. !is is signi#cantly di$erent from the pro- also found that the rate of metabolism and blood "ow nounced volume reduction seen in neurodegenera- decreased with successful antidepressant treatment tive disorders such as Alzheimer disease. Second, the but increased again with the return of depressive reduction is seen early in the disease process with symptoms. Other researchers reported that activity evidence of subsequent slow progression of volume in the le& amygdala was a$ected in depressed subjects loss. !ird, volume loss may be a$ecting certain parts when viewing fearful faces and sad words (!omas et of the hippocampus more than others (some stud- al., 2001; Siegle et al., 2002; Drevets, 2003). In addition, ies report the volume loss to a$ect mainly the anter- histopathological studies have shown reduced glial ior half of the hippocampus). !is #nding suggests cell number in the amygdala but no loss of neurons or that not all hippocampal functions are impaired in synapses (Eastwood and Harrison, 2000; Cotter et al., schizophrenia. 2002); Hamidi et al. (2004) stated that the glial loss was Recent studies extended the #ndings to at-risk chil- due to loss of the myelin-producing oligodendrocytes. dren (children of patients with schizophrenia). Pantelis et al. (2003) followed 75 high-risk subjects for one year. Posttraumatic stress disorder Subjects with smaller right hippocampal formation, Studies have found that blood "ow to the right lim- prefrontal, and cingulate cortical regions (23 subjects) bic and paralimbic structures including the amyg- developed psychotic symptoms. !ese subjects had no dala increased in patients with PTSD under provoked psychotic symptoms on entry to the study. Fi&y-two conditions (Figure 11.8). !e activation of these brain other subjects with more normal cortical volumes (also areas is hypothesized to re"ect intense emotions or high-risk subjects) did not develop psychotic symp- emotional memory and may not be speci#c to PTSD toms within the follow-up period. (Rauch et al., 1996). !ere is evidence of reduced hippocampal volume in adults who have been exposed to Depression/bipolar disorder childhood stress but not in children and adolescents Major depressive disorder and bipolar disorder have with PTSD (DeBellis et al., 2002; Bremner, 2003). the major depressive episode in common. Anxiety Hendler et al. (2003) and Lindauer et al. (2004) symptoms are common in major depressive episodes. reported that patients (versus control subjects) exposed Anxiety is part of panic disorder, social phobia, post- to reminders of traumatic events exhibited greater traumatic stress syndrome and obsessive-compulsive response in the amygdala and reduced activation of 186 disorder (Kessler et al., 2005). Mood disorders are the ventral medial prefrontal cortex. !ese results Functional and behavioral considerations

Figure 11.8. A–D. Positron emission tomography statistical parametric maps of traumatic minus control conditions for all subjects (n=8; 16 scans per condition) are displayed with a Sokolo# color scale reproduced in black and white in units of z score. Patients were presented with 30–40 s audio taps of two separated traumatic experiences based on past personal events (traumatic condition) or two neutral scripts (e.g., brushing one’s teeth, emptying the dishwasher; neutral condition). Dashed outlines re!ecting boundaries of speci"ed brain regions, as de"ned via a digitized version of the Talairach atlas, are superimposed for anatomical reference. Whole-brain slice outlines are demarcated with solid lines. All images are transverse sections parallel to the intercommissural plane, shown in conventional neuroimaging orientation (top = anterior, bottom = posterior, right = left, left = right). Each transverse section is labeled with its z coordinate, denoting its position with respect to the intercommissural plane (superior > 0). For the traumatic minus neutral condition, activation is located within right anterior temporal and insular cortex, the amygdala (A), and secondary visual cortex (B). C. For the traumatic minus teeth-clenching condition, the pattern of activation shown parallels that are seen in panel B. D. For the neutral minus traumatic condition, activation is located within the left Broca’s area (representing a decrease in relative blood !ow associated with the traumatic condition). (Modi"ed with permission from Rauch, S.L., van der Kolk, B.A., Fisler, R.E., Alpert, N.M., Orr, S.P., Savage, C.R., Fischman, A.J., Jenike, M.A., and Pitman, R.K. 1996. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch. Gen. Psychiatry 53:380–386.) support a model that involves increased reactivity of most studied (Joëls, 2009). !rough a cascade of events the amygdala and associated fear. !is is coupled with the transmission of excitatory signals through CA1 is inadequate suppression of the amygdala by the ventral attenuated along with long-term potentiation in the medial prefrontal cortex (Rauch et al., 2006). hippocampus (Wiegert et al., 2006). !e initial phase Exposure to stress activates a number of systems of arousal is terminated and hippocampal activity (epinephrine, acetylcholine, corticosteroid, etc.) sim- returns to pre-stress levels (Joëls et al., 2008). !is all ultaneously. !ese systems act in concert rather than has a governing e$ect on the hypothalamo-pituitary- individually to produce their end results. !ese systems adrenal axis. have mixed e$ects but for the most part have an excita- Exposure to life-threatening events strongly acti- tory in"uence on neurons in the amygdala and hippo- vates neurons in the amygdala. A model of PTSD pro- campus. !ey not only initiate increased neuronal poses that vulnerable individuals have a dysfunction #ring patterns but also facilitate long-term responses of the pituitary-adrenal axis combined with enhanced [long-term potentiation (Lynch, 2004)]. Long-term sympathetic activity (Yehuda, 2006). !ese individuals potentiation is thought to be important in the process express the early excitatory phase governed by sympa- of encoding information (Joëls et al., 2008). thetic drive. !ey lack the full inhibitory e$ect of the Corticosteroid levels increase over 30–60 min- second phase. As a result central excitation continues utes as opposed to the almost instantaneous neural and may even be enhanced, unrestrained by the nor- response. !is results in a late phase of the stress mal adaptive mechanisms mediated by corticosteroid 187 response. Glucocorticoid receptors in CA1 are the hormones (Joëls et al., 2008). Limbic system: Temporal lobe

Borderline personality disorder Bauman and Kemper (1985) found increased neuronal density and reduced neuron size in the hippo- Several studies have reported reduced amygdala vol- campus and portions of the amygdala in children with ume in subjects with borderline personality disorder autism. (BPD) compared with controls (Schmahl et al., 2003; Tebartz et al., 2003). !is has not been replicated in Panic disorder other studies (Zetzsche et al., 2006; New et al., 2007). Smaller amygdala volume has been reported in panic One study found exposure to negative emotion-pro- disorder (Massana et al., 2003) and early onset bipo- voking images produced increased activity in BPD lar disorder (Dickstein et al., 2005). Dysfunctional over controls but no di$erence when presented with neurogenesis may be a contributing factor to these neutral images (Herpertz et al., 2001). !e amygdala #ndings (MacKinnon and Zamoiski, 2006). Similar hyperresponsiveness was interpreted to be the result size reductions have not been found in studies with of decreased inhibition by the medial prefrontal cortex adult patients with bipolar disorder (Strakowski et al., (New et al., 2008). 2005). Sharma et al.(2003) reported volume reduc- Autism tion in the medial prefrontal cortex and subgenual anterior cingulate gyrus, which is closely linked to the Volume reductions in the amygdala and hippocampus amygdala. as well as in the superior temporal gyrus and anterior !ere is evidence of activation of norepinephrin- parietal cortex in children may re"ect a genetic vulner- ergic neurons during development of panic attacks ability to schizophrenia and schizotypal disorder. !e (Bailey et al., 2003) and mania as well as in bipo- volume reductions were greatest in the superior tem- lar individuals (Young et al., 1994; Joyce et al., 1995). poral gyrus and amygdala (Yuii et al., 2009). Amygdala Activation of prefrontal cortex has been reported to be volume has been reported to be increased in younger both enhanced and depressed when bipolar and cur- (3–4 years) but not in older autistic children (13–19 rently manic individuals were compared with controls years) (Sparks et al., 2002; Schumann et al., 2004). (Blumberg et al., 2000). Reduced amygdala volumes have been seen in adults It is proposed that the onset of manic, depressive with autism (Aylward et al., 1999; Pierce et al., 2001). and panic episodes results from false or misperception Munson et al. (2006) found that increased right amyg- of the emotional importance of familiar objects. !e dala volume at 3–4 years correlated with poorer social pathological state persists until the de#cit can be cor- functioning at age 6. rected. !is implies that the amygdala overreacts in the In Mosconi and colleagues’ (2009) study, amyg- assignment of emotions to relatively neutral stimuli. dala volume was increased bilaterally by 16% in aut- !e pathological state persists until the medial pre- ism subjects over controls between 2 and 4 years of frontal cortex is able to suppress activity in the amyg- age; however, the rate of growth did not di$er between dala (MacKinnon and Zamoiski, 2006). the two groups, and the right amygdala volume in the autism group was disproportionately enlarged. Scores representing social eye contact showed sig- Select bibliography ni#cant positive association with amygdala volume Aggleton, J.P. ed. !e Amygdala: A Functional Analysis. even though the autistic children expressed less (Oxford: Oxford University Press, 2000.) social eye contact. Reduced eye contact has also been Christianson, S.A. ed. !e Handbook of Emotion reported to associate with reduced amygdala volume and Memory: Research and !eory. (Hillsdale, N.J.: Lawrence Erlbaum Associates, 1992.) in adolescents and adults with autism (Nacewicz et Ekman, P., Campos, J.J., Davidson, R.J., and deWaal, F.B.M. al., 2006). An “allostatic overload” model of autism Emotions inside out. Annals of the New York Academy of is proposed that contends that repeated exposure to Sciences (vol. 1000). (New York: !e New York Academy a highly stimulating event leads to a compensatory of Sciences, 2003.) response (allostasis) that is seen as increased den- Gloor, P. !e Temporal Lobe and Limbic System. (New dritic arborization in the amygdala. Once a threshold York: Oxford University Press, 1997.) is reached (allostatic overload), excess production of McGinty, J.F. ed. Advancing from the ventral striatum to the stress hormones results in cell death in the amyg- extended amygdala. Annals of the New York Academy of 188 dala (Nacewicz, et al., 2006; Schumann and Amaral, Sciences (vol. 877). (New York: !e New York Academy 2006). of Sciences, 1999.) References

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196

CChapterhapter 12 Limbic system: Cingulate cortex

Introduction Early studies divided the cingulate gyrus into just an anterior portion and a posterior portion. Although Several brain regions have emerged relatively recently some current studies report #ndings using this two- as major contributors to the human psychological sys- part model, most investigators have now adopted a tem. A good example is the cingulate cortex. As early four-part model. !e “old” anterior cingulate gyrus is as the 1930s, it was observed that cats become mute now divided into the anterior cingulate gyrus and the and akinetic following lesions of the cingulate cortex. midcingulate gyrus. !e “new” anterior cingulate gyrus However, it was not until the 1950s that the cingulate is further subdivided into the pregenual anterior cingu- gyrus was examined more carefully. !is gyrus (Figure late gyrus and subgenual cingulate gyrus. !e “old” pos- 12.1) together with the parahippocampal gyrus, which terior cingulate gyrus is now divided into the posterior lies below it, form a large arcuate convolution that sur- cingulate gyrus and retrosplenial cingulate cortex. rounds the upper brainstem and constitutes what Broca referred to as the grande lobe limbique (Figure 13.1). Anterior cingulate cortex Anatomy and behavioral !e anterior cingulate cortex (ACC) consists of the considerations cortex of the cingulate gyrus that lies anterior and !e cingulate cortex lies deep within the longitudinal inferior to the anterior end of the corpus callosum cerebral #ssure and spans the corpus callosum like a (Figure 12.1). !e ACC receives input from the intrala- great arc (Figure 12.1). It is separated from the frontal minar and midline thalamic nuclei and has reciprocal and parietal cortex above by the cingulate sulcus, connections with the medial and lateral prefrontal cor- within which much of the cingulate cortex lies. Four tex. It is remarkable in comparison with the remainder major subdivisions of the cingulate cortex and a con- of the cingulate gyrus for massive input from the amyg- necting bundle can be identi#ed. dala. It is a$ected in major depression (see below).

Cingulate sulcus Figure 12.1. The cingulate cortex is shaded. The cingulate cortex consists of Supplementary the pregenual anterior cingulate cortex dPCC motor cortex (pACC), the subgenual anterior cingulate cortex (sACC), the midcingulate cortex, anterior and posterior (aMCC and pMCC), vPCC the posterior cingulate cortex, dorsal and pMCC ventral (dPCC and vPCC), the retrosplenial aMCC pACC cortex (RSC), and parasplenial area (PS). G, rpus callosum Co genu of corpus callosum; SG S, splenium of corpus callosum. See Frontal Figure 1.1 for general orientation. Occipital pole pole PS RSC sACC

Pons Cerebellum Medulla 197 Limbic system: Cingulate cortex

!e ACC lies in a position to #lter and control the relationship between the emotional limbic system and autonomic portions of the nervous system. Skeletomotor responses may be through connections with the midcingulate cortex. Its close ties with the basal ganglia and orbitofrontal cortex recognize it as part of a cortico-basal ganglia-thalamus-cortical loop (Mega and Cummings, 2001; Middleton and Strick, 2001). It is important in error detection and the appreciation and expression of emotions. It is a key component of the anterior (rostral) limbic system. Studies indicate the ACC receives information about an emotion-evoking stimulus, selects an appropriate response, monitors the action, and adapts behavior if there is a violation of expectancy (Haznedar et al., 2004). !e Figure 12.2. Functional magnetic resonance study demonstrates rostral ACC seems to be active a&er an error commis- activation of the anterior cingulate gyrus region in the monitoring sion indicating an error response function. !e dorsal of con!ict (incongruent trials). (Reproduced with permission from ACC is active a&er both an error commission and feed- Kerns et al., 2004.) See also color plate. back suggesting a more evaluative function (Bush et al., 2002; Polli et al., 2005; Taylor et al., 2006). !e evalu- were being addressed. ACC blood "ow decreased when ation is emotional in nature and re"ects the degree of the task required that internally stored information be distress associated with a certain error (Drevets et al., suppressed (Deary et al., 1994). 1997). Activity in the ACC occurs well in advance of the execution of the behavior, suggesting that it func- Pregenual anterior cingulate cortex tions in an executive and planning capacity. It plays a !e ACC is subdivided into a pregenual region (pACC) central role in shi&ing attention during working mem- and a subgenual region (sACC). !e pregenual region ory. Connections between the ACC and le& prefrontal (pACC) lies anterior to the corpus callosum and cortex [Brodmann’s area (BA) 46, BA 44, and BA 9] are includes anterior portions of BA 24, BA 33, and por- particularly important (Kondo et al., 2004). !e ACC tions of BA32. !e pACC is involved with sensations of recruits con"ict control mechanisms that appear to take emotion and is responsible for the storage of emotional place in the dorsolateral prefrontal cortex (Figure 12.2) memories. It is activated by internally generated emo- (Kerns et al., 2004). tions and is important in the retrieval of fear memory !alamic projections carrying signals from the (Frankland et al., 2004). For example when stimulated hippocampus and mammillary body of the hypothal- in this area, a patient reported, “I was afraid and my amus (Figures 12.3, 12.5 and 12.6) project to portions heart started to beat.” Bancaud and Talairach (1992) of both the anterior and posterior cingulate cortex. !e also reported sensations of euphoria, pleasure, and agi- ACC is believed to be involved in early acquisition of tation during stimulation of the pACC. It is activated memory in novel situations (Raichle et al., 1994). !e during reward-based decision making (Bush et al., pregenual cortex appears to be particularly important 2002). It is sensitive to pleasant touch in contrast to the in memory. Grasby et al., (1993) hypothesized that the midcingulate cortex, which is sensitive to painful touch ACC responds to the attentional demands of response (Rolls et al., 2003). Bartels and Zeki (2000) found that it selection to memory tasks and may serve both short- was activated by images of individual with whom their term and long-term memory function. !e ACC plays subjects were currently romantically involved. Vogt an active role during tasks that require the memoriza- et al. (2003) found that that the pACC was activated tion of words, of faces, or of a series of connected events when subjects reported experiencing happy emotions found in a story. whereas the subgenual ACC (sACC) was activated An increase in regional cerebral blood "ow was seen when experiencing sad emotions. However, in another in the ACC of subjects who performed an attention- study, the pACC was also activated when subjects were demanding auditory addition test. It appeared that the exposed to pain stimuli and the authors suggested it 198 increase occurred when internal information stores is associated with the “su$ering” component of pain Anatomy and behavioral considerations

Motor areas of Figure 12.3. Some of the major e#er- frontal lobe ent projections of the cingulate cortex. Fibers to the motor areas of the frontal lobe arise from the skeletomotor control region of the midcingulate cortex. The bold arrows within the cingulate Precuneus cortex represent connections of the default brain network that includes the pus callosu Cor m subgenual anterior cingulate cortex and retrosplenial cortex. PAG, periaqueductal Occipital Frontal gray. pole pole

PAG Striatum Pontine nuclei, Brainstem spinal cord autonomic centers Cingulum Hippocampal Cingulum formation

(Ploner et al., 2002). pACC has also been implicated nucleus, putamen, pontine gray, and spinal cord: all in motivational aspects of pain (Sewards and Sewards, motor control centers. 2003) as well as empathy for pain experienced by others !e anterior MCC (aMCC) is involved in error (Hein and Singer, 2008). detection (con"ict monitoring). It detects con"icts in information processing and signals the occurrence Subgenual anterior cingulate cortex to other areas where motor responses may be made. !e subgenual region of the anterior cingulate cortex Botvinick et al. (1999) reported that activity increased (sACC) lies inferior to the genu (knee) of the corpus with high levels of con"ict. It is hypothesized that the callosum and consists primarily of BA 25 along with aMCC determines the most cost-e$ective option and small portions of posterior, inferior BA 12, BA 32, and selects the one option judged to be the most preferred BA 33. !e sACC is recognized as an autonomic con- (Assadi et al., 2009). trol center. It responds to emotions and determines !e posterior MCC (pMCC) contains two motor the autonomic expressions of emotion. !e sACC has areas. !e pMCC is important in planning skeletomo- projections to the central nucleus of the amygdala, tor reactions to emotional sensations (Durn and Strick, parabrachial nucleus, and periaqueducal gray, all of 1991; Morecra& and Van Hoesen, 1992). For example which relay signals for the expression of autonomic it is activated during aversive movements in anticipa- tone. Direct projections to the solitary nucleus, dor- tion to a learned painful stimulus (Yágüez et al., 2005). sal vagal nucleus and spinal cord lateral horn provide However it may initiate cognitive activity that does a route for direct control of expression of emotions not necessarily require movement (Bush et al., 2002). in terms of the sympathetic and parasympathetic Cognitive activity includes anticipation of movement, divisions. Vogt (2005) argues that the sACC is true motor imagery, mismatch detection, and establish- limbic cortex and not infralimbic as it is sometimes ing changes in new motor programs. Motor behavior described. associated with the MCC includes attention to speci#c external stimuli; including orienting movements of Midcingulate cortex the eyes and head toward a signi#cant stimulus as well !e midcingulate cortex (MCC) occupies posterior as inhibition of attention to less relevant internal and portions of BA 24, BA 32, and BA 33. It consists of the external stimuli. !e MCC is involved in obsessive- middle third of the cingulate gyrus. Like the pACC it compulsive disorder (see below). receives input from the amygdala and registers emo- Earlier studies that describe behaviors seen during tional sensations, but instead of contacting autonomic stimulation of the ACC may re"ect stimulation of the centers it sends projections to motor areas. Reciprocal posterior ACC that is now considered MCC. Studies connections link the MCC with the motor cortex. have described simple and complex movements simi- Projections from the MCC also include #bers to the red lar to those seen a&er stimulation of the premotor areas 199 Limbic system: Cingulate cortex

found on the lateral aspect of the frontal lobe (Chapter correlated with reward size (McCoy et al., 2003; McCoy 6; Luppino et al., 1991). Behavioral changes have also and Platt, 2005). been seen, including primitive gestures such as knead- Both the PCC and retrosplenial cortex have con- ing or pressing the hands together, lip-smacking, and nections with the superior temporal sulcus and super- picking at bedclothes. Devinsky et al. (1995) found that ior temporal gyrus. !ese connections may play a these movements were modi#ed with sensory stimu- role in the localization of sounds (Seltzer and Pandya, lation and could be resisted by voluntary e$orts of the 2009). patients. Connections between the MCC and supple- !e PCC is important in successful retrieval of mentary cortex may underlie these behaviors. Lesions autobiographical memories. Maddock et al. (2001) that interrupt these connections may account for the demonstrated that the PCC showed strong activa- motor neglect that is sometimes seen a&er damage to tion during successful retrieval of memories elicited this region. by name-cued recall of family members and friends !e MCC makes decisions on the basis of the (Figure 12.4). !e authors speculated that dysfunc- reward value of the anticipated outcome of a particular tion of this area may be involved early in Alzheimer motor response. !e pMCC is part of the medial pain disease related to its strong ties to the hippocampal for- system that is involved in the a$ective and/or cognitive mation. Simultaneous reduction in blood "ow in early dimensions of pain processing. In addition, through its Alzheimer disease in both the entorhinal area and PCC motor centers, the pMCC is responsible for fast orien- provides some evidence in support of the above claim tation and motor withdrawal responses to pain inputs (Hirao et al., 2006). (Frot et al., 2009). !e emotional aspect of pain as well Cognitive impairment correlates with alterations as empathy for others who are su$ering pain activates in activity in the posterior cingulate cortex (Martinez- the MCC (Vogt, 2005; Hein and Singer, 2008). Bisbal et al., 2004). Elfgren et al. (2003) reported that subjects with isolated memory impairment coupled Posterior cingulate cortex with slight verbal and/or visuospatial impairments !e posterior cingulate cortex (PCC) includes BA showed reduced cerebral blood "ow in the posterior cin- 23 and BA 31 and is sometimes divided into a dorsal gulate cortex. !is group was at high risk for Alzheimer (dPCC) and ventral (vPCC) component. !e PCC disease. Individuals with mild cognitive impairment and adjacent retrosplenial cortex make up the “pos- are at high risk of developing Alzheimer disease. In terior cingulate area” (Takahashi, 2004). !e PCC another study, subjects who developed Alzheimer dis- receives input from the anterior thalamic nucleus ease demonstrated signi#cantly decreased regional and frontal, occipital and posterior parietal cortices. cerebral blood "ow in the le& posterior cingulate cor- It receives heavy input from the hippocampal forma- tex two years previously (Huang et al., 2002). tion (Kobayashi and Amaral, 2003). In contrast to the Mouras et al. (2003) reported decreased activity ACC, it receives little if any input from the amygdala. in the right PCC when men reported sexual desire in !e PCC is strongly linked to saccade circuitry and response to viewing sexually stimulating photographs. is involved in visuospatial orientation in response to Parietal areas (attention) and frontal areas (motor prep- somatosensory input. In animal studies, PCC neurons aration and imagery) were also activated. In another were activated when monkeys had to choose by gen- study, the PCC also showed deactivation in subjects erating saccades between two rewards of similar value in response to photographs of individuals with whom but reward certainty di$ered. Neuron responsiveness they were in love (Bartels and Zeki, 2000).

200 Figure 12.4. Functional magnetic resonance study demonstrates activation of the posterior cingulate gyrus region (including retrosplenial cortex) in assessing the familiarity of a person (faces or voices). (Reproduced with permission from Shah et al., 2001.) See also color plate. Anatomy and behavioral considerations

Retrosplenial cortex (RSC) value since noxious stimuli applied anywhere on the body result in activation of these neurons. !is gener- !e retrosplenial cortex (RSC) includes BA 29 and BA alized activation coupled with the fact that the MCC 30, which extend around the splenium of the corpus receives projections from medially located di$use callosum. Most of the RSC is found on the inferior thalamic nuclei as opposed to laterally located relay aspect of the cingulate gyrus. !e PCC/RSC and BA nuclei (Chapter 9, Table 9.1), makes the MCC part of 23 are adjacent and are reciprocally connected. !ere the medial pain system (Vogt et al., 1993). !e ACC/ are also strong connections between pACC and BA 23, MCC appears to be involved in specifying the a$ect- providing an intimate link between the RSC and sACC ive content of the noxious stimulus, selecting a motor (Figure 12.3). !e PCC and RSC are part of the default response to the stimulus, and with learning associated brain network (Chapters 4 and 6) (Buckner et al., 2008; with the prediction and avoidance of noxious stimuli. Hayden et al., 2009). !ey are active during the resting, It is speculated that the MCC organizes appropriate mind-wandering state. Glucose levels in the PPC/RSC skeletomotor responses to pain. One response to pain area were measured to be about 20% above other brain is the inhibition of activity in the prefrontal cortex dur- regions when in the resting state. !is network is active ing noxious stimulation (Devinsky et al., 1995). !e during mind-wandering. Memories associated with MCC projects to the midbrain periaqueductal gray emotional states stored in the pACC may be released (PAG in Figure 12.3), an area known to regulate pain to consciousness by activity in the PCC or RSC. For perception (Chapter 10). !ese #ndings are consistent example, Maddock et al. (2003) reported that the PCC/ with the data showing that cingulotomy may be e$ect- RSC was signi#cantly activated bilaterally when hear- ive in otherwise refractory pain. ing both unpleasant and pleasant words although the !e MCC is activated by application of noxious strongest activation was observed in the le& sACC. stimuli (Casey et al., 1994). Response to noxious A lesion of the le& RSC can produce an amnestic heat stimulus has been reported to increase activ- syndrome characterized by anterograde loss of ver- ity in the contralateral MCC in humans (Talbot et al., bal and nonverbal memories accompanied by a mild 1991). Derbyshire et al. (1994) found that blood "ow retrograde amnesia. A lesion of the right RSC results increased in the MCC during application of noxious in amnesia for topographical features. Familiar build- stimuli, while at the same time prefrontal cortex blood ings and landscapes are recognized but the positional "ow decreased. A lesion surgically introduced in the relationship of two familiar locations is lost. !e RSC anterior cingulum bilaterally is referred to as cingulot- may play a role in encoding novel locations and their omy. Foltz and White (1962) found that patients with relationships (Takahashi, 2004). chronic pain who had been treated with cingulotomy Cingulum continued to feel the pain but that the pain did not bother the patient and did not trigger an adverse emo- !e cingulum is a large bundle of #bers that parallels the tional reaction. In other studies, psychiatric patients arc of the cingulate gyrus (Figures 12.3 and 12.5). !e who received surgical lesions of the cingulate cortex cingulum appears in some publications as the “sagit- or cingulum, or both, reported relief from chronic, tal bundle of the gyrus fornicatus.” It is an association intractable pain (Ballantine et al., 1967). Many other bundle and contains short #bers that interconnect dif- studies have found mixed results (Cetas et al., 2008). ferent areas of the cingulate cortex. Long #bers located within the cingulum project to the occipital cortex and to the hippocampus (Figures 12.3 and 12.5). !e cin- Social interactions gulum also contains #bers that connect the cingulate Social interactions require complex processing of infor- cortex reciprocally with the prefrontal, temporal, and mation from a number of sources, including the mem- parietal areas (Figure 12.6). ory of past events. !e ACC appears to play a pivotal role in the generation of socially appropriate behav- Nociception (pain) ior. It lies in a position to evaluate the consequences !e MCC is a major component of the medial pain sys- of future behavior by the prefrontal cortex with motor tem. !e area of the MCC involved in pain lies behind and autonomic responses to ongoing social behavior. and below the skeletomotor control region (Figure 12.1; Lesions of the ACC in animals commonly result in NCC, Figure 12.7). Neurons in this region respond to reduced aggressivity, diminished shyness, emotional 201 noxious stimuli. !e region seems to have no localizing blunting, impaired maternal–infant interactions, and Limbic system: Cingulate cortex

Cortex Figure 12.5. An overview of the connections associated with the cingulate Frontal ParietalT emporal Occipital gyrus. Papez’s circuit is shown with bold lines (compare with Figure 13.8). The Cingulum cingulum is an association bundle that Cingulum Posterior cingulate Anterior cingulate interconnects one part of the cingulate gyrus gyrus gyrus with the other as well as with other cortical areas. Many "bers course ven- Cingulum trocaudally in the cingulum to terminate in the entorhinal cortex (right). Others course rostroventrally to terminate in the AN orbital cortex, caudate nucleus, and other structures (left). The majority of the "bers from the hippocampus to the hypo- Entorhinal cortex Hypothalamus Orbital cortex thalamus terminate in the mammillary nucleus. Many cortical connections are reciprocal (see text). AN, anterior nucleus Fornix of the thalamus, a major component of the “limbic thalamus.” Hippocampal Caudate nucleus formation

Parietal cortex Motor areas of Figure 12.6. Some of the major projec- frontal lobe tions to the cingulate cortex. The area served by the amygdala is restricted to the “a#ect” portion of the cingulate cortex and does not overlap the area served by the parietal cortex.

pus callosu Cor m Occipital Frontal pole pole

Amygdala

Limbic thalamus, Auditory areas temporal lobe limbic structures, prefrontal cortex

NCC SMCC Figure 12.7. The cingulate cortex can be divided functionally into regions that SM subserve vocalization (VOCC), viscero- Cognition Affect motor functions (VMCC), skeletomotor functions (SMCC), and nociception (NCC) as well as a posterior region that appears call orpus osum to function in spatial orientation and spa- Occipital C tial memory (SM). The anterior cingulate pole VMCC Frontal cortex can be divided into regions that pole serve a#ect and cognition. The border between these two regions is indicated by the dashed line (after Devinsky et al., 1995). VOCC VMCC

inappropriate intraspecies social behavior. !e fact that psychosis, and compulsive behavior (Devinsky et al., aggressive behavior is reduced following bilateral cin- 1995). 202 gulotomy in animals led to the use of this procedure in Patients with cingulate lesions or with cingulate humans in an attempt to reduce aggression, agitation, epilepsy may express impulsivity, apathy, aggressive Anatomy and behavioral considerations

behavior, psychosis, and sexually deviant behavior as Clinical vignette (cont.) well as obsessions and compulsions. Hypometabolism had a history of sociopathic behavior (15 years) that seen in the ACC of patients with borderline personality began about 1 year after a mild head injury. During disorder is speculated to be related to impulsiveness, a a seizure the patient would exhibit grotesque facial main characteristic of this disorder (De La Fuente et al., contortions, tongue thrusting, a strangulated yell, 1997). Surgical cingulotomy, which removes cortex in and bilateral arm and leg extensions with side-to- the region of BA 24 and BA 32 and the cingulum, may side thrashing. This patient similarly had no pre- or produce impaired social behavior. In some cases the postictal problems. Consciousness was preserved behavior of patients with cingulate lesions has resulted unless the seizure generalized. Interictally, the patient in institutionalization (Bancaud and Talairach, 1992). was irritable and demonstrated poor impulse control with sexual preoccupation and deviance. Depth EEG !e skin conductance of one patient following bilateral recording showed that the seizures stemmed from the cingulate and orbitofrontal cortex surgery showed no right cingulate cortical region. After surgery his family response to emotional stimuli (Damasio et al., 1990). reported that his irritability was diminished and that Clinical vignette he exhibited better social conduct. At last follow-up he was employed and married (Devinsky et al., 1995). The following three clinical vignettes demonstrate the intertwined relationship between neurological and psychiatric aspects of abnormal brain processing, which involves brain regions that are responsible for Connections of the cingulate cortex emotional or cognitive regulation. !e limbic thalamus provides input to all regions of the Case 1 cingulate cortex (Figure 12.3; Bentivoglio et al., 1993). !e major component of the limbic thalamus is the An 11-year-old girl had been having seizures since 2 5 years. At age 3 she developed obsessive features and anterior thalamic nucleus (Chapter 9). !e anterior by age 8 she was preoccupied with Satan, feared pun- nucleus is actually a nuclear complex that consists of ishment for real and imagined behaviors, and spent the anterior ventral, anterior medial, and anterior dor- long periods of time washing her hands, brushing her sal nuclei. Projections from anterior ventral and anter- teeth, and showering. Depth electroencephalographic ior dorsal nuclei favor the PCC, whereas the anterior (EEG) recording documented seizure onset from the medial nucleus projects to the ACC. !e anterior right anterior cingulate region. Surgical destruction of nuclear complex is part of the circuit of Papez and 4 cm of the a#ected cortex eliminated her seizures and lies between the mammillary body and the cingulate markedly reduced her obsessive-compulsive behav- cortex (Figures 12.5 and 13.8; Chapter 13). Although iors during the "rst 15 postoperative months (Levin the entire cingulate cortex also receives a$erents from and Duchowny, 1991). the lateral dorsal thalamic nucleus, the lateral dorsal Case 2 nucleus preferentially targets the PCC. !e lateral dor- A 43-year-old man had a long history of medically sal nucleus is also part of the limbic thalamus and is intractable complex partial seizures. The seizures were a relay nucleus that transfers sensory information and stereotyped and characterized by laughter, repetition especially visual information from the lateral genicu- of the phrase “Oh my God,” and bilateral arm exten- late body of the thalamus and from the pretectum of sions followed by repeated touching of the forehead the midbrain. !e pretectum of the midbrain is an area and mouth. The seizures were short (<10 seconds) where vision, touch, and hearing converge. !e pretec- and were without auras or postictal confusion. The tum–lateral dorsal nucleus connection is therefore a patient was amnestic for the seizure. Eventually he became reclusive and lost his job. Depth EEG record- route by which visual, touch (somesthesis), and audi- ing showed that the seizures originated from the right tory signals can reach the cingulate cortex. anterior cingulate region. After resection of this region, !e ventral anterior nucleus and ventromedial the seizures improved and the patient was able to live nucleus are part of the motor thalamic region. independently and entered into a romantic relation- Projections from both of these thalamic motor nuclei ship (Devinsky et al., 1995). favor the MCC, which contains the skeletomotor region Case 3 of the cingulate cortex. Midline and intralaminar thalamic nuclei, which are considered “di$use” nuclei, A 42-year-old man similarly had a long history of intractable complex partial seizures. In addition he project to all regions of the cingulate cortex with a 203 preference for the ACC. !e midline and intralaminar Limbic system: Cingulate cortex

nuclei are signi#cant structures in the medial pain sys- During the last two decades, highly re#ned neuro- tem and play a role in the a$ective responses to painful surgical procedures have emerged that can alleviate stimuli (Vogt et al., 1993). some of the most recalcitrant psychiatric symptoms !e PCC receives a large number of #bers from the [Rapoport and Ino$-Germain (1997)]. Current pro- parietal lobe, including the primary somesthetic area. cedures are usually labeled “functional neurosurgery” It has been suggested that the PCC coordinates activ- and depend on the ability to perform microsurgical ities between the limbic system and the somesthetic procedures guided by stereotactic knowledge. !e cortex (Van Hoesen et al., 1993). Targets of #bers from procedures are very di$erent from the old “lobotomy” the PCC are similar to those of the ACC with several in that the surgical lesions made are extremely small exceptions. !e PCC has reciprocal connections with and are placed in very speci#c structures bilaterally. the motor cortex, but they are much less extensive than Surgery can be performed under local anesthesia, those of the ACC. Both regions of the cingulate project although general anesthesia is used most o&en. Such to the neostriatum (caudate nucleus and putamen), but procedures have been developed for the treatment of PCC projections favor the caudate nucleus. !e caudate depression, anxiety, and chronic pain. Four procedures is recognized to function in emotionally related behav- are in current use. iors (Chapter 7). Considering the connections with the Cingulotomy is the most commonly reported psy- hippocampus and mammillary bodies, it is not surpris- chosurgical procedure used in the United States and ing that animal studies have shown that both the PCC Canada. It has proved e$ective in the relief of pain, and ACC are involved in memory. !e inferior portion anxiety, obsessive-compulsive disorder, and depres- of the PCC (BA 29) in particular has been implicated in sion with minimal psychiatric, neurological, or gen- spatial memory (Sutherland and Hoesing, 1993). eral medical morbidity (Ballantine et al., 1987; Jenike E$erent #bers from the cingulate gyrus contribute et al., 1991; Cosgrove and Rauch, 1995; Marino and heavily to the cingulum (Figures 12.3 and 12.5). Many Cosgrove, 1997). A second operation is o&en necessary cingulum #bers curve ventrally in a caudal direction to six months to a year a&er the initial procedure. About terminate in the entorhinal cortex (Figure 11.2). !e 75% of depression patients showed partial or substan- cingulum is o&en depicted in diagrams of Papez’s cir- tial improvement (Shields et al., 2008). Bilateral lesions cuit, which emphasize the link between the cingulate are created that measure approximately 8–10 mm in gyrus and the hippocampus (Figures 12.5 and 13.8). lateral diameter and extend about 2 cm dorsally from However, an equally large number of #bers course ros- the corpus callosum. !e lesion destroys the anterior trally in the cingulum to make connections with other cingulate gyrus and interrupts the cingulum (Ovsiew brain structures. !ese # bers also curve ventrally. and Frim, 1997). Many fan out to terminate in the orbital cortex of the Subcaudate tractotomy, developed in the United frontal lobe. Others continue to arch ventrocaudally Kingdom, is used to treat unresponsive a$ective dis- to terminate in the striatum, the anterior and medi- order (Poynton et al., 1995). Bilateral lesions are placed odorsal nuclei of the thalamus, and the hypothalamus in the white matter beneath and in front of the head of (Chapter 8). !is account of the elaborate connections the caudate nucleus using either small radioactive rods between the cingulate cortex and all areas of the lim- or thermocoagulation. During the weeks a&er the sur- bic system highlights the important and central role gery, patients show a signi#cant but transient perform- that the cingulate cortex plays in mediating our emo- ance de#cit on recognition memory tests (Kartsounis tion and cognitive function on one hand and motor et al., 1991). response on the other. Capsulotomy was developed in Sweden and is sometimes performed in the United States. It is used to Behavioral disorders and neurosurgery treat refractory anxiety disorders including obsessive- !ere is no clear-cut syndrome associated with cin- compulsive disorder. !e lesion produced in the anter- gulate lesions. Electrical stimulation of human cingu- ior third of the internal capsule is approximately 4 mm late cortex has been reported to produce a spectrum wide and 16 mm long (Ovsiew and Frim, 1997). of behaviors, including speech arrest and involun- Limbic leukotomy was developed in the United tary vocalization, as well as autonomic, a$ective, and Kingdom (Figure 12.8). It consists of a subcaudate psychosensory phenomena (Devinsky and Luciano, tractotomy bilaterally accompanied by cingulotomy 204 1993). (Mindus and Jenike, 1992). Anatomy and behavioral considerations

(Benes et al., 1991; Benes, 1996, 1998). !e authors speculated that the lost interneurons are GABAergic inhibitory neurons and the axon terminals are from glutamatergic neurons located in the prefrontal cortex (Benes et al., 1991; Benes, 1996, 1998). !e concentration of serotonin [5-hydroxytryptamine

(HT)1A] receptors was increased in BA 24 in schizophrenia patients, whereas the concentration of sero-

tonin (5-HT2A,C) receptors was decreased in the same area. !ese #ndings correlate with hypofrontality (Gurevich and Joyce, 1997). !e loss in cingulate cortex in schizophrenia is #rst seen during adolescence compared with frontal cortex loss seen prior to adolescence (Vidal et al., 2006). !e white matter tracts in the ACC were also disrupted in early-onset schizophrenia (Kumra et al., 2005; White et al., 2008). Increased activity in the pACC (BA 32) was coincident with decreased activity in the dorsolateral prefrontal cortex leading the authors to suggest a kind of disconnection or connection-disruption syndrome (Glahn et al., 2005). Schizophrenia patients also demonstrated reduced glucose metabolism in the ACC that correlates with attentional dysfunction seen in these patients (Tamminga et al., 1992; Carter et al., 1997). Both the prefrontal cortex and the ACC are implicated in the psychomotor poverty syndrome of schizophrenia (Liddle et al., 1992). Poverty of movement and catato- Figure 12.8. Sagittal (A) and low axial (B) magnetic resonance nia are consistent with a decrease in the motivational imaging (MRI) of acute limbic leukotomy lesions. The dorsal lesion aspect of ACC function. (A, top arrow) involves the anterior cingulate gyrus in the same location as a cingulotomy. The ventral lesion (A, bottom arrow) !e le& ACC along with other structures was is located similarly to those produced in subcaudate tractotomy. activated when schizophrenia patients experienced (Modi"ed from Ovsiew, F., and Frim, D.M. 1997. Neurosurgery for psy- auditory hallucinations. !e PCC was prominently chiatric disorders. J. Neurol. Neurosurg. Psychiatry 63:701–705.) activated when a schizophrenia patient experienced visual hallucinations (Silbersweig et al., 1995). Schizophrenia patients demonstrate oculomotor Schizophrenia abnormalities and use catch-up saccades during pur- A number of studies have revealed abnormalities in suit eye movements. !e motor region of the MCC the ACC as well as other areas, including the hippo- projects to the frontal eye #elds. !e frontal eye #eld of campus and dorsolateral prefrontal cortex in patients the prefrontal cortex is well known for its involvement with schizophrenia. Reduced total volume (gray and in saccadic (fast) eye movements, but it is also involved white matter) (Haznedar et al., 2004; Choi et al., in smooth pursuit tracking (MacAvoy et al., 1991). 2005) as well as reduced gray matter volume of the ACC (Crespo-Facorro et al., 2000; Job et al., 2003a; Depression and bipolar disorder Yamasue et al., 2004) have been reported for patients Reductions in gray matter volume have been reported with schizophrenia. Job et al. (2003b) found di$er- for the cingulate in patients with major depression ences between control and subjects at high risk for (Ballmaier et al., 2004; Pezawas et al., 2005). !e sACC schizophrenia as well as #rst episode patients. !e is recognized as part of a neural network involved number of interneurons have been reported to be in depression (Seminowicz et al., 2004; Ressler and 205 reduced but the number of axon terminals increased Mayberg, 2007). Mayberg et al. (1999) found that Limbic system: Cingulate cortex

provoked sadness increased metabolic activity in indirect pathways through the basal ganglia. !e dir- sACC and insula along with decreases in activity in ect pathway is excitatory and the indirect pathway is the pMCC and PCC. Successful drug treatment of inhibitory (Chapter 7). the depressed patients resulted in decreased activity !e direct and indirect pathways are in balance in in sACC and insula along with increases pMCC and the normal condition. Obsessive thoughts may result PCC. Successful treatment with vagus nerve stimula- from an imbalance between the two pathways with tion has also been reported to reverse abnormal meta- overactivity of the direct pathway (Saxena and Rauch, bolic activity (Zobel et al., 2005). Other studies have 2000). found direct stimulation of the sACC using deep brain !ree areas have been implicated in obsessive-com- stimulation in treatment-resistant depressed patients pulsive disorder (OCD): orbitofrontal cortex, ACC/ resulted in improvements in symptoms of depression MCC, and the head of the caudate nucleus (Figure 12.9). along with decreased activity in the sACC (Hauptman !ese areas are hyperactive at rest in OCD, become et al., 2008; Lozano et al., 2008). !e changes seen in even more active with symptom provocation, and cingulate gyrus metabolism in depression were linked show less activity at rest following successful treatment to changes seen in frontal lobe cortex. with either medication or cognitive-behavioral ther- Reductions in gray matter volume are reported for apy (Saxena and Rauch, 2000; Whiteside et al., 2004; the sACC (Wilke et al., 2004; Houenou et al., 2007) Maia et al., 2008). It is unknown whether these areas and PCC in bipolar disorder (Lochhead et al., 2004; are hyperactive as a consequence of some abnormal- Farrow, et al., 2005; Kaur et al., 2005) but without ity elsewhere or re"ect attempted inhibition of obses- neuron loss (Öngür et al., 1998). Glial cell loss was sive thoughts (Shafran and Speckens, 2005; Roth et al., reported (Todtenkopf et al., 2005). !ere is some 2007). evidence that the reduction in gray matter volume ACC/MCC gray matter volume has been found increases with the duration of the illness (Farrow et to be greater in children with OCD than in controls al., 2005; Kaur et al., 2005; Lyoo et al., 2006). Dunn (Rosenberg and Keshavan, 1998; Szeszko et al., 2004). et al. (2002) reported that metabolism in the sACC In contrast, decreased ACC/MCC gray matter is a increased during the depressive phase. A decreased consistent #nding in adults with OCD (Pujol et al., response in the ventral pACC to faces (emotional 2004: Valente et al., 2005; Yoo et al., 2008). processing) has been reported for euthymic bipolar !e two main symptoms of OCD are obsessive- patients compared with control subjects (Shah et al., compulsive behaviors and anxiety. Anxiety is believed 2009). In contrast, tasks designed to elicit emotional to be mediated through the hippocampus, amygdala, responses have been shown to result in greater activa- septal nuclei, mammillary bodies (hypothalamus), tion in euthymic bipolar patients in the ACC and PCC and anterior thalamic nuclei. !e cingulum is a major (Malhi et al., 2007; Wessa et al., 2007). In other stud- common pathway. Cingulotomy as well as lesions of ies, patients with mania had reduced activity in the the MCC have been used with some success in treat- sACC and increased activity in the PCC in response to ment of resistant OCD. !e cingulum contains #bers images of sad faces. Medicated patients did not exhibit that project from the ACC/MCC to the orbitofron- this pattern suggesting that mood stabilizing drugs tal cortex and to the caudate nucleus (Figure 12.5). reverse the abnormal activity (Blumberg et al., 2005; Psychosurgical lesions limited to the ACC/MCC have Strakowski et al., 2005). resulted in reduced anxiety (Chiocca and Martuza, 1990). Obsessive-compulsive thoughts and sensations Obsessive-compulsive disorder are more likely to be mediated through the interaction !e ACC/MCC and orbitofrontal cortex are intimately between the orbitofrontal cortex and the caudate connected to the basal ganglia and to each other. !e nucleus (Baxter, 1992). It is theorized that a loop con- ACC/MCC and orbitofrontal cortex each participate necting the frontal region with the caudate nucleus in a loop that runs parallel to each other. !e two loops and passing through the thalamus and back to the originate in variable areas of the cortex, pass through frontal area subserves obsessive-compulsive symp- the head of the caudate nucleus, the anterior nucleus toms (Figure 7.9). A lesion that interrupts the caudate- of the thalamus and then to either the ACC/MCC or frontal axons (subcaudate tractotomy) is believed to orbitofrontal cortex (Mega and Cummings, 2001; directly decrease obsessive-compulsive symptoms 206 Middleton and Strick, 2001). !ere are both direct and (Martuza et al., 1990). Anatomy and behavioral considerations

Figure 12.9. Positron emission tomographic omnibus subtraction images of provoked minus resting conditions for all subjects (N = 8; 13 scans per condition) displayed with a “hot iron” scale in units of z score, superimposed over a normal magnetic resonance image transformed to Talairach space, for the purpose of anatomical reference. Patients with obsessive-compulsive disorder were provoked with stimuli tailored to each patient’s symptoms. All images are transverse sections parallel to the anterior commissure–posterior commissure plane, shown in conventional neuroimaging orientation (top = anterior, bottom = posterior, right = left, and left = right). Areas of signi"cant activation include the orbitofrontal cortex, caudate nucleus and cingulate cortex. (Reproduced by permission from Rauch, S.L., Jenike, M.A., Alpert, N.M., Baer, L., Breiter, H.C.R., Savage, C.R., and Fischman, A.J. 1994. Regional cerebral blood !ow measured during symptom provocation in obsessive- compulsive disorder using oxygen 15–labeled carbon dioxide and positron emission tomography. Arch. Gen. Psychiatry 51:62–70.)

Posttraumatic stress disorder word rape) resulted in slower response times in abuse- related or combat-related PTSD (McNally et al., 1990; Posttraumatic stress disorder (PTSD) is character- Foa et al., 1991). Bremner et al. (2004) showed that this ized by a state of heightened responsiveness to threat- was associated with decreased function of the pACC ening stimuli and/or a state of insu%cient inhibitory (BA 24 and BA 32) in abused women with PTSD but control over exaggerated threat-sensitivity (Liberzon not in abused non-PTSD women. and Sripada, 2008). It re"ects dysregulation of the !e hypothalamic-pituitary-adrenal axis is a$ected hypothalamic-pituitary-adrenal axis, the amygdala, in PTSD (Liberzon et al., 1999a; Phan et al., 2004). medial prefrontal cortex and ACC. Several studies had Ottowitz et al. (2004) showed that adrenocorticotropic reported that provocative stimuli (emotional images hormone (ACTH) and cortisol levels during mood and negative words) produced increased activation of induction in subjects with PTSD correlated positively the ACC, amygdala, and medial prefrontal cortex in with activity in the ACC, but correlated negatively in subjects with PTSD (Rauch et al., 1996; Lanius et al., control subjects. Activity in the ACC and medial pre- 2002; Protopopescu et al., 2005). frontal cortex appears to mediate cortisol and sym- Studies have also shown that activity in the amyg- pathetic responses to stress (Liberzon and Sripada, dala increased with symptom severity in response to 2008). combat sounds in subjects with PTSD (Liberzon et al., 1999b; Protopopescu et al., 2005). Lanius et al. (2001, 2003) found that activity in the ACC and medial pre- Akinetic mutism frontal cortex decreased in response to provocative Akinetic mutism may be seen a&er bilateral damage to stimuli. !e decrease in ACC appears to be speci#c to the ACC or to the adjacent supplementary motor cor- PTSD. Others have reported that an emotional com- tex, or to both. A patient who showed recovery a&er one ponent of the Stroop test (e.g., say the color of the month reported that during the period of mutism “she 207 Limbic system: Cingulate cortex

did not talk because she had nothing to say,” her mind such as episodic outbursts or #xed and intermittent was “empty,” and she “felt no will to reply” (Damasio psychotic behavior. Patients with cingulate seizures and Van Hoesen, 1983). have more paroxysmal aggressive outbursts, greater sociability, and less logorrhea (increased speech) than Tourette syndrome patients with temporal lobe epilepsy. !ese behavioral !e pathogenesis and the exact anatomical basis of aberrations frequently improve a&er removal of the Tourette syndrome (GTS) remain unknown (Chapter abnormal cingulate cortical tissue by cingulectomy 7). It has been suggested that the ACC has a central (Ledesma and Paniaqua, 1969; So, 1998). role in GTS since stimulation of the ACC in animals produces vocalizations. !e targets of projections Select bibliography from the ACC include areas involved in vocaliza- Bouckoms, A.J. Limbic surgery for pain. In: P.D. tion, and dopaminergic hyperactivity is postulated Wall, and R.Melzack (eds.) Textbook of Pain. as a primary cause of GTS. In addition, glucose util- (Edinburgh: Churchill Livingstone, 1994.) ization in the ACC of patients with GTS is decreased, Jenike, M.A. Obsessional disorders. Psychiatric Clinics of and cingulotomy has successfully reduced obsessive- North America (vol. 15). (Philadelphia: Elsevier, 1992). compulsive behaviors in these patients (Devinsky et Rodgers, J.E. Psychosurgery: Damaging the Brain to Save the al., 1995; Anandan et al., 2004). Abnormalities in gray Mind. (New York: Harper Collins, 1992.) and white matter volumes have been reported in the Vogt, B.A. ed. Cingulate Neurobiology and Disease. (New prefrontal cortex and midbrain (Peterson et al., 2001; York: Oxford University Press, 2009.) Fredericksen et al., 2002; Kates et al., 2002; Garraux et al., 2006). References Decreased gray matter volume in patients with GTS has been reported in the middle (lateral surface) Anandan, S., Wigg, C.L., !omas, C.R., and Co$ey, B. 2004. Psychosurgery for self-injurious behavior in Tourette’s and medial (medial surface) frontal gyri (BA 4, BA 6, disorder. J. Child Adolesc. Psychopharmacol. 14:531–538. and BA 8) and the MCC, along with the le& caudate Assadi, S.M., Yucel, M., and Pantelis, C. 2009. Dopamine nucleus and le& postcentral gyrus (Müller-Vahl et al., modulates neural networks involved in e$ort-based 2009). Symptom severity correlated with frontal vol- decision-making. Neurosci. Biobehav. Rev. 33:383–893. ume reductions. White matter reductions were also Ballantine, H.T., Cassidy, W.L., Flanagan, N.B., and found located deep to the right inferior frontal gyrus Marino, R. Jr. 1967. Stereotaxic anterior cingulotomy and le& superior frontal gyrus. !e authors hypoth- for neuropsychiatric illness and intractable pain. J. esized that abnormalities in the frontal-basal ganglia Neurosurg. 26:488–495. loops result dysfunction of caudate nucleus. Caudate Ballantine, H.T., Bouckoms, A.J., !omas, A.K., and dysfunction in turn results in disinhibition of the cin- Giriunas, I.E. 1987. Treatment of psychiatric illness by gulate gyrus. stereotactic cingulotomy. Biol. Psychiatry 22:807–819. Ballmaier, M., Toga, A.W., Blanton, R.E., Sowell, E.R., Lavretsky, H., Peterson, J., Pham, D., and Kumar, A. Cingulate cortex seizures 2004. Anterior cingulate, gyrus rectus, and orbitofrontal !e description of seizures originating from the cin- abnormalities in elderly depressed patient: An MRI- gulate cortex provides strong evidence for the involve- based parcellation of the prefrontal cortex. Am. J. ment of this region in a$ective regulation. A number Psychiatry 161:99–108. of common features seem to characterize ictal events Bancaud, J., and Talairach, J. 1992. Clinical semiology of of cingulate cortex origin. While consciousness may frontal lobe seizures. Adv. Neurol. 57:3–58. be preserved in spite of bilateral motor involvement, Bartels, A., and Zeki, S. 2000. !e neural basis of romantic love. Neuroreport 11:3829–3834. in the majority of patients the level of attention or of consciousness is a$ected. Automatisms (complex oral, Baxter, L.R. Jr. 1992. Neuroimaging studies of obsessive compulsive disorder. Psychiatr. Clin. North Am. 15: facial, or appendicular movements) occur early in the 871–884. seizure. Patients may even assume a fetal position, utter Baxter, L.R., Schwartz, J.M., Mazziotta, J.C., Phelps, M.E., brief phrases such as “Oh my God,” or exhibit hitting Pahl, J.J., Guze, B.H., and Fairbanks, L. 1988. Cerebral movements (Devinsky et al., 1995). glucose metabolic rates in non-depressed obsessive- 208 Interictally, patients with cingulate seizures have compulsives. Am. J. Psychiatry 45:1560–1563. been reported to show marked behavioral aberrations References

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214 Figure 5.5. This functional magnetic resonance image shows activation of the “fusiform face area” responsive to human faces. The right hemisphere appears on the left. The brain images at the left show (in color in the color plate) the voxels that produced a signi"- cantly higher magnetic resonance signal intensity during the epochs containing faces than during those containing objects. These signi"- cance images are overlaid on a T1-weighted anatomical image of the same slice. In each image, the region of interest is shown outlined in green. (Reproduced with permission from Kanwisher et al., 1997.)

Figure 6.5. Functional magnetic resonance images demonstrating greater activation to words than to consonant letter strings during a nonlinguistic visual feature detection task. The images illustrate a left hemisphere language network for reading, probably including temporal-occipital visual word form and lexical regions, an inferior parietal phonological encoding region, and Broca’s area in the inferior frontal lobe. The right hemisphere also participates but to a much smaller degree than the left hemisphere. See also color plate. (Reproduced with permission from Price et al., 1998.) Figure 11.7. Functional magnetic resonance imaging demonstrates activation of both the left and right amygdalae when processing facial expressions of fright (green – see color plate) as well as during conditioned fear (red). Expressions of fright produce activity more in the left side of the upper amygdala than in the right side, whereas the response to conditioned fear is more evenly distributed. (Reproduced with permission from Vass, 2004.) Figure 12.2. Functional magnetic resonance study demonstrates activation of the anterior cingulate gyrus region in the monitoring of con!ict (incongruent trials). (Reproduced with permission from Kerns et al., 2004.)

Figure 12.4. Functional magnetic resonance study demonstrates activation of the posterior cingulate gyrus region (including retrosplenial cortex) in assessing the familiarity of a person (faces or voices). (Reproduced with permission from Shah et al., 2001.)

CChapterhapter 13 Limbic system: Overview

Introduction found in the hippocampus and anterior cingulate cortex. Glutamate also has been implicated in schizophre- !e term limbic lobe was used by the French physician, nia (Tamminga, 1998). Paul Broca, to designate the structures on the limbus or margin of the neocortex. !ese structures lie in a Anatomy C-shaped arc on the medial and basilar surfaces of the !e basic anatomical components of the limbic system cerebral hemispheres that surround the lateral ventri- include: cles (Figure 13.1). Broca de#ned the limbic lobe as the parahippocampal and cingulate gyri (le grand lobe lim- t Cortical structures: bique). In addition to the limbic cortex, a number of t Parahippocampal gyrus. subcortical structures can be added that make up what t Cingulate gyrus. is today considered the limbic system. !e subcortical t Subcortical structures: structures include the hippocampus, the amygdala and t Hippocampal formation. the septal nuclei. Depending on the author, the list of limbic structures can be expanded to include portions t Amygdala. of the hypothalamus and thalamus, the habenula, the t Septal nuclei. raphe nuclei, the ventral tegmental nucleus, the nucleus Structures that are closely linked with the limbic accumbens, the basal nucleus (of Meynert), the poster- system include: ior frontal orbital cortex, and others (Trimble, 1991; t Olfactory system. Van Hoesen et al., 1996). t Sensory association cortices. !e limbic system works in collaboration with t Hypothalamus. other brain systems. !erefore, a more complete theory t Nucleus accumbens. of the function of the limbic system can be developed only in tandem with a more complete understanding t Orbital prefrontal cortex. of the entire brain. !e limbic system provides the animal with a means of coping with the environment and with other members of the species found in that environment. More basic parts of the system are concerned with primal activities (i.e., food and sex), while others yrus P te g are related to feelings and emotions. More sophisticated ula A ing parts of the system combine the external and internal C inputs into one whole reality. !is chapter attempts to CC present an overview of the limbic system. P Imaging studies show that the localization of patho- ara hipp logical functioning in schizophrenia is predominantly ocampal gyrus in the anterior cingulate and hippocampal/parahippocampal cortices (Tamminga, 1998). !e limbic cortices are a major target of dopaminergic #bers, and dopa- Figure 13.1. The limbic lobe consists of the parahippocampal mine has been implicated in schizophrenia (Chapter 3). gyrus and cingulate gyrus, which form an arch around the corpus In addition, the highest concentration of N-methyl-*- callosum (see Figure 12.1). A, anterior; P, posterior; CC, corpus aspartic acid (NMDA)-sensitive glutamate receptors is callosum. 215 Limbic system: Overview

!e limbic system is the anatomical substrate of Hippocampal formation and related behaviors including social behaviors that assure the survival of the individual and of the species. Social structures interaction in many species continues to rely on the Parahippocampal gyrus importance of olfactory cues. Olfactory cues are of lesser importance to humans but the emotions and !e rostral parahippocampal gyrus includes portions behaviors controlled by the limbic system remain of the pyriform lobe and receives primary olfactory critical for human survival. !e complex intercon- information. !e caudal part of the parahippocampal nections that allow the limbic system to perform its gyrus is represented by the entorhinal cortex (Figures many functions can be simpli#ed into two subsys- 11.2 and 13.2). !e primary source of input into the tems. !e hippocampus and septal nuclei make up entorhinal cortex is the multimodal association areas of one subsystem; the hippocampal formation is asso- the cortex. !e entorhinal cortex represents the port of ciated with memory. !e second subsystem revolves entry into the hippocampal formation (Chapter 11). around the amygdala and is involved with the assign- Hippocampal formation ment of anxiety to sensory stimuli. A brief discus- !e hippocampal formation consists of the hippocam- sion of the olfactory system is followed by an overall pus proper along with the dentate gyrus and the subicu- view of the interactions of limbic structures and their lum (Figure 11.3). Sensory signals are directed toward interactions. the hippocampus by way of relays in the entorhinal cortex and the dentate gyrus (Figures 11.3 and 13.4). In Olfactory structures addition to information arriving from the entorhinal !e olfactory system plays an important role in lim- cortex, there is input from the hypothalamus, the sep- bic function in many animals. !e olfactory stria is tal nuclei, and the amygdala. made up of #bers that arise from the olfactory bulb Outgoing projections from the hippocampal for- and terminate in limbic structures (Figure 13.2; no. 1 mation are represented by the axons of the pyramidal and 2, Figure 13.3). !e targets of these olfactory #bers neurons of the hippocampus as well as axons from the include prepyriform and pyriform areas, the entorhi- subiculum. !ese axons are distributed largely through nal cortex, and the underlying amygdala (Figures the fornix (no. 2, Figure 13.5). !e fornix projects to the 11.1 and 13.2). For many years these connections led septal nuclei, to the ventromedial hypothalamus and to authors to assume that the limbic system processed the mammillary bodies of the hypothalamus (no. 20, olfactory cues. Figure 13.5). !e #bers of the fornix that terminate in Olfactory connections with the limbic structures the septal nuclei make up the precommissural fornix account for the emotional aspects of olfaction. !e (no. 14, Figure 13.5). !e #bers from the hippocampus olfactory cues are vital to many animals for appro- to the septal nuclei contribute to the “septohippocam- priate social interaction and for a%liative behavior. pal axis,” which is especially important to nonprimate Olfactory cues, however, are relatively unimportant to mammals. Other #bers project directly to the amyg- humans. dala (Canteras and Swanson, 1992).

Figure 13.2. The ventromedial tem- Pa poral lobe is rolled back (arrow) and enlarged to show the components of the pyriform lobe (see Figure 5.2). These components include the prepyriform area (Pp), the periamygdaloid area (Pa) Ent Pp Lo and the entorhinal area (Ent). Other Mo structures include the lateral olfactory U stria (Lo), medial olfactory stria (Mo), On uncus (U), optic nerve (On), and optic chiasm (Oc).

216 Oc ab Anatomy

Hippocampal formation

Hippocampus

Dentate gyrus Subiculum

Entorhinal cortex Integrated sensory signals

Figure 13.4. The hippocampal formation consists of the dentate gyrus, the subiculum, and the hippocampus proper. Sensory signals enter the hippocampal formation by way of the entorhinal cortex. A feedback loop exists between the hippocampus and the entorhinal cortex. This circuit facilitates the memory function of the hippocampus.

Figure 13.3. Dorsal view of some of the connections of the amygdala. 1–4, olfactory structures; 5, anterior commissure; 6, olfactory tubercle; 7, limen insulae; 8, diagonal band (of Broca); 9, inferior thalamic peduncle; 10, medial telencephalic fasciculus; 11, ventral amygdalofugal pathway; 12–17, amygdala; 18, lateral hypothalamic area; 19–20, nucleus and stria medullaris; 21, stria terminalis; 22, habenular commissure; 23, habenular nuclei; S, septal nuclei. (Modi"ed with permission from Nieuwenhuys, R., Voogd, J., and Van Huijzen, C. 1988. The Human Nervous System. New York: Springer-Verlag.)

Figure 13.5. Limbic system structures located close to the mid- Septal nuclei and nucleus accumbens line. 1, stria terminalis; 2–3, fornix and commissure; 4, stria medullaris; 6, medial thalamic nuclei; 8, mammillothalamic tract; 9, habenular !e septum pellucidum is a thin, membranous midline nuclei; 10, habenular commissure; 11, habenulointerpeduncular structure that separates the le& and right lateral ventri- tract; 12, inferior thalamic peduncle; 13, anterior commissure; 14, cles (Figure 7.1). !e space between the two lea"ets of precommissural fornix; 15, stria terminalis; 17, lamina terminalis; 20, mammillary body; 21, red nucleus; 22, mammillotegmental tract; 23, the septum pellucidum is called the cavum septum pel- interpeduncular nucleus; 24, dorsal tegmental nucleus; 25, central lucidum. !e cavum is seen during fetal development superior nucleus (raphe); A, amygdala; P, pineal. (Modi"ed with per- but normally disappears during infancy. !e nuclei that mission from Nieuwenhuys, R., Voogd, J., and Van Huijzen, C. 1988. The Human Nervous System. New York: Springer-Verlag.) make up the septal complex are situated below the corpus callosum and just in front of the anterior commissure. !e lateral septal nucleus lies on the lateral aspect the medial septal nucleus. Both of these nuclei are rela- of the base of the septum pellucidum (Figure 7.1). Just tively small. !e nucleus of the diagonal band of Broca 217 below and slightly medial to the lateral septal nucleus is is included as part of the septal nuclear complex. All Limbic system: Overview

Clinical vignette 1980). Dopaminergic #bers arrive from the ventral tegmental area (Figure 10.2). Other connections link the Case 1 amygdala directly with the orbital cortex of the frontal A 35-year-old patient with a history of treatment-re- lobe (Figure 13.6). !e extended amygdala consists of sistant schizophrenia since age 21 was readmitted for a corridor of cells that extend forward from the amyg- an acute exacerbation. The patient had a signi"cant dala to the nucleus accumbens (Alheid and Heimer, formal thought disorder with loosening of association 1996). In addition, a special relationship exists between and tangential speech. Neurological examination the amygdala and the hippocampal formation (Figure revealed subtle dysmetria and dysdiadochokinesia of the left arm. A computed tomographic scan revealed a 13.7). !ere are direct #bers between these two limbic large, cyst-like structure interposed between the bod- structures as well as an indirect link from the amyg- ies of the lateral ventricles (Wolf et al., 1994). Agenesis dala back to the hippocampal formation by way of the of the septum pellucidum has been described in some entorhinal cortex (Figures 11.3, 13.6, and 13.7). cases of chronic psychosis but much less frequently One group of #bers that leaves the amygdala than agenesis of the cavum septum pellucidum. Direct makes up the stria terminalis, which arches dorsally pathways from the cerebellum to the septum may be and terminates in the hypothalamus, thalamus, and related to the dysmetria (Heath et al., 1978). nucleus accumbens (21, Figure 13.3; 1, Figure 13.5). A second contingent of #bers projects ventrally from the Case 2 Figure 13.6. The A 31-year-old male patient presented with a long Orbital cortex history of chronic paranoid schizophrenia that was amygdala and septal nuclei unresponsive to treatment. He had a history of enur- both interact esis and febrile seizures between the ages of 2 and 4 directly with the and was reported to be notably awkward at sports Hypothalamus orbital cortex. as a child. He also had developed polydipsia after the Hippocampal onset of psychosis. On examination he demonstrated input to the orbital cortex is by way of di!culty with tandem walking. He had a total IQ score the hypothalamus. of 120 with a 136 for verbal and 95 for performance. Septal nuclei Amygdala Magnetic resonance imaging revealed the absence of the septum pellucidum and marked dilation of the lat- Fornix eral ventricles (Wolf et al., 1994). Lesions of dysgenesis of the septal region may have cognitive or emotional Hippocampal formation manifestations, or both, given the region’s key role in the limbic system.

of these nuclei are important sources of acetylcholine (Gaykema et al., 1990). Cingulate cortex !e nucleus accumbens lies immediately lateral to the septal nuclei. It is generally considered to be part of the corpus striatum (Chapter 7). Nucleus accumbens Anterior thalamic nucleus consists of a core and more medially located shell. Separate functions have been assigned to each (Ito et al., 2004). Mammillary body Amygdala !e many nuclei of the amygdala are summarized in Septal nuclei Amygdala Chapter 11 (12–17, Figure 13.3). Overall, the amygdala has access to integrated sensory information from high- Fornix Hippocampal er-order cortical areas. !e sensory information that formation reaches the amygdala provides details that help identify Figure 13.7. The amygdala projects to the cingulate gyrus via the the object rather than determine its location (Amaral stria terminalis and the ventral amygdalofugal pathway. The septal 218 et al., 1992). Auditory signals may arrive directly from nuclei and amygdala interact with the hippocampus and the circuit the medial geniculate body (Norita and Kawamura, of Papez. Behavioral considerations

amygdala to the septal nuclei, the nucleus accumbens, Cingulate gyrus and the orbital cortex as well as to the hypothalamus and thalamus (no. 8–11, Figure 13.3; Gloor, 1997). Anterior thalamic nucleus Behavioral considerations !e limbic system has extensive connections within itself and with almost all other areas of the brain. Most Mammillary body of the data supporting such circuitry come from animal work. It should be noted that although much of the limbic circuitry has been identi#ed, the speci#c contri- Hippocampus butions of each circuit to our emotional and cognitive behaviors are not yet fully known. !e loop formed by the hippocampus, fornix, and Entorhinal cortex mammillary bodies, mammillothalamic tract, anterior Figure 13.8. The classic circuit of Papez provides feedback to the thalamic nuclei, cingulate gyrus, and projections back hippocampus by way of the cingulate gyrus (compare with Figure to the hippocampus form the circuit of Papez (Figures 12.3). The fornix connects the hippocampus with the mammillary 12.3 and 13.8). Papez (1937) described this circuit as body. The mammillothalamic tract ascends to the anterior thalamic nucleus. The cingulum contains the e#erents from the cingulate the substrate of “a harmonious mechanism which may gyrus to the entorhinal cortex. elaborate the functions of central emotions.” Two functional divisions of the limbic system have been suggested (Mega et al., 1997). An older paleocor- information for only a short time. !e long-term storage tical division has the amygdala and orbital prefrontal of new information is dependent on neocortical areas cortex at its center. !e newer archicortical division and may be coincident with the same sensory association has the hippocampus and cingulate cortex at its cen- areas that #rst supplied the information to the hippoc- ter. !e older division functions in the integration of ampal formation. Feedback signals from the hippocam- a$ect, drive, and object association, while the newer pus to sensory association areas may be important in division functions in explicit sensory processing, the consolidation of new memory. !e hippocampal– encoding, and attentional control. !e authors sug- entorhinal circuit provides a feedback pathway and is gest that the distinction between the orbital prefrontal/ hypothesized to be a reinforcement circuit that lowers amygdala division (emotional associations and appe- the threshold of the neurons of the entorhinal cortex in titive drives) and the hippocampal/cingulate division order to more quickly recognize a pattern of sensory sig- (mnemonic and attentional processes) can further our nals (Figure 13.4; Buzsaki et al., 1990). interpretation of limbic system disorders. !ey further Memory is believed to re"ect a conceptual cogni- suggest that psychiatric disorders can be reinterpreted tive map that is inherent to the hippocampal formation within a brain-based framework of limbic dysfunc- and possibly to the hippocampus itself (Jarrard, 1993). tion and divided into three general groups: decreased Verbal and contextual memory may have developed (e.g., depression, Kluver–Bucy), increased (e.g., mania, from mechanisms already in place in the hippocampal obsessive-compulsive disorder), and dysfunctional formation. !e mapping concept has been extended by (e.g., psychosis) limbic syndromes. some authors to include linguistic and semantic relationships (Gloor, 1997). Hippocampal formation and related Bilateral damage to the hippocampal formation has a devastating e$ect on the ability to store and recall new structures information. Even minor damage to the hippocampus !e hippocampal formation is of primary importance can produce signi#cant and lasting memory impair- in the storage and in the recall of new information in the ments (Zola-Morgan and Squire, 1993). Le& temporal form of declarative memory (Chapter 11). Declarative lobe damage a$ects verbal learning, whereas right tem- memory is based on con#gural learning in both space poral lobe damage a$ects nonverbal learning. and time. Nondeclarative memory (e.g., motor skills, Projections from the hippocampal formation make habits, emotions) is independent of the hippocampus up the fornix, and many of the #bers of the fornix ter- 219 (Squire, 1992). !e hippocampal formation retains new minate in the septal nuclei and in the mammillary bodies Limbic system: Overview

(nos. 2 and 20, Figure 13.5; S, Figure 13.3; Figures 13.6 and 13.7). Lesions of the fornix are reported to produce amnesia (Von Cramon and Schuri, 1992). Lesions seen in the mammillary bodies in Korsako$ syndrome also correlate with amnesia (Kopelman, 1995). Damage to other related structures including the medial thalamus (Chapter 9) can also produce amnesia. !e theta rhythm is an electroencephalographic (EEG) pattern ranging from 4 Hz to 12 Hz that has been recorded from the hippocampus of rodents and rabbits during certain behavioral conditions (Vanderwolf, 1988). It has been speculated that the theta rhythm is important in arousal and in the creation of a spatial map that is conducive to learning. Surprisingly the theta rhythm appears to be absent in primates and humans (Huh et al., 1990). Septal nuclei and nucleus accumbens !e septal nuclei have been implicated in memory (S, Figure 13.3). !ey, along with the basal nucleus (of Meynert) are cholinergic nuclei and exhibit degeneration in Alzheimer disease (Arendt et al., 1983; Coyle et al., 1983). Lesions in humans that include the septal area can produce memory loss along with hyperemotionality (Bondi et al., 1993). A cavity in the septum pellucidum (cavum septum pellucidum) of varying size has been reported to occur in up to 85% of the population (Figure 13.9; Nopoulos et al., 1996, 1997). !e presence or absence of a cavum septum pellucidum does not di$erentiate between control and psychiatric patients. However, a signi#cant number of moderate to large (grade 3–4) cavum septi pellucidi were found only in schizophrenia (Shioiri et al., 1996) and in patients with a$ective Figure 13.9. A cavum septum pellucidum is found in both normal disorder and schizotypal personality disorder (Kwon and schizophrenia populations; however, it is consistently larger in et al., 1998). !e closure of the cavum is in"uenced schizophrenia. The cavum septum pellucidum in normal individuals is rated “small” (top arrow) when seen on up to two contiguous developmentally by the enlargement of the corpus cal- magnetic resonance (MR) 1.5 mm coronal slices. The cavum septum losum and hippocampus. !e large cavum may re"ect pellucidum is rated “large” when seen on at least four contiguous the relatively small size of the corpus callosum and MR 1.5 mm coronal slices (bottom arrow). (Modi"ed with permission from Nopoulos, P., Swayze, V., Flaum, M., Ehrhardt, J.C., Yuh, W.T., and hippocampus during the developmental period when Andreasen, N.C. 1997. Cavum septi pellucidi in normals and patients the cavum normally closes. !is is consistent with the with schizophrenia as detected by magnetic resonance imaging. uncon#rmed speculation that the severity of cavum Biol. Psychiatry 41:1102–1108.) septum pellucidum enlargement may correlate with childhood-onset schizophrenia (Nopoulos et al., 1998; to coincide with dopamine release in the nucleus Takahashi, et al., 2008). accumbens (Self and Nestler, 1995). Peoples et al. (2004) !e nucleus accumbens is well recognized as a showed that neurons of nucleus accumbens increased reward center of the brain (Figures 7.1 and 13.10). activity with the onset of cocaine administration. In It is associated with locomotor activity and reinfor- contrast, drugs that block the dopamine receptor sites cing actions of psychostimulants and other drugs of result in an increase in alcohol consumption in rats (Dyr 220 abuse. !e action of mood-elevating drugs is believed et al., 1993). Components of drug withdrawal correlate Behavioral considerations

Orbital cortex between drugs and the stimuli that predict their avail- Socially acceptable behavior ability (Di Chiara, 1998). !is learning is described as pathological because it does not undergo habituation as does the food-associated learning (Bassareo et al., 2003; Everitt and Robbins, 2005). !e core is believed Nucleus to operate in conjunction with the prefrontal cortex to accumbens Amygdala provide motivation to seek out a reward and convert Sense of Anxiety the motivation to action (Di Chiara, 1999). well-being Zubieta et al. (2002) found that women showed reduced activation of the µ-opioid system in the accumbens nucleus ipsilateral to a pain stimulus when Anteroinferior Hypothalamus temporal lobe compared with men. !eoretically this reduction would allow more e%cient pain transmission and is Brainstem consistent with studies that found that women show Endocrines Association cortex autonomic nuclei higher perceptual responses to pain (Fillingham and Figure 13.10. A speculative overall scheme of the elements of the Maixner, 1995; Coghill et al., 1999). Women are also limbic system suggests that a balance normally exists between the diagnosed more frequently with persistent pain condi- septal nuclei (contentment) and the amygdala (anxiety). Incoming tions (Unruh, 1996). sensations are identi"ed by cortical association areas and are labeled with a degree of familiarity by the anterior inferior temporal lobe, including the hippocampus. The orbital cortex serves as a Amygdala and related structures reservoir of past experience with social situations. The assignment New incoming sensory signals arriving at the sensory of emotion by the septal–amygdala complex is in!uenced by the current autonomic state. The septal–amygdala complex e#ects association cortices are made available simultaneously emotional responses via the hypothalamus and brainstem auto- to the amygdala and the hippocampus. !e hippocam- nomic centers. pus recalls speci#c facets of the sensory experience and links them with details of past events, especially with with a decrease in dopamine release and an increase regard to visual signals. It has been suggested that sen- in acetylcholine release in the nucleus accumbens sory information reaches the amygdala by two routes. (Rossetti et al., 1992). Anxiety coincident with drug One route is direct via the thalamus and supports a withdrawal may be due to an increase in activity in the quick, primitive emotional response. !e second route amygdala subsequent to a decrease in dopamine from is indirect via the cortex and results in a slower, more the ventral tegmental area (Pilotte and Sharpe, 1996). cognitive response (Kandel and Kupfermann, 1995). A decrease in dopamine in the amygdala and hippo- Once the stimulus arrives in the amygdala it is rec- campus is hypothesized to produce anxiety or cravings, ognized and an a$ective dimension is attached to the or both, for substances that provide temporary relief by stimulus. Evidence suggests that the amygdala repre- releasing dopamine (Blum et al., 1996). sents the central fear system and that it is critical in the !e shell of the nucleus accumbens is an import- acquisition and expression of conditioned fear as well as ant target for psychoactive drugs. !e shell appears to anxiety (Davis, 1992). !e appropriate emotional sig- strengthen stimulus-reward associations in response to ni#cance is attached if the current event occurs in the dopamine. Addictive drugs increase dopamine in the context of a previously learned psychoa$ective atmos- extracellular space in the accumbens shell rather than phere related to social events and other forms of a%lia- the core in both rats and humans (Di Chiara, 2002). !e tive behavior. !e amygdala responds by activating bed nucleus of the stria terminalis, part of the extended three sets of connections. First, the amygdala recruits amygdala, is also sensitive to psychoactive drugs. appropriate autonomic and endocrine responses Ca$eine is a nonaddictive drug and does not increase through its connections with the hypothalamus and dopamine in the shell (Acquas et al., 2002; Ikemoto, brainstem. Second, the amygdala sends signals back 2003). Food rewards (e.g., chocolate) also produce to the hippocampus to rea%rm the emotional signi#- dopamine release in the accumbens shell (Bassareo cance of the signals that have simultaneously entered et al., 2002; Di Chiara and Bassareo, 2007). Less activa- the hippocampus. Finally both the hippocampus and tion was seen for both in the core. Release of dopamine the amygdala project signals back to the sensory asso- in the shell is instrumental in learning the association ciation cortices, where, with time, the memory of the 221 Limbic system: Overview

event is probably created. !e next time the same con- died from stu%ng their mouths with inedible objects stellation of sensory signals arrives at the sensory asso- (e.g., Styrofoam cups, surgical gauze, toilet paper, etc.; ciation cortex the learned emotional response will be Mendez and Foti, 1997). Hypersexuality is rare; how- elicited more e%ciently. If, in the future, less than the ever, inappropriate sexual commentary is common entire set of sensory signals is experienced, the amy- (Trimble et al., 1997). gdala-hippocampus axis may be triggered to respond with the same emotions (Kesner, 1992). Temporal lobe epilepsy Connections between the amygdala and the orbital A full-blown temporal lobe seizure is o&en preceded by prefrontal cortex are important in formulating reac- an aura indicating limbic involvement. !e aura may tions to socially signi#cant stimuli and for controlling include olfactory hallucinations, visceral sensations, aggressive behavior (De Bruin, 1990). In some cases a fear, dèjá vu, and motor automatisms. Behavioral dis- minimal set of stimuli may be able to reactivate a vague orders may be seen in the interictal period (Trimble recollection of a past experience without the speci#cs of et al., 1997). !ese disorders include depression, schiz- that experience, producing the sense of déjà vu (Gloor, ophreniform psychosis, and an interictal behavior 1997). Connections with the posterior cingulate gyrus syndrome that consists of a$ective disturbances and have been implicated to be important in the conscious long-term personality changes. Delusions may appear appreciation of anxiety (McGuire et al., 1994); however, several years a&er the onset of seizures. others believe that the prefrontal cortex is of particular A subset of these patients present with the Gastaut– importance in the appreciation of emotions generated Geschwind syndrome, which consists of a constellation in the amygdala (Kandel and Kupfermann, 1995). of behaviors that include hyperreligiosity, hyper- Kluver and Bucy (1939) showed that a bilateral graphia, exaggerated philosophical concerns, sexual lesion of the anterior temporal lobe produced a marked dysfunction, and irritability. !is syndrome has been change in the behavior of the normally aggressive rhe- subdivided into three subgroups of behavior (Bear, sus monkey. Lesioned animals were remarkably tame. 1986). !e #rst is an alteration of physiological drives Fear and aggression were lost. When released in the including sexual behavior, aggression, and fear. !e wild the monkeys showed no aggressive response second is a preoccupation with religious, moral, and when attacked by strangers. !ey were aloof of the philosophical concepts. Finally, the patient is unable to social group and lost all social status. Although in the terminate an idea, o&en during a conversation, and to laboratory they exhibited abnormal sexual behavior move on to another topic. with greatly increased autoerotic homosexual or het- Patients with temporal lobe epilepsy may exhibit erosexual activity, they engaged in no sexual behav- hyperemotionality and increased aggression. !irty ior in the wild. Mothers lost interest in their infants. percent of psychiatric patients with intermittent violent Oral behavior was exaggerated and they examined outbursts have temporal lobe epilepsy (Elliot, 1992). everything orally. !ey became indiscriminate in their Projections from the temporolimbic area to the brain- dietary preferences. !ey ate previously rejected foods stem periaqueductal gray and raphe nuclei (Figures and ate nonfood items including feces. !ey exhibited 10.2 and 11.5) may account for the decreased levels of hypermetamorphosis, which is a tendency to attend to serotonin reported to be associated with violent behav- and to react to every visual stimulus. At the same time ior and suicide (Marazziti and Conti, 1991). they exhibited visual agnosia. !ese behaviors make up Hallucinations and delusions are associated with the Kluver–Bucy syndrome. limbic dysfunction that involves both super#cial and deep structures of the temporal lobe (Elliott et al., Other behavioral considerations 2009). !e delusions are o&en of the paranoid type and are seen in approximately 10% of patients with Kluver–Bucy syndrome temporal lobe epilepsy. Delusions are more o&en seen !e complete Kluver–Bucy syndrome is seldom seen in if the le& temporal lobe is involved, whereas the pres- humans (Yilmaz et al., 2008; Kile et al., 2009). Humans ence of auditory or visual hallucinations correlates with bilateral temporal lobe damage who are described with right temporal lobe epilepsy. Recruitment of the as exhibiting the Kluver–Bucy syndrome are very pla- frontal lobe may be required together with temporal 222 cid and are indiscriminate in dietary preferences. !ey lobe activity to produce a delusion (Trimble et al., tend to examine all objects orally, and several have 1997). References

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225

Chapter Interhemispheric connections 14 and laterality

Introduction right-handedness and improved motor skills. Cerebral blood "ow dominance shi&s from right to le& during A hallmark of human brain function is cerebral lateral- the third year of life (Chiron et al., 1997). ization and specialization. !is specialization neces- Speech has long been recognized to be localized in sitates an e%cient interhemispheric communication the le& (dominant) hemisphere. !e right hemisphere system. No other mammal possesses the degree of has been hypothesized to be specialized in emotional localization of function seen in the human. Only the and visuospatial functions that are important in sur- human brain has the intellectual and computational vival of the species (Geschwind and Galaburda, 1985). capabilities necessary to study how neural systems Norepinephrinergic and serotonergic pathways project both generate and respond to the intense information more heavily to the right hemisphere (Robinson, 1985). demands of the environment. At #rst glance the anatomical brain appears largely symmetrical. More careful analysis reveals “typ- Interhemispheric communication ical counterclockwise hemispheric torque,” which is re"ected in the fact that the le& parieto-occipital region Corpus callosum is wider and extends further posteriorly than the right. !e corpus callosum is larger in the human than in any On the right side the frontal lobe is larger than the other mammal. It is a broad thick plate of #bers that le& and extends further anteriorly (Glicksohn and reciprocally interconnects broad regions of the corre- Myslobodsky, 1993). !is di$erence is called petalia sponding lobes of the cortex of the le& and right side (Hadziselimovic and Cus, 1966). Fiber bundles inter- (Figures 14.1, 14.2, and 14.3). !e #bers of the corpus connect the le& and right sides. It must be assumed that callosum make up the "oor of the longitudinal cerebral these bundles play a role in the behavioral specializa- #ssure, form most of the roof of the lateral ventricle, tions that are re"ected in the laterality of behavior. and fan out in a massive callosal radiation as they dis- Cerebral blood "ow is greater on the right than on tribute to various cortical regions. the le& in infants. Le& parietal dominance emerges !e corpus callosum can be divided into a series of at about 2.5 years concordant with the onset of function-speci#c channels (Zaidel et al., 1990), which are as follows. Cingulate sulcus Splenium of CC Post. parietal Genu of CC Post. parietal, Post- and ulate Sup. temporal precentral Cing gyrus Body of CC Occipital, Premotor, Inf. temporal, Suppl. motor, Sup. parietal Prefrontal

I PB AB A Midbrain Rostrum of CC S Pons Anterior commissure Cerebellum Figure 14.2. Cortical areas whose "bers contribute to each sub- Medulla division are indicated. The corpus callosum can be divided approximately in half by the junction of the anterior midbody (AB) and the Figure 14.1. The corpus callosum (CC) consists of the rostrum, posterior midbody (PB). The anterior third includes the rostrum, 226 genu, body, and splenium. It forms the !oor of the longitudinal genu, and anterior body (A). The splenium (S) accounts for about cerebral "ssure and lies below the cingulate gyrus. the posterior "fth of the corpus callosum. I, isthmus. Interhemispheric communication

Frontal pole Figure 14.3. olfaction. A lesion sparing the splenium o&en Diagram matic horizontal section of results in minimal loss of function (Berlucchi, the brain shows the 2004). corpus callosum interconnecting !e corpus callosum has been divided into seven the cortex on each regions for research purposes by Giedd et al. (1994, side. a&er Witelson, 1989). !e maximum length was taken between the most anterior and posterior points and divided into half, thirds and a posterior #&h. A #nal perpendicular line was drawn through the anterior convexity of the anterior callosum. !e between-hemisphere corticocortical pathways and within-hemisphere corticocortical pathways have a common embryological origin (Trevarthen, 1990). Many of the #bers are unmyelinated, indicating that interhemisphere information transfer is relatively slow. In addition to providing communication between the le& and right hemispheres, many of the neurons that Occipital pole give rise to the callosal #bers also give rise to within- hemisphere collateral #bers. Wherever the callosal #bers terminate in the contralateral hemisphere, the t Rostrum, genu, and anterior body (Figures collateral #bers end in the homologous region of the 14.1 and 14.2): !ese make up the anterior ipsilateral hemisphere. !ese are referred to as sym- third of the corpus callosum. !ese anterior metrical heterotopic connections and are common in channels contain interconnecting #bers from the association regions of the cortex (Liederman, 1995). prefrontal, premotor, supplementary, and possibly !e corpus callosum provides a channel for com- anteroinferior parietal cortex. Anterior callosal munication between the two hemispheres. It serves channels are important for the interhemispheric three categories of tasks. First, callosal relay tasks are transfer of control signals. those tasks that can be performed by only one hemi- t Anterior midbody: !e anterior midbody contains sphere. !e corpus callosum allows stimuli to be #bers that interconnect the precentral and relayed from one hemisphere to the other where the postcentral gyri and possibly the midtemporal task can be performed. Second, it provides for coordin- cortex. !is channel is particularly important ation of direct access tasks, which are tasks that can be because it interconnects the primary motor cortex performed by either hemisphere. !ird, it provides for of the right and le& sides. transfer of signals for tasks that require the interaction t Posterior midbody: !e posterior midbody of both hemispheres (Zaidel, 1995). interconnects the postcentral gyrus, the posterior Some investigators speculate that maturation of the parietal cortex, and possibly the midtemporal corpus callosum is a prerequisite to the #nalization of cortex. !e two midbody channels coordinate hemispheric specialization. In humans, completion motor activity across the midline. of callosal myelination approximately coincides with t Isthmus: !e isthmus interconnects the posterior puberty. !e splenium tends to contain more #bers parietal and superior temporal cortices, including in females than males, although there is signi#cant the auditory cortex. overlap in the number of #bers between sexes. !e t Splenium: !e splenium contains #bers that midsagittal area of the corpus callosum is signi#cantly interconnect the inferior and ventral temporal larger in the female rat than in the male. Early postnatal cortices as well as the visual cortex of the occipital exposure to cocaine abolishes this sexual dimorphism lobe. !e more posterior channels interconnect (Ojima et al., 1996). sensory signals such as visual, auditory, and Disconnection of the hemispheres (“split brain”) in touch. !e anterior corpus callosum is organized an adult produces few disturbances of ordinary daily topographically but the splenium contains behavior, temperament, or intellect. Visual signals 227 #bers that represent all sensory areas including reach both sides of the cortex by way of #bers that cross Interhemispheric connections and laterality

in the optic chiasm and auditory signals that cross in Figure 14.4. The patient’s magnetic the brainstem. Special tests that project sensory sig- resonance image nals to either the le& or right side have been performed (T1-weighted, (Gazzaniga, 2005). Results indicate that identical sig- midsagittal view) revealed marked nals presented to the opposite cortex may sometimes thinning of the produce con"icting emotional responses. corpus callosum as a result of demyelination. (Reprinted Clinical vignette with permission from Mendez, 1995.) A 38-year-old right-handed woman developed a personality change over a two-month period. She became progressively apathetic and disengaged. On examination, she had prominent psychomotor slowing, pallor of the left optic disk, left central facial nerve weakness, gait instability, sensory loss on the left side the le& hand, and le& visual anomia. Obvious symp- of her body, and upper motor neuron signs. Magnetic toms usually appear only a&er large callosal lesions resonance imaging disclosed multiple subcortical and (Peru et al., 2003). Certain lesions involving the cor- periventricular lesions and pronounced atrophy of pus callosum, or association areas of the cortex that the corpus callosum (Figure 14.4). An eventual frontal give rise to commissural #bers, produce disturbances brain biopsy con"rmed the presence of advanced of brain functions collectively known as disconnec- multiple sclerosis. The patient’s neuropsychological tion syndromes. Split-brain patients may be slow to evaluation disclosed an interhemispheric disconnec- respond. Once one hemisphere is activated, it may be tion syndrome from demyelination of her corpus callosum. She could formulate and write sentences with very di%cult for the split-brain patient to activate the her right hand but not with her left. She could draw inactivated hemisphere. In such a situation, Sperry and copy "gures with her left hand but not with her (1962) has questioned whether consciousness may right. The spatial elements of her constructions were have been shi&ed entirely to the active hemisphere. A worse with her right hand than with her left hand. She common sequela of callosectomy is neglect. !ere is a had greater trouble naming items placed out-of-sight signi#cant tendency to neglect le&-sided targets, and in her left hand as compared with her right hand. With it is argued that this is due to underactivation of the her left hand, the patient had di!culty saluting, mim- nondominant hemisphere (Liederman, 1995). Mutism ing the use of a toothbrush, $ipping a coin, pretending following callosal section is an extreme example of to comb her hair, and other praxis tasks. Finally, on a such an imbalance. Mutism is more common if speech tachistoscopic task, the patient could not read any of is centered in one hemisphere and control of the dom- the items presented in her left hemi"eld. inant hand in the opposite hemisphere. !e role of the corpus callosum in conscious awareness and cogni- !e presence of a number of small tracts inter- tively determined behavior continues to be the subject connecting the le& and right temporal lobes allows of much research. abnormal ongoing epileptic activity to be transmitted A role for the corpus callosum in the pathogenesis between the two lobes without necessarily involving of schizophrenia has been suggested (Crow, 1997). the much larger corpus callosum. Since the corpus cal- Nasrallah (1985) proposed a mechanism for schizo- losum is not involved, generalization of the epileptic phrenia signs and symptoms based on a body of evi- activity may not occur. In such cases, the patient may dence pointing to a disturbance of interhemispheric be able to maintain some contact with the environment integration. Velek et al. (1988) reported a case of con- while at the same time experiencing a complex partial genital agenesis of the corpus callosum that presented seizure. !is should not be taken as evidence that the with strong features of #rst-rank Schneiderian symp- seizure is of psychogenic origin (pseudoseizure). toms. !e posterior subregions and the body of the Signs and symptoms of complete callosal damage corpus callosum have been found to be signi#cantly may include le& ideomotor apraxia, right or bilateral smaller in individuals with autism (Piven et al., 1997), construction apraxia, le& agraphia, le& tactile anomia, and lack of normal asymmetry is also reported in le& alien hand sign, impaired bimanual coordination, schizophrenia (Crow, 1990, 1997). 228 alexia in the le& visual #eld, anomia for objects felt with Interhemispheric communication

Longitudinal cerebral fissure A reduction in the total midsagittal corpus callo- Corpus callosum sum area along with a reduction in the overall center- line length has been reported in adults with Tourette syndrome (Peterson et al., 1994). In contrast, another study found that the anterior corpus callosum was signi#cantly larger in children with Tourette syndrome Lateral fissure but signi#cantly smaller in children with attention- de#cit hyperactivity disorder (Baumgardner et al., 1996). !e corpus callosum is thinner and the white Temporal lobe matter is less dense in children with attention-de#cit hyperactivity disorder and bipolar disorder (Caetano Anterior commissure et al., 2008; Hamilton et al., 2008; Luders et al., 2009). Figure 14.5. Diagrammatic coronal view of the brain shows the Seidman et al. (2005) found that the posterior region corpus callosum dorsal to the anterior commissure. The anterior commissure interconnects anterior portions of the temporal cortex was more a$ected, and several other studies found that on each side. that medial and posterior regions were also a$ected in posttraumatic stress disorder and borderline personality disorder (Villarreal et al., 2004; Rusch et al., 2007; Jackowski et al., 2009). Alterations in the size of the Hippocampal commissure corpus callosum may re"ect alterations in the cortical Habenular commissure Corpus callosum areas served by the corpus callosum. Posterior A rather intriguing disorder called alien hand sign commissure Fornix can develop with a lesion that involves the region of Midbrain the anterior corpus callosum (Chapter 6). Reportedly there is a feeling of loss of voluntary control over the Anterior commissure Cerebellum nondominant hand (Brion and Jednyak, 1972). A feel- Hypothalamus ing of estrangement for the nondominant hand (la main étrangère) is reported. Other features include a Optic chiasm tendency for the arm to dri& o$ and assume odd pos- Basilar pons tures, especially when the eyes are closed or when there is intermanual con"ict or competition. Indeed, stud- Figure 14.6. Diagrammatic midline view of the brain shows "ve commissures: the corpus callosum, the anterior commissure, ies of patients in whom the corpus callosum has been the posterior commissure, the hippocampal commissure, and the sectioned have led to the notion that these individuals habenular commissure. The corpus callosum is shown divided into function with two independent minds, the le& under the seven regions described by Giedd et al. (1994). the control of consciousness and the right largely functioning unconsciously and automatically (Bogen, dimorphic in rats, and prenatal stress eliminates the 1993). male–female di$erence (Jones et al., 1997). !e number of axons in the anterior commissure is 17% greater in Anterior commissure mice with a hereditary absence of the corpus callosum. !e anterior commissure is a small compact bundle However, the regions of the brain served by the axons that crosses the midline rostral to the fornix (Figures remain the same (Livy et al., 1997). It is hypothesized 14.1, 14.5, and 14.6). !is commissure consists of two that the larger anterior commissure seen in females divisions that are not distinguishable on gross exam- provides for better intercommunication between the ination: a small anterior division that interconnects two amygdalae and predisposes females to be more olfactory structures on either side, and a large pos- emotionally intelligent and socially sensitive (Joseph, terior division that connects the anterior, middle, and 1993). inferotemporal regions. !e role of the anterior commissure remains unre- Hippocampal commissure solved (Zaidel, 1995). Prenatal stress in rats disrupts !e hippocampal commissure (fornical commis- sexual di$erentiation and sexual behavior. !e anter- sure or psalterium) consists of #bers that originate in ior division of the anterior commissure is sexually the hippocampus and cross the midline beneath the 229 Interhemispheric connections and laterality

splenium of the corpus callosum (Figure 14.6). !is Asymmetries that involve the entire hemisphere are commissure interconnects the hippocampus of both presented in this section. sides and is poorly developed in the human. Left hemisphere Supraoptic commissure Language is the #rst area of behavior for which !e small supraoptic commissure lies dorsal to the optic hemispheric dominance was demonstrated. !e le& chiasm (Figure 14.6). It consists of several bundles of hemisphere is dominant for linguistic functions in #ne #bers that cross the midline. Included among these approximately 98% of individuals. !e le& hemisphere bundles is the hypothalamic commissure, which fans is specialized for the manipulation of numbers in the out into the lateral preoptic-hypothalamic area. A ven- process of calculation. trally located bundle (ventral supraoptic decussation) Roughly 90% of the population is right-handed. is thought to arise from the reticular formation of the In these people the le& hemisphere is specialized for rostral pons and ascends in association with #bers of #ne motor control. Most le&-handed people, how- the medial longitudinal fasciculus. A dorsally located ever, have their speech centers located in the le& bundle (dorsal supraoptic decussation) may intercon- hemisphere. nect parts of the basal ganglia. !e supratemporal plane (planum temporale), a Papez (1937) believed that these decussations region generally included in Wernicke’s area, is lar- linked the thalamus with the hypothalamus and sug- ger on the le& side of the brain in 65% of individuals. gested that they played a role in emotions and in emo- !e right planum is larger in only about 10% of brains tional expression. (Geschwind and Levitsky, 1968). !is asymmetry is speculated to play a role in the le& hemispheric lan- Habenular commissure guage superiority. !e habenular commissure lies immediately beneath !e le& cerebral hemisphere of right-handers is the pineal and is a small commissure whose #bers ori- believed to be specialized for tool use. !e network ginate from the stria medullaris (Figure 14.6). Some responsible for this function favors the inferior parietal of these #bers link the habenula with the superior col- lobule and the middle frontal gyrus. A second network liculus. Other #bers within the habenular commissure that controls hand-to-target interaction lies slightly interconnect the amygdala and the hippocampus of superiorly in the intraparietal and dorsal premotor the two sides. !e function of this commissure is not areas and operates contralateral to the hand being used known. at the time (Johnson and Gra&on, 2003). Posterior commissure !e posterior commissure lies at the junction of the mid- Clinical vignette brain and diencephalon (Figure 14.6). It contains #bers A 76-year-old right-handed man developed environ- that join the pretectal nuclei as well as #bers that inter- mental disorientation after a stroke. He had di!culty connect oculomotor control nuclei located in the periaq- "nding his way in the hospital and in his neighbor- ueductal gray of the midbrain. !ese #bers are important hood. He had special problems with corridors, public in the pupillary re"ex and in lid and vertical eye move- bathrooms, and theaters. At one point, he could not ments (Yun et al., 1995; Kokkoroyannis et al., 1996). get out of a public bathroom because he could not "nd the exit. He was able to read a map, draw an accurate $oor plan of his house, and give verbal directions Hemispheric specialization of familiar routes, yet he quickly got lost when taken !e anatomical projection of #bers to primary regions out on familiar routes. This patient had a relatively of the cortex is generally equally distributed between isolated environmental disorientation, or topograp- the hemispheres. In contrast, control of many complex hagnosia, from a stroke involving the parahippoc- functions is markedly asymmetrical. It is possible that ampal place area located in the right hemisphere. His complex functions can be more e%ciently executed in neurological examination was otherwise remarkable a restricted unilateral site, while relying on transcor- only for a visual "eld de"cit in his upper left quadrant. tical #bers to interconnect with the contralateral hemi- Magnetic resonance imaging con"rmed the presence of an infarction involving the right posterior-inferior sphere. Some asymmetry may be localized to speci#c 230 temporal and occipital lobes (Figure 14.7). lobes of the cerebral cortex and is discussed below. Lobular specializations

ability to understand, name, or discriminate emotional expressions. Patients with right hemisphere stroke can be impaired at recognizing facial displays. Right hemisphere lesions may impair the patient’s ability to determine if two faces, previously unknown to the patient, are the same or di$erent people. Patients with right hemisphere lesions are impaired at determining the emotional content of verbal descriptions (Blonder et al., 1991a). Patients with le& hemisphere lesions tend to be agitated, anxious, and depressed (“catastrophic reaction”), whereas those with right hemisphere lesions tend to be indi$erent to their predicament or may even be mildly euphoric. !e patient’s inability to express emotion may Figure 14.7. The patient’s magnetic resonance image (!uid contribute to the appearance of indi$erence. De#cits attenuated inversion recovery [FLAIR], horizontal view) revealed in the display of emotional expressions are associated a posterior circulation stroke in the right medial occipitotemporal with right frontal lesions similar to lesions that cause region extending to the presumed parahippocampal place area. (Reprinted with permission from Mendez and Cherrier, 2003.) Broca’s aphasia on the le& hemisphere. A de#cit in the expression of emotion is termed expressive aprosodia. Patients with right hemisphere lesions are less emo- Right hemisphere tionally expressive (Blonder et al., 1991b). Complex nonlinguistic perceptual skills, facial rec- Frontal hemisphere activation is asymmetrical in ognition, and spatial distribution of attention are patients with panic disorder. Right frontal activation centered in the right hemisphere. Patients with right appears to represent acute activation of avoidance- hemisphere lesions, especially in the posterior areas, withdrawal and is associated with negative emotions have a much greater impairment in complex visuo- (Wiedemann et al., 1999). spatial tasks than do those with equivalent le&-sided lesions. !e identi#cation of faces is a most complex Lobular specializations perceptual task that is also of great biological importance (Chapter 5, see Fusiform gyrus and fusiform face Occipitoparietal lobe area). Under certain circumstances either hemisphere A lesion of the inferiomedial aspect of the le& occipito- can recognize faces. However, the right hemisphere is temporal lobe below the splenium of the corpus callo- specialized in face recognition (Sergent, 1995; Mandal sum can produce color agnosia. A$ected individuals and Ambady, 2004). Recent works point to the fact that can sort colors according to hue but cannot name the right hemisphere is also specialized for determin- colors. !ese individuals usually also have right hom- ing the distribution of attention within the extraper- onymous hemianopia and alexia. sonal space. !is leads to marked contralateral neglect A lesion of the right occipitotemporal region can a&er right hemispheric injury. Contralateral neglect is produce prosopagnosia, although this disorder is more seldom seen a&er the occurrence of a le& hemisphere frequently seen a&er the occurrence of a bilateral lesion. lesion. !e patient with prosopagnosia is unable to recognize !e right hemisphere is more important than the familiar faces, o&en including his or her own face. le& both in experiencing and in expressing emotions. A large lesion of the parietal lobe can produce sen- It contains records of prototypic facial emotional rep- sory neglect in the contralateral hemi#eld. !e right resentations. !ese records are innate and appear to be lobe plays a greater role in controlling attention and localized to the temporal lobe (Heilman and Bowers, contains a map of both visual #elds, and therefore sen- 1996). Limbic and temporal association areas were sory neglect is more o&en seen a&er the occurrence more activated on the right during sexual arousal in of a right-sided parietal lesion. A lesion in the right men (Stoléru et al., 1999). parietal lobe can produce confusion and disorientation for place. A patient with a large le&-sided par- Lesions in the right temporoparietal area can 231 produce receptive aprosodia, disrupting the patient’s ietal lesion involving the supramarginal gyrus may Interhemispheric connections and laterality

react inappropriately to painful stimuli. Patients who to appreciate the emotional content of speech based demonstrate construction apraxia a&er a parietal lobe on pitch and intonation, although they comprehend lesion may di$er in their ability to draw based on the the semantic meaning. In contrast, a person with side of the lesion. With a right-sided parietal lesion, Wernicke’s aphasia will not understand the meaning the drawing maintains its complexity, but the le& side of the words but will react to the emotion (e.g., anger) of the drawing is missing. With a le&-sided lesion, the expressed by the speaker. drawing is symmetrical, but details are missing and it is Volume of the le& temporal lobe is reduced in drawn slowly. Gerstmann syndrome is seen following a schizophrenia (Turetsky et al., 1994), and the le& lat- le&-sided parietal (angular gyrus) lesion (Chapter 4). eral #ssure is larger (Rubin et al., 1993). Reite et al. (1997) reported that male schizophrenia patients dem- Temporal lobe onstrated a smaller superior temporal gyrus than that Both visual and auditory responses can result from of male control subjects, and female schizophrenia stimulation of the temporal lobe; however, these patients demonstrated less laterality than did female responses are seen more o&en when the right temporal controls. !e le& temporal lobe exhibits higher meta- lobe is stimulated (Gloor, 1990). Cell densities in the bolic activity than the right. Whether there is a le& le& hippocampus were found to be greater than in the hypometabolism or a right hypermetabolism when right hippocampus of men. !e le& planum temporale compared with controls remains an open question is larger in females than in males, but the asymmetry (Gur et al., 1995). seen in the planum temporale in males is not present Surgical removal of portions of the temporal lobe in females. No di$erences were seen between sexes or is sometimes e$ective in the treatment of epilepsy. It between hemispheres for the primary auditory area is essential to determine the hemisphere that is dom- (Heschl’s gyrus) (Kulynych et al., 1994). Asymmetries inant for language and speech before surgery. !e in women are less apparent in both the planum tempo- lateral portion of the temporal lobe, which contains rale and the hippocampus (Zaidel et al., 1994). the receptive speech area, is served by the middle Patients with lesions of the temporal lobe that a$ect cerebral artery (Figure 2.5). !e Wada test can be audition have di%culty distinguishing words if the used in this situation to determine laterality. In this lesion is on the le& and di%culty distinguishing non- test, short-acting barbiturates are injected into the verbal sounds, including music, if the lesion is on the internal carotid artery. Aphasia is induced when the right. Le& temporal lobe lesions that a$ect memory barbiturate perfuses the dominant hemisphere. More involve the loss of language-related information. Right recently, the use of transcranial magnetic stimulation temporal lesions a$ect the memory of musical melod- (TMS) has been proposed as a less invasive proced- ies and of geometrical shapes. ure to determine language and speech dominance Lesions of the le& posterior superior temporal gyrus (George, 2003). including Brodmann’s area (BA) 22 produce receptive aphasia (Wernicke’s). Comprehension of verbal lan- Frontal lobe guage is primarily a$ected. If the lesion extends into !e pars opercularis (Broca’s region) is larger in the the inferior parietal lobe, reading may also be a$ected. le& than in the right frontal lobe (Geschwind and In some le&-handed individuals, the le& hemisphere Galaburda, 1985). Folds surrounding the lateral #s- may be dominant for comprehension whereas the right sure appear earlier on the right than on the le& side hemisphere is dominant for the production of speech. (Simonds and Scheibel, 1989). Patients with epileptogenic foci localized to the !e le& frontal region is proposed to be responsible le& temporal lobe tend to be paranoid and to exhibit for approach behavior, including planning, intention, schizophrenia-like and antisocial behavior. Patients and self-regulation. !e right frontal region is respon- with right-sided temporal foci tend to show emotional sible for withdrawal (Davidson, 1995). Ten-month-old extremes, manic-depressive symptoms, and denial infants who cry frequently show more right frontal (Sherwin et al., 1982; Bear, 1986). Exceptions have activation (Fox and Davidson, 1988). Davidson (1995) been reported in which patients with right-sided foci found that children at 38 months of age who spent more present with thought disturbances (Sherwin, 1982). time proximal to their mother in a novel situation were A lesion of the right posterior temporoparietal area inhibited and showed greater right frontal activation 232 can produce aprosodia in which patients are unable than uninhibited children. References

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236 Index

3D analyses, 46 bipolar disorder/depression, 205–6 auditory areas, 62 abulia, 124 obsessive compulsive disorder, 206 autism, 7 ACC see anterior cingulated cortex posttraumatic stress disorder, 207 autism spectrum disorder (ASD), 107 acetylcholine (ACh), 19 schizophrenia, 205 autoreceptors, 17 addictive behavior, see alcoholism; social interactions, 201–3 autoscopic phenomena, 71–72 cocaine Tourette’s syndrome, 208 axons, 14, 15–16 adenosine, 24–25 anterior cingulate gyrus, 85, 197 adhesion molecules, 17 anterior commissure, 229 Balint syndrome, 50 adrenergic receptors, 22 anterior insular cortex, 68–69 basal ganglia, 7, 8, 122–39 aging, 10–11 anterior intraparietal area, 46 basal nucleus, 129–30 acetylcholine, 19 anterior midbody, 227 basilar artery, 8 neurogenesis, 184 anterior midcingulate cortex (aMCC), basolateral nuclei, 179–82 occipital lobes, 39–40 199 BDNF see brain-derived neurotropic akinetic mutism, 207–8 anterior parietal lobe, 40, see also factor alcoholism, 102 parietal lobes BPD see borderline personality alien hand sign, 229 anterior temporal lobe, see temporal disorder alvear pathways, 177 lobes bipolar disorder, 105 Alzheimer’ disease anterior thalamic nuclei, 156, 203 cingulate cortex, 201–05 amygdala, 184 anterograde amnesia, 178 frontal lobes, 186 cingulate cortex, 200 anterograde axon transport, 15 blindness, see prosopagnosia frontal lobes, 107 antipsychotics, 23–24 blindsight, 38–39 locus ceruleus, 172–73 antisaccades, 90 blood-brain barrier, 9 aMCC see anterior midcingulate antisocial personality disorder, 48 body movements, 44 cortex anxiety, 39 borderline personality disorder (BPD), α-amino-3-hydroxy-5-methyl-4- anterior insular cortex, 68 50 isoxazole proprionate (AMPA), cingulate cortex, 206 bottom-up processes, 41 20, 21 frontal lobes, 96 brain-derived neurotropic factor amnesia, 178 locus ceruleus, 172 (BDNF), 21 AMPA see α-amino-3-hydroxy-5- nucleus accumbens, 221 brainstem, 4, 167–75 methyl-4-isoxazole proprionate apathy, 97 Broca’s area, 90–91 amygdala, 182–84 aphasia, 71 anxiety, 68, 96 apraxia, 49 cadherins, 27 autism, 188 aprosodia, 50 capsulotomy, 204 bipolar disorder, 105 ARAS see ascending reticular activating cardiac control cortex, 68 depression, 186 system caudal raphe nuclei, 169 limbic system, 179, 216, 221–22 archicortical limbic system divisions, caudate nucleus, 123, 134, panic disorder, 188 219 see also neostriatum posttraumatic stress disorder, arcuate nucleus, 145–46 cavum septum pellucidum, 186–87 arousal, 97, 129, 131 217, 220 temporal lobes, 65 ascending reticular activating system CCAS see cerebellar cognitive a#ective amygdaloid nuclear complex, 218–19 (ARAS), 167–68 syndrome amyloid hypothesis, 26 ASD see autism spectrum disorder central nucleus, 181 angular gyrus, 47 association circuits, 127–28 centromedian nucleus, 161, 162 anterior body, 227 association "bers, 41 cerebellar cognitive a#ective syndrome anterior cerebral artery, 9 astrocytes, 26 (CCAS), 7 anterior cingulate cortex (ACC), attention-de"cit hyperactivity disorder, cerebellum, 4–6 237 197–98, 204 173 cerebral blood $ow, 41 Index

cerebral cortex, 9 dopamine (DA), 22–24, 134, face recognition, 231, cerebrum, 7–8 see also cocaine; substantia nigra see also prosopagnosia Charles Bonnet syndrome, 39 habenula, 151 fasciculus telencephalicus medialis chemical synapses, 16, 17–18 nucleus accumbens, 220–21 see medial forebrain bundle chronic pain, 197–201 schizophrenia, 103–4 feeling-of-a-presence, 72 cingulate cortex, 162, 197–214 ventral tegmental area, 130 FEF see frontal eye "eld cingulotomy, 204 dorsal attention networks, 48 FFA see fusiform face area cingulum, 201 dorsal longitudinal fasciculus, 147 $occulonodular lobe, 4–5 cocaine dorsal pallidum, 125 fornix, 216, 219–20 amygdala, 184 dorsal striatopallidum, 123–28 frontal eye "eld (FEF), 89–91 dopamine, 23 dorsal striatum, 123–25 frontal lobes, 7, 84–104 excitotoxicity, 25 dorsal supraoptic decussation, 230 frontotemporal dementia (FTD), 107 glutamate, 20–21 dorsal temporal pole, 66 fusiform face area (FFA), 64–65 cognitive functions, 5–6 dorsal visual stream, 35, 36, 45 fusiform gyrus, 64–65 complex hallucinations, 37–38 dorsolateral prefrontal cortex complex partial seizure status, 71 (DLPFC), 94–95 gamma-aminobutyric acid (GABA), conductance regions, 15 dorsomedial nucleus, 146 17, see also skeletomotor circuits consciousness, 43–44 dorsomedial prefrontal cortex Gastaut-Geschwind syndrome, 222 contralateral neglect, 231 (MdPFC), 98–100 G-coupled metabotropic receptors, 25 corpus callosum, 226–29 dual-hemisphere interaction tasks, 227 GCS see glycine cleavage system cortical routes, 182 dyslexia, 73 geniculate bodies, 161 corticosteroids, 187 genu, 227 corticotropin-releasing hormone EDS see environmental dependency globus pallidus, 125, (CRH), 145 syndrome see also paleostriatum cortisol, 181 EEG see electroencephalogram GLU see glutamate CRH see corticotropin-releasing electrical synapses, 16 glucose metabolism, 92 hormone electroencephalogram (EEG), 9–10 glutamate (GLU), 22 cytokines, 27 electrostatic charge, 15 glutamatergic hypothesis, 185 electrotonic coupling, 16 glycine (GLY), 21–22 DA see dopamine elementary hallucinations, 37, 38 glycine cleavage system (GCS), 21–22 DBS see deep brain stimulation emotion processing goal-directed behaviors, 95 deafness, 60 amygdala, 182–83, 221–22 Golgi apparatus, 14 decision making, 101 cingulate cortex, 198–99 G-proteins, 18 declarative memory, 177–78 hyppocampus, 145 gray matter, 10–11, 85 deep brain stimulation (DBS), 132 interhemispheric connections, 231 GTS see Tourette’s syndrome default brain networks, 97–98 emotional bias, 39 gyri, 7, 8 delusions see hallucinations emotional brain see limbic system dementia see frontotemporal empathy, 101 habenula (HB), 150–51 dementia entorhinal cortex, 177 habenular commissure, 230 dendrites, 14, 15 environmental dependency syndrome hallucinations, 37–38 depression (EDS), 93 handedness, 229, 230 basal ganglia, 134 epilepsy, 222 HB see habenula cingulate cortex, 205–1 epileptogenic foci, 232 heautoscopy, 72 frontal lobes, 91, 92, 104–5, 186 epiphysis, 149–50 hemiakinesia, 233 locus ceruleus, 172–73 episodic memory, 104 hemispheric specialization, 230 neurogenesis, 185 epithalamus, 7, 140, 149–51 Heschl’s gyrus, 61 suprachiasmatic nucleus, 144–45 error detection, 198 hippocampus temporal lobes, 70–71 ETD see eye tracking dysfunction autism, 188 diencephalon, 7, 140–55, 156–66 excitatory projection neurons, 21 bipolar disorder/depression, 186 di#usion, 15 excitotoxicity, 25 interhemispheric connections, direct access tasks, 227 executive function de"cits, 95 229–30 disconnection syndromes see split- executive processing, 94 limbic system, 176–79, 216, 219–20, brain syndromes external medullary lamina, 161 221–22 distortions, 37, 38 extrastriate body, 35 schizophrenia, 185–86 DLPFC see dorsolateral prefrontal extrastriate visual cortex, 34 histamine, 24–25 cortex eye movements see frontal eye "eld 5-HT see serotonin 238 dominant superior parietal lobule, 42 eye tracking dysfunction (ETD), 89 Huntington’ disease, 19, 25, 134 Index

5-hydroxytryptamine see serotonin leukotomy, 204 migraine visual aura, 38 hyperexplexia, 22 LHb see lateral habenular nucleus mirror neurons, 87 hyperkinetic movement disorders, ligand-gated ionotropic receptor, 25 monosynaptic hypothalamic 133 limbic striatum, 129 pathways, 141 hypokinetic movement disorders, limbic system, 8, 176–96, 197–214, motor cortex, 84–91 133–34 215–25 motor neglect, 89 hypothalamus, 7, 140–49 limbic thalamus, 162 motor plans, 40–41 lobular specializations, 231–33 MPFC see medial prefrontal cortex ictal fear, 183 local circuit interneurons, 21 MST see superior temporal lobe ideational apraxia, 49 locus ceruleus (LC), 169–70, 171–73 MT areas, 35, 36, 38–39 illusions, 37, 38 luteinizing hormone, 143 muscarinic receptors, 19 inferior olivary complex, 173 MvPFC see ventromedial prefrontal inferior parietal lobe (IPL), 47 magnocellular pathway, 35 cortex insular cortex, 68–69, 73–74 mammillary bodies, 146 myelin, 25–26, see also external intention evaluations, 99 mania, 105, see also panic medullary lamina interhemispheric connections, mapping processes, 40 226–33 MCC see midcingulate cortex navigation in space, 46 intermittent explosive disorders, MdPFC see dorsomedial prefrontal NE see norepinephrine 149 cortex neocortical structures, 59–83 internal capsule, 8 mediadorsal nucleus, 158–59 neostriatum, 8, 123–25 internal carotid system, 8–9 medial forebrain bundle, 146–47 neurexins, 17 internal medullary lamina, 156 medial geniculate bodies, 161 neuroactive peptide internodes, 26 medial habenular nucleus (MHb), 151 neurotransmitters, 25 intralaminar nuclei, 161–62 medial hypothalamic zones, 143 neuro"laments, 15 intralaminar thalamic nucleus, medial intraparietal area, 45–46 neurogenesis, 184–85 203–4 medial nuclei, 156–59, 181 neuroglia, 25–26 intraparietal sulcus (IPS), 44–45 medial prefrontal cortex (MPFC), neuroleptics, 162 introspection, 98–99 97–98 neuroligins, 17 introversion, 92 medulla, 4 neurons, 14–15 inversion illusion, 72 medullary raphe nuclei, 169 neuropeptides, 19 ion pump, 15 melatonin see pineal gland neurosurgery, 204 ionotropic receptors, 17–18, memory neurotransmitters, 18–25, see also adenosine; gamma- amygdala, 181 see also dopamine aminobutyric acid, N-methyl-D- cingulate cortex, 198, 200 nicotinic receptors, 19 aspartate hippocampus, 177–78, 179, 219 Nissl substance, 14 IPL see inferior parietal lobe interhemispheric connections, N-methyl-D-aspartate (NMDA), IPS see intraparietal sulcus 233 19–20, 21 isthmus, 227 neurogenesis, 185 nociception, 201 thalamus, 162, see also Alzheimer’ non-dominant superior parietal Kluver-Bucy syndrome, 183, 222 disease; episodic memory; lobule, 42 koniocellular layer, 35 working memory norepinephrine (NE), 22, meninges, 10 see also locus ceruleus language, 230 mentalizing, 98 noxious stimuli, 201 lateral cerebellar lobes, 6 metabotropic receptors, nucleus accumbens, 129, 217–16, lateral dorsal thalamic nucleus, 203 18, see also adenosine; 220–21 lateral geniculate bodies, 161 norepinephrine nucleus paragigantocellularis, 171 lateral habenular nucleus (LHb), MHb see medial habenular nucleus nucleus prepositus hypoglossi, 171 150–51 microglia, 26–27 lateral hypothalamic zones, 146–47 microtubules, 15 obesity, 134 lateral intraparietal area, 45 midbrain, 4 obsessive compulsive disorder (OCD) lateral nuclei, 179–82 midbrain raphe nuclei, 169 basal ganglia, 132–33 lateral tegmental nucleus, 171–73 midcingulate cortex (MCC), 199–200, cingulate cortex, 206 lateral thalamic nuclei, 160 205–6 frontal lobes, 105–6 laterality, 226–33 middle cerebral artery, 9 pulvinar, 160 LC see locus ceruleus midline nuclei, 156–59 thalamus, 159 le% hemisphere, 230 midline thalamic nucleus, 203–4 occipital lobes, 7–8, 33–40 lentiform nucleus, 125 midsagittal area, 227 occipitoparietal lobes, 231–32 239 Index

OCD see obsessive-compulsive pineal gland, 149–50 pyramidal cells, 23, 104, 177 disorder pituitary gland, 141, 145 pyramidal neurons, 23 oculomotor circuits, 127–28 planum temporale (PT), 62–64 OFC see orbitofrontal cortex pleasure, 147 raphe nuclei, 169–70 olfactory cues, 215–16 pMCC see posterior midcingulate receptive aphasia, 71 olfactory structures, 216 cortex receptive aprosodia, 67 oligodendroglial cells, 26 polysynaptic hypothalamic pathways, receptive regions, 15 opiates, 172 141–42 receptor mechanisms, 17 µ-opoid system, 221 pons, 4 reduplicative paramnesia, 71 optic ataxia, 49 postcentral gyrus, 41 relay tasks, 227 orbitofrontal cortex (OFC), 93, 96–97 postcentral sulcus, 41 reticular formation, 167–68 bipolar disorder, 105 posterior cerebral artery, 9 reticular nucleus, 161 networks, 101–2 posterior cingulate cortex (PCC), retina, see also eye movements; visual obsessive-compulsive disorder, 198–200, 201, 204 processing 105–6 posterior cingulate gyrus, 197 retrograde axon transport, 15–16 out-of-body experiences, 72 posterior commissure, 230 retrosplenial cingulate cortex, 197 output regions, 15 posterior insular cortex, 69 retrosplenial cortex (RSC), 201 oxytocin, 144 posterior intraparietal area, 46 right hemisphere, 231 posterior midbody, 227 room-tilt illusion, 72 pACC see pregenual anterior cingulate posterior midcingulate cortex (pMCC), rostral pontine raphe nuclei, 169 cortex 199 rostrum, 227 PAG see periaqueductal gray posterior parietal lobe, 40 rough endoplasmic reticulum, 14 pain postsynaptic elements, 16 RSC see retrosplenial cortex anterior insular cortex, 68–69 posttraumatic stress disorder (PTSD) cingulate cortex, 200, 201 cingulate cortex, 207 sACC see subgenual anterior cingulate nucleus accumbens, 221 frontal lobes, 106 cortex pulvinar, 161 temporal lobes, 186–87 saccade eye movements, 89–90 thalamus, 159–60, 162–63 PPTg see pedunculopontine tegmental schizophrenia, 7 paleocortical limbic system divisions, nucleus acetylcholine, 19 219 precuneus, 42–45 basal ganglia, 134 paleostriatum, 125 prefrontal cortex (PFC), 85, 91–102 cingulate cortex, 205 panic, 73 pregenual anterior cingulate cortex dopamine, 23–24 parabrachial nucleus, 168–69 (pACC), 198–99 frontal lobes, 90, 102–4 parafascicular nuclei, 161, 162 pregenual anterior cingulate glutamate, 20 parahippocampal gyrus, 216 gyrus, 197 hypothalamus, 145 parallel circuits, 127–28 premotor cortex, 86–87 interhemispheric connections, parallel visual pathways, 35–37 preoptic hypothalamic areas, 140–41, 228, 232 paramnesia, 71 142–43 neurogenesis, 185 parietal lobes, 7–8, 33, 40–50, pre-SMA see supplementary nucleus accumbens, 129 see also occipitoparietal lobes motor area occipital lobes, 37 parietal operculum, 41 prestriate cortex, 34 parietal lobes, 47–48 parietal reach and grasp region, 46 presynaptic elements, 16 pulvinar, 161 parietal reach region, 45–46 primary auditory area, 61 temporal lobes, 69–70, 185–86 parietal saccade region, 45 primary motor cortex, 85–87 thalamus, 159, 162 Parkinson disease, 23, 125 primary somatosensory cortex (SI), 41 ventral tegmental area, 130 pars compacta, 125, 126 primary visual cortex, 34–33 second messenger systems, 18 pars reticulata, 125, 126 procaine, 223 secondary somatosensory cortex (SII), parvocellular pathway, 35 prosoccades, 90 41 PCC see posterior cingulate cortex prosopagnosia, 73, 231 secondary visual cortex, 34–35 pedunculopontine tegmental nucleus PT see planum temporale seizures (PPTg), 168 PTSD see posttraumatic stress cingulate cortex, 208 perforant pathways, 177 disorder frontal lobes, 107 periaqueductal gray (PAG), 170–71 pulvinar, 160–61 temporal lobes, 71, see also epilepsy periventricular hypothalamic zones, pursuit, 89 selective reuptake inhibitors (SSRIs), 143 pusher syndrome, 160 24 PFC see prefrontal cortex putamen. 123, see also lentiform self-awareness, 44 240 phasic modes, 172 nucleus, neostriatum mentalizing, 98 Index

temporal lobes, 67 substantia nigra, 130 tranquilizing organs see pineal gland sensory overload, 162 subthalamic nucleus, 8 trichotillomania, 134 septal nuclei, 216–17, 220–21 subthalamus, 125 trigger regions, 15 septum pellucidum, 217 sulci, 7 tuberal regions, 145–46 serine hydroxymethyltransferase superior parietal lobule (SPL), 42 (SHMT), 21 superior temporal gyrus (STG), uncontrolled crying, 170 serotonin, 24, 106–7, 149 63–64 uncus, 181–83 habenula, 151 superior temporal lobe (MST), limbic circuits, 131–32 36–37 vagus nerve stimulation, 70 raphe nuclei, 169–70 superior temporal regions, 69 vasculature, 8–10 sexual behavior, 143, 146 superior temporal sulcus (STS), vasopressin, 144, 149 sexual dimorphism, 10–11 63–64 ventral lateral nucleus, 159 SHMT see serine supplementary motor area (SMA), ventral amygdalofugal pathway, hydroxymethyltransferase 87–91 180–81 short-term working memory, 94 supplementary motor complex (SMC), ventral anterior nucleus, 159 SI see primary somatosensory cortex 87–91 ventral anterior thalamic nucleus, 203 SII see secondary somatosensory suprachiasmatic nucleus, 144–45 ventral attention networks, 48 cortex supramarginal gyrus, 46–47 ventral intermediate nucleus, 160 skeletomotor circuits, 127–28 supraoptic commissure, 230 ventral intraparietal area, 46 sleep, 178 supraoptic regions, 143–45 ventral pallidum, 129 SMA see supplementary motor area sympathetic arousal, 69 ventral posterior nucleus, 159 small-molecule neurotransmitters, sympathy, 187 ventral striatopallidal system, 19–16 synapses, 14, 16–18 131–32 SMC see supplementary motor synaptic pruning, 103 ventral striatopallidum, 129–31 complex ventral striatum, 129 social brain, 66–67 temporal association areas, 64 ventral supraoptic decussation, 230 anterior insular cortex, 70 temporal lobes, 7–8, 59–83, 176–96 ventral tegmental area, 130 cingulate cortex, 201–4 epilepsy, 222 ventral temporal pole, 66 prefrontal cortex, 97–98 interhemispheric connections, ventral thalamic nuclei, 159–60 solitary nucleus, 181 232 ventral visual streams, 45 soma, 14 limbic system, 222 ventrolateral prefrontal cortex Somatic Marker Hypothesis, 101 temporal pole, 66 (VLPFC), 95–96 sound see also auditory processing temporoparietal junction (TPJ), ventromedial nucleus, 146 speech see also auditory processing; 66–67 ventromedial prefrontal cortex language tertiary visual cortex, 34–35 (MvPFC), 100–1 SPL see superior parietal lobule thalamus, 7, 156–66 ventromedial thalamic nucleus, 203 splenium, 227 cingulate cortex connections, vermis, 4–6 split-brain syndromes, 227–28 203–4 vertebral arteries, 8 startle disease, 22 dorsomedial prefrontal cortex, vesicles, 17 STG see superior temporal gyrus 99–100 vestibular sensations, 72 stress see also posttraumatic stress locus ceruleus, 171 visual agnosia, 38 disorder theory-of-mind (ToM), 66 visual processing, 64 stria terminalis, 180–81 theta rhythm, 220 VLPFC see ventrolateral prefrontal striate body, 35–36 thinking brain see neocortex cortex striate visual cortex, 33–34 third person-view sympathising, 99 VN areas, 34–35, 36, 38–39 STS see superior temporal sulcus ToM see theory-of-mind subcaudate tractotomy, 204 tonic modes, 172 Wernicke’s area, 90 subcortical extrastriate pathway, 182 top-down processing, 41 white matter, 10–11, 85 subcortical regions, 233 Tourette’s syndrome, 133 Williams syndrome, 50 subgenual anterior cingulate cortex cingulate cortex, 208 Wilson disease, 134 (sACC), 198–99 interhemispheric connections, 229 Wisconsin Card Sorting Test, 95 substance P, 145–46 TPJ see tempoparietal junction working memory, 23, 103–4

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