Introduction and General Organization of the Nervous System Course

Home , Epineurium, Intermediate nerve, Interthalamic adhesion, Nuclear bag fiber, Nuclear chain fiber, Rubrospinal tract

7/20/2012

CourseIntroduction Review and (Preview), General Grading, Faculty,Organization Resources of the‐‐‐‐‐‐ Nervous System

August 6, 2012

Grading: 6 Quizzes 20 Total 20 20 120 20 20 340 20 1 Midterm 100 220 1 Final 120

Grade % points

Honors 90 306

High Pass 80 272

Pass 70 238

There will be no rounding up! 305.9999999999999999999999999999999 = a High Pass

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Faculty:

Mike Dauzvardis, Ph.D Gregory Gruener, MD, MBA John Lee, MD, Ph.D Evan Stubbs, Ph.D Lydia DonCarlos, Ph.D Jorge Asconape, MD Michael Merchut, MD

And a host of neurologists, neurosurgeons, and neuropathologists assisting in the 3 small group sessions.

Resources:

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Use Dr. Merchut’s handouts!!!!

Since our “new book” has little clinical content, Dr. Merchut has put together his own extensive handouts relying on the old book and Netter images. Please sleep with these! Also come to the Clinical Correlation sessions given by Dr. Merchut —they are not taped.

Also—use the resources on the Neuroscience Website:

Labeled sections in the old lab section Self‐Quizzable sections labeled by Mike Leukam and Dauzvardis The big long practical (which I will be constantly updating)

Fresh brains and models will be provided in the basement

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Have fun and learn

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Introduction and General Organization of the Nervous System

Neuroscience Chapters 1,3‐‐EOTHB

Michael Dauzvardis, Ph.D.

Chapter 1: Introduction to the Nervous System

THE BRAIN HAS SEVERAL CENTRAL AND PERIPHERAL PARTS

CNS = Brain + Spinal Cord

Figure 1‐1 Major components of the brain (the spinal cord has been cut off at its junction with the brainstem). A, The left side of a brain; anterior is to the left. B, The right half of a hemisected brain; anterior is to the left. C, A coronal section of a cerebrum, in the plane indicated in B. A, Amygdala; H, hypothalamus; L, lenticular nucleus; M, midbrain; Me, medulla; P, pons; T, thalamus.

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THE BRAIN HAS SEVERAL MAJOR DIVISIONS AND SUBDIVISIONS

The Principal Cellular Elements of the Nervous System are Neurons and Glial Cells

Node

Internode

Myelin

Dendrites

Axons

Figure 1‐2 Principal components of a typical neuron.

NEARLY ALL NEURONS FALL INTO ONE OF SIX CATEGORIES:

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NEURONS COME IN A VARIETY OF SIZES AND SHAPES, BUT ALL ARE VARIATIONS ON THE SAME THEME GLIA

Satellite cells NEURONS Microglia Unipolar Schwann cells Pseudounipolar Oligodendrocytes bipolar Fibrous astrocytes

Protoplasmic astrocytes

Choroid or ependyma

Figure 1‐27 Summary diagram of cell types in the nervous system, showing the distribution of glial cell types in the CNS and PNS. A layer of end‐feet of protoplasmic astrocytes (PA) forms a leaky membrane that covers the surface of the CNS, separating it from the PNS. Other end‐feet of protoplasmic astrocytes are distributed in the gray matter, abutting either neurons or capillaries (Cap). Fibrous astrocytes (FA) are interspersed among nerve fibers in the white matter, many of which are myelinated by oligodendrocytes (Ol). Small microglial cells (M) act as scavengers in response to injury, and ependymal cells (E) line the ventricular cavities (V) of the CNS. Schwann cells and their variants are the principal glial cells of the PNS, forming the myelin of peripheral nerve fibers (S1), enveloping unmyelinated axons (S2), and forming satellite cells (S3) surrounding sensory neurons in peripheral ganglia such as dorsal root ganglia (DRG) and autonomic ganglia (AG). The direction of information flow in various neurons is indicated by arrows. Processes of sensory neurons convey information to the CNS (A), in this case from skin. Information leaves the CNS to reach skeletal muscle directly (B) or to reach smooth muscle and glands (C) after a synapse in an autonomic ganglion. (Based on a drawing in Krstić RV: General biology of the mammal, Berlin, 1985, Springer‐Verlag.)

Moron the Major Six Categories of Neurons:

1. Sensory

2. Motor

3. Preganglionic autonomic

4. Postganglionic autonomic

5. Local Interneurons

6. Projection

Figure 1‐3 Categories of neurons in the nervous system, as seen in the spinal cord. Some neurons do not fit comfortably into one of these categories (e.g., rods and cones of the retina), but most do. 1, Sensory neurons, in this case a dorsal root ganglion cell (DRG); 2, motor neurons; 3, preganglionic autonomic neurons; 4, postganglionic autonomic neurons, with cell bodies in autonomic ganglia (AG); 5, local interneurons; 6, projection neurons.

NEURONAL ORGANELLES ARE DISTRIBUTED IN A PATTERN THAT SUPPORTS NEURONAL FUNCTION

Key Concepts

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MAJOR ORGANELLES OF A TYPICAL NEURON

Figure 1‐4 Major organelles of a typical neuron.

SCHWANN CELLS ARE THE PRINCIPAL PNS GLIAL CELLS

CNS GLIAL CELLS INCLUDE OLIGODENDROCYTES, ASTROCYTES, EPENDYMAL CELLS, AND MICROGLIA

SCHWANN CELLS FLATTEN OUT AND BECOME SATELLITE CELLS AS THEY SURROUND A DORSAL ROOT GANGLION

Figure 1‐22 Schwann cells flattened out as satellite cells (Sa) surrounding a single dorsal root ganglion cell from a rat. The actual size of the cell is about 20 × 30 μm. The inset at the lower left is a light micrograph of part of a dorsal root ganglion in which the nuclei (arrows) can be seen in flattened satellite cells surrounding individual, much larger dorsal root ganglion cells (arrowhead). (Electron micrograph, from Pannese E: Neurocytology: fine structure of neurons, nerve processes, and neuroglial cells, New York, 1994, Thieme Medical Publishers. Inset, courtesy Dr. Nathaniel T. McMullen, University of Arizona College of Medicine.)

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NINE UNMYELINATED AXONS IN THE DORSAL ROOT ALL SURROUNDED BY A SINGLE SCHWANN CELL

Figure 1‐26 Unmyelinated nerve fibers in a dorsal root of a rat. Nine axons, each with the usual complement of microtubules, neurofilaments, and mitochondria, are embedded in a single Schwann cell (S). Even though no myelin is present, seven of the axons are almost completely ensheathed, communicating with the adjacent extracellular spaces only through small clefts (arrows) in the Schwann cell wrapping. The other two axons (*) are partially exposed at the surface of the Schwann cell. (From Pannese E: Neurocytology: fine structure of neurons, nerve processes, and neuroglial cells, New York, 1994, Thieme Medical Publishers.)

MYELINATION IN THE PNS; THE SCHWANN CELL

Figure 1‐24 Schematic diagram of the formation of myelin in the PNS. A, A single Schwann cell forms an internode, unrolled from the axon it would normally be wrapped around. The cell is flattened into a two‐membrane‐thick sheet, with cytoplasm (c) remaining only as a thin rim around the periphery and as a few thin fingers extending between the membranes. B, Longitudinal section through the internode resulting from the Schwann cell in A spiraling around the axon. Most of the internode consists of tightly wrapped Schwann cell membranes. Some cytoplasm remains on the surface of the internode near the nucleus, as small pockets near the node, and as Schmidt‐Lanterman incisures. (Redrawn from Krstić RV: Illustrated encyclopedia of human histology, Berlin, 1984, Springer‐Verlag.)

NODES AND INTERNODES

Figure 1‐23 Myelin sheaths and nodes of Ranvier in peripheral nerve fibers. A fixed peripheral nerve was teased apart into individual nerve fibers and stained with osmium (a lipophilic stain for membranes). The axon is the central pale area in each fiber, and the myelin sheath stands out on both sides of each axon as a more densely stained area; a few nodes of Ranvier (arrowheads) are visible. The occasional diagonal clefts (arrows) that appear to cross the myelin sheaths are known as Schmidt‐Lanterman incisures; they correspond to thin extensions of Schwann cell cytoplasm that spiral around with the myelinating membranes (see Fig. 1‐24). (Courtesy Dr. Nathaniel T. McMullen, University of Arizona College of Medicine.)

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MYELINATION IN THE CNS: THE OLIGODENDROCYTE

Figure 1‐30 Schematic diagram of the formation of myelin in the CNS. A series of processes (p) emanate from an oligodendrocyte, each one giving rise to a flattened expansion that wraps around an axon to form an internode. As in the case of myelin in the PNS (see Fig. 1‐24), most of the internode consists of tightly wrapped membranes, but small rims and fingers of oligodendrocyte cytoplasm (c) are also carried along. (Redrawn from Krstić RV: Illustrated encyclopedia of human histology, Berlin, 1984, Springer‐Verlag.)

ONE BIG OLIGO

Figure 1‐31 A single oligodendrocyte (OL) in the spinal cord white matter of a young rat, myelinating two different axons (A1, A2). This cell and its processes stand out because in young rats, like many other young mammals, myelin has not yet developed around many axons. Note that the oligodendrocyte is connected to its myelin sheaths by thin processes; this tenuous connection has been cited as a possible reason for the paucity of remyelination after injury to myelin sheaths in the brain and spinal cord. Scale mark equals 2 μm. (From Waxman SG, Sims TJ: Brain Res 292:179, 1984.)

ANSWER ME THIS!

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ANSWERS

1‐b 2‐a 3‐c 4‐b 5‐a 6‐e 7‐f 8‐c 9‐b 10‐f 11‐e 12‐c 13‐g 14‐b

Chapter 3

Gross anatomy and General Organization of the Central nervous System

The Long Axis of the CNS Bends at The Cephalic Flexure

Figure 3‐1 Directions in the CNS.

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Hemisecting a Brain Reveals Parts of the Diencephalon, Brainstem, and Ventricular System

Figure 3‐2 Major CNS subdivisions. Arrow, Primary fissure of the cerebellum; *, anterior commissure; B, G, S, body, genu, and splenium of the corpus callosum.

Coronal Section Through Frontal Lobes Just Posterior to the Genu of the Corpus Collosum

Figure 3‐19 Section through the frontal lobes, slightly posterior to the genu of the corpus callosum. Inferior to the body of the corpus callosum is the septum pellucidum, a thin, paired membrane that intervenes between the corpus callosum and the fornix and separates portions of the two lateral ventricles. At this level, which is anterior to the diencephalon, the basal ganglia are represented by the putamen and the head of the caudate nucleus, with part of the internal capsule between them. Inferiorly, note the continuity between these nuclei. I, inferior frontal gyrus; M, middle frontal gyrus; S, superior frontal gyrus.

Coronal Section Through Anterior Commissure

Figure 3‐20 Section through the anterior commissure, which interconnects portions of the temporal lobes as well as certain olfactory structures. At this level, both parts of the lenticular nucleus (putamen and globus pallidus) are present. The section is at the anterior end of both the interventricular foramen and the thalamus and cuts through the fornix tangentially as it curves down toward the hypothalamus.

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Coronal Section Through the Anterior Part of the Diencephalon (Thalamus, Epithalamus, Subthalamus and Hypothalamus)

Figure 3‐21 Section through the anterior part of the diencephalon. Parts of both the thalamus and the hypothalamus can be seen. At this level and at more posterior levels, the internal capsule is found between the lenticular nucleus and the thalamus. The third ventricle can be seen in the midline, above and below the interthalamic adhesion. The section passes through the anterior part of the uncus, revealing the amygdala.

Parts of the Diencephalon and Nearby Structures Seen in a Sagittal or Hemisected Brain

Figure 3‐3 Parts of the diencephalon and nearby structures, seen in a hemisected brain. The dashed line indicates the shallow sulcus (hypothalamic sulcus) in the wall of the third ventricle that separates the thalamus and hypothalamus. 4, Fourth ventricle; A, anterior commissure; Aq, cerebral aqueduct; IA, interthalamic adhesion (a gray matter connection between the two thalami, present in most but not all brains); IF, interventricular foramen; N, nodulus (part of the cerebellar vermis); O, optic chiasm; ON, optic nerve; Pi, pineal gland.

Cerebellum: Flocculonodular lobe, Tonsils, Nodulus, Flocculus, Primary Fissure, Anterior lobe, and Posterior lobe

Flocculus

Tonsil

Figure 3‐16 Inferior surface of a brain, showing the locations of the cranial nerves (CN). (Dissection by Dr. Norman Koelling, University of Arizona College of Medicine.)

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Flocculus and Tonsil

Figure 3‐17 Close‐ups of the anterior (A) and lateral (B) surfaces of the same brain shown in Figure 3‐16. Cranial nerves III to XII are indicated by roman numerals. BP, basal pons; CP, cerebral peduncle; DL, dentate ligament (suspensory ligament of the spinal cord); Fl, flocculus; Inf, infundibular stalk (former attachment of the pituitary gland); MB, mammillary body; MCP, middle cerebellar peduncle; OC, optic chiasm; Ol, olive; ON, optic nerve (cranial nerve II); OT, optic tract; Pyr, pyramid; U, uncus; VIIi, intermediate nerve (part of the facial nerve); VR, cervical ventral root. (Dissection by Dr. Norman Koelling, University of Arizona College of Medicine.)

Named Sulci and Gyri Cover the Cerebral Surface

Figure 3‐6 Superior and left lateral views of the brains of eight different individuals, with the age and gender of each subject indicated. These images were reconstructed from magnetic resonance imaging scans and show the range of sizes and shapes of the normal brain. The left central sulcus (green lines) is in about the same place in each brain and has roughly the same configuration, but the details differ from one brain to another. Other features (e.g., folding pattern of the superior frontal gyrus, configuration of the superior temporal sulcus) vary more substantially. (Method from Tosun D et al: NeuroImage 23:108, 2004. Images, courtesy Dr. Jerry Prince; magnetic resonance data from Baltimore Longitudinal Study of Aging; participants provided by the Intramural Research Program of the National Institute on Aging.)

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The Insula is Hidden Deep in the Lateral or Sylvian Fissure by Parts of the Frontal, Parietal, and Temporal lobes

Figure 3‐8 Location of the insula, demonstrated by prying open the lateral sulcus (A) and then cutting away the frontal, parietal, and temporal opercula (B). The surface of the insula is convoluted, like other cortical areas, typically into about three short gyri and two long gyri.

Cortical Lobes and Their Function

Figure 3‐4 Lobes of each cerebral hemisphere.

Major Cortical Gyri and Location of Primary Cortical Areas

Figure 3‐5 Major cerebral gyri and functional areas. IPL, Inferior parietal lobule; Or, orbital gyri; OTG, occipitotemporal gyrus; PHG, parahippocampal gyrus; SPL, superior parietal lobule.

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Most Cranial Nerves are Attached to the Brainstem

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Sections of the Cerebrum Reveal the Basal Ganglia and Limbic structures

Parts of the Nervous system are Interconnected in Systemic Ways;

Repeating: Axons of primary Afferents and Lower Motor Neurons Convey Information to and From the CNS

Figure 3‐7 Primary afferents and lower motor neurons (LMN).

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Somatosensory Inputs Participate in Reflexes, Pathways to the Cerebellum, and Pathways to the Cerebral Cortex

Somatosensory pathways to the Cerebral Cortex Cross the midline and Pass Through the thalamus

Figure 3‐29 Implications of different sensory pathways crossing the midline at different levels of the CNS. In the somatosensory system, the second‐order neurons for the principal pain‐ temperature pathway (spinothalamic tract; blue) are located in the spinal cord and cross there. In contrast, the second‐order neurons for the principal touch‐position pathway (posterior column‐medial lemniscus pathway; green) are located in the medulla. Hence damage to one side of the spinal cord (A) would cause diminution of touch on the side ipsilateral to the lesion and diminution of pain on the side contralateral to the lesion. Damage rostral to the medulla (B) would cause diminution of both touch and pain on the side contralateral to the lesion.

Somatosensory Cortex contains a Distorted map of the Body

Figure 3‐30 Somatotopic mapping in human somatosensory (A) and motor (B) cortex obtained by electrical stimulation of the surface of the brains of conscious patients during neurosurgery. The size of a given part of the homunculus is roughly proportional to the size of the cortical area devoted to that body part. (From Penfield W, Rasmussen T: The cerebral cortex of man. © 1950 Macmillan; renewed 1978 by T. Rasmussen.)

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Each Side of the Cerebellum Receives Information about the Ipsilateral Side of the Body

Other Sensory systems are Similar to the Somatosensory System:

Reflex arcs, use of the cerebellum, distorted maps, etc—big difference;‐‐laterality: Taste, olfaction are uncrossed, Auditory system is bilateral. Olfaction bypasses the Thalamus.

Higher Levels of the CNS Influence the Activity of Lower Motor Neurons.

Corticospinal axons cross the midline

Figure 3‐9 Crossing of corticospinal axons. LMN, Lower motor neuron.

Higher Levels of the CNS Influence the Activity of Lower Motor Neurons.

The basal ganglia indirectly affect contralateral motor neurons (basal ganglia connect ipsilaterally to the cerebrum but the cerebrum projects contralaterally to the spinal motor neurons)

Think about it

Figure 3‐10 General pattern of connections of the basal ganglia. LMN, Lower motor neuron.

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Higher Levels of the CNS Influence the Activity of Lower Motor Neurons.

Connections between the cerebellum and cerebrum are crossed ; connections between the cerebrum and spinal motor neurons are crossed—THUS—unilateral cerebellar damage causes ipsilateral deficits!

Think about it

Figure 3‐11 General pattern of connections of the cerebellum with the cerebrum. LMN, Lower motor neuron; P, neuron in the basal pons.

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ANSWERS

ANSWERS CHAPTER 3 CONTINUED:

17 Neuroscience L.L. Doncarlos, Ph.D.

EARLY DEVELOPMENT OF THE NERVOUS SYSTEM

KEY CONCEPTS AND LEARNING OBJECTIVES

1. Describe the origin of the nervous system from the trilaminar embryonic stage.

2. Explain the general concepts of nervous system organization: polarity, bilateral asymmetry, and regionalization and the concept that positional cues are critical to neural development.

3. Explain the process of neurulation.

4. Identify the 3 primary brain vesicles and the secondary vesicles and specific landmarks in relation to their adult position and counterparts.

5. Describe the basic cause (not mechanisms) of the most common neural tube defects.

6. Explain the development of the ventricular system and relationship to the brain vesicles.

7. Explain the orientation of sensory and motor components of the spinal cord and how that orientation changes in the brainstem.

8. Distinguish the neural tube from neural crest.

9. List the neural crest derivatives and the potential range of birth defects that could arise from abnormal migration of neural crest cells. Development of the Nervous System Dr. Lydia DonCarlos [email protected] 6‐4975 Bldg 102, Room 5663

* Commit to memory

Key concepts in early development:

The CNS develops from a flat plate of cells that rolls up into a hollow tube.

The tube bulges, flexes and then grows.

Some parts of the tube grow more than others.

Regionalization arises very early in gestation and dictates identity and adult function.

Regionalization and specificity arise due to differential exposure to gradients of signaling molecules (space/time).

1 Neurulation

Longer movie at: http://www.youtube.com/watch?NR=1&feature=endscreen &v=iHmBIJs77ZQ

Week 3- Primitive streak appears, mesoderm forms, induces formation of neuroectoderm. Key to numbers: 1+2+3 primitive streak 4,5 not important here 7 Mesoderm 8 Endoderm 9 Posterior neuropore

Primitive streak “opens” caudally in the epiblast, moves cranially. Cells proliferate in the medial epiblast and migrate between the two layers of the bilaminar disk. Axial (medial) mesoderm forms notochord which induces formation of neuroectoderm.

Ectoderm= dorsal layer (forms nervous system, epidermis, etc.) Mesoderm= middle layer (forms muscles, skeleton– required for formation of nervous system) Endoderm= inner layer (gut)

Now have trilaminar embryo. adapted from http://www.embryology.ch/anglais/hdisqueembry/triderm01.html

2 Regionalization arises very early in gestation and dictates identity and adult function.

Neuroectoderm forms neural plate.

At this early stage, it demonstrates:

Polarity

Bilateral symmetry

Regionalization *

Neurulation= process of formation of neural tube (which becomes the Central Nervous System)

forebrain midbrain

hindbrain

adapted from Langman’s Medical Embryology

Scanning electron micrographs

Notochord induces formation of neural plate. Neuroepithelial cells contact ventricular surface and pial (outer) surface * adapted from Nicholl’s et al., 2001

3 Ectoderm= dorsal layer (forms nervous system, epidermis, etc.) Mesoderm= middle layer (forms muscles, skeleton– induction factors from mesoderm are required for formation of nervous system) Endoderm= inner layer (gut)

Congenital neurological disorders related to neurulation

o CNS malformations account for 40% of deaths during 1st year of life

o Neural tube defects– most common birth defect

o Any failure of brain, spinal cord, meninges, skull or vertebral column to develop completely

o Hydrocephalus–poor drainage of CSF

Neural tube defects

Most common birth defect

Often lead to spontaneous termination of pregnancy

Varying levels of severity– benign to fatal

Occur early in pregnancy

Due to lack of closure of neural tube or lack of development of meninges, skull or vertebral column Spina bifida occulta: Very common Incidence decreased by adding Least severe folic acid to cereal, white flour Often asymptomatic (folic acid essential to cell proliferation) Sensorimotor impairment from none to severe Neural tube may be closed, but vertebral arch is not fused

adapted from Neuroscience: An Outline Approach, 2002, Castro, Neafsey, Wurster & Merchut, 2002 *

4 Spina bifida cystica

adapted from Langman’s Medical Embryology, 5th edition, 1985, TW Sadler

Spina bifida SB cystica with occulta meningocele

SBc with SBc with meningomyelocele myeloschisis

adapted from Neuroscience: An Outline Approach, 2002, Castro, Neafsey, Wurster, & Merchut, 2002

. Spinal cord abnormalities . spinal bifida – failure of vertebral arches to form or neural tube to close usually at posterior end . clinically= both neural and vertebral defects . most common regions= lower thoracic, lumbar, sacral

. Spinal bifida occulta- nonfusion of vertebral halves . most common and least severe

. Spinal bifida cystica= protrusion of meninges and/or spinal cord

5 Congenital malformations of the nervous system: examples of failure to develop at anterior pole

anencephaly- absence of the microcephaly- normal face size; tiny cranial vault; cranium; may be fatal, often causes generally fatal; abnormal intellectual development & Hydrocephaly= developmental delays, but not adapted from CDC, accumulation of CSF National Center on Birth always Defects and due to obstruction of Developmental Disabilities flow; various causes, including neural tube defects; implanted shunts may drain excess *

Next major events: •Brain vesicles differentiate and begin to bend lengthwise •(vesicles- membranous sacs filled with liquid)

•Ventricular System takes shape

•Neural crest cells migrate

Primary Brain Vesicles form: Prosencephalon= Forebrain Mesencephalon= Midbrain Rhombencephalon= Hindbrain

Lamina terminalis– rostral pole of central nervous system

Conus medullaris– caudal pole of spinal cord

adapted from P. Mason, Medical Neurobiology, 2011 *

6 Secondary Vesicle formation: Prosencephalon telencephalon and diencephalon

telencephalon *

diencephalon

coronal view—dorsal (superior) is up

cerebral cortex

horizontal view * basal ganglia amygdala *= lamina terminalis

coronal hemisection * adapted from P. Mason, Medical Neurobiology, 2011

Mesencephalon midbrain

Rhombencephalon metencephalon and myelencephalon rostral metencephalon = pons (not shown) caudal metencephalon = cerebellum and associated cell groups that migrate ventrally

myelencephalon = medulla

* adapted from P. Mason, Medical Neurobiology, 2011

7 posterior/dorsal

anterior/ventral

AP= alar plate= sensory BP = basal plate= motor

Regionalization and specificity arise due to differential exposure to gradients of signaling molecules (space/time).

basal plate

The amount of signal a cell receives determines its fate. N- notochord; FP- floorplate; MN- motoneuron; V- ventral interneurons

for a video demonstration, see: http://www.hhmi.org/biointeractive/media/SSH_demo-lg.wmv

Ventricles = lumen of original neural tube In spinal cord, simple canal In telencephalon, not as simple Filled with cerebrospinal fluid

spinal cord- central canal

* adapted from P. Mason, Medical Neurobiology, 2011

8 Primary vesicles Secondary vesicles Regions Ventricles Forebrain= telencephalon cerebral cortex lateral prosencephalon basal ganglia (foramen of amygdala Monro) diencephalon thalamus hypothalamus 3rd pituitary (neurohypophysis) pineal gland Midbrain= mesencephalon midbrain cerebral mesencephalon aqueduct Hindbrain= metencephalon pons 4th ventricle cerebellum rhombencephalon myelencephalon medulla

Brain flexures– the tube begins to bend*. Cervical flexure: Cephalic flexure: hindbrain perpendicular to spinal 3-4w; will bring forebrain cord; by birth, not evident perpendicular to (straightens in 8th week) midbrain and hindbrain Pontine flexure: 6w; cerebellum will sit over pons and medulla

Primary vesicles

Secondary vesicles

* Neuroscience. 2nd edition. Purves, Augustine, Fitzpatrick, et al., eds. Sinauer Associates; 2001.

Flexures of neural tube

http://www.youtube.com/watch?v=YXTA0lUBZW4 (1:18 – 2:26 min)

9 Neural crest migration occurs during weeks 4-7 of gestation.

Migration of neural crest derived neurons is extensive.

Nervous system related neural crest derivatives:

Disorders of neural crest development may cause puzzling variety of symptoms (eg abnormal pigmentation plus sensory disturbances or GI impairment), easy to understand once the neural crest origin is resolved. *

10 Neural crest cells migrate during weeks 4-7 of gestation (later for the sacral crest cells) and give rise to:

Peripheral nervous system Spinal sensory ganglia Cranial sensory ganglia (general sensory input) Autonomic ganglia Enteric nervous system– GI tract (invisible but mighty) Schwann cells that myelinate peripheral axons Satellite cells (peripheral “astrocytes”)

CNS/PNS related structures Meninges: arachnoid and pia Adrenal medulla (chromaffin cells, secrete epinephrine)

Mesoectodermal derivatives (eg musculoskeletal system of some of head; odontoblasts, dermis of face, tracheal and laryngeal cartilages– this is not a complete list) Melanocytes

For today: Nervous System organization begins in the neural plate stage

• Topographically flat sheet of cells = neural plate

• Neural plate formation and closing of neural tube‐ neurulation

• CNS develops as hollow tube

• PNS forms from neural crest cells that migrate peripherally

• Gradual and continuous process

• Begins early in gestation but continues postnatally

11 Foundational Neuroscience Course Meningeal Coverings & Ventricular System August 8, 2012 G. Gruener, MD, MBA

MENINGEAL COVERINGS & the VENTRICULAR SYSTEM

Date: August 8, 2012 – 9:30 AM Preparation Assignment: Essentials of the Human Brain by Nolte ; Chapter 4 & 5 Meningeal & Ventricular presentation – Gruener

KEY CONCEPTS & LEARNING OBJECTIVES

I. After studying the assigned material and attending lecture you need to be able to: a.) Identify and where appropriate describe: functions of meningeal coverings, differences between spinal versus cranial meninges b.) Identify the ventricles on radiological images c.) Define or describe: Blood-CSF barrier, choroid plexus, CSF “origin”, CSF function, CSF versus blood composition d.) Define or describe: meningeal spaces, brain herniation, hydrocephalus II. After review of the clinical correlation sessions, within small groups, you need to be able to demonstrate: a.) Suggest a site of dysfunction that will explain signs and symptoms for a clinical case b.) Identify the (expected) site of abnormality on an MRI (or CT) scan of the brain c.) “Develop” three potential diagnoses, appropriate to the patients’ clinical scenario, course and medical history, which would explain the etiology of their presentation.

Additional References for the Interested

Biller J. Practical Neurology , 4 th Ed., Lippincott Williams & Wilkins 2012 Castro, Merchut, Neafsey, Wurster; Neuroscience: An Outline Approach , 2002 Fitzgerald MJT, Gruener G, Mtui E. Clinical Neuroanatomy and Neuroscience , 6th Ed., W. B. Saunders, 2012 Nolte J, Sundsten J. The Human Brain: An introduction to its functional anatomy . 6th Ed., Mosby Elsevier, 2010

Oreškovi ć D, Klarica M. Development of hydrocephalus and classical hypothesis of cerebrospinal fluid hydrodynamics: Facts and illusions . Progress in Neurobiology 2011;94:238-258

FINAL COPY RECEIVED: 7/9/2012 1 7/10/2012

Meningeal coverings & Ventricular system SSOM Foundational Neuroscience Course

August 8, 2012

Gregory Gruener, MD, MBA Senior Associate Dean, SSOM Department of Neurology, LUHS

Objectives  Identify & Describe functions of meningeal coverings  List the differences between spinal vs. cranial meninges  Identify the ventricles on radiological images  Define or describe: Blood-CSF barrier, Choroid plexus, CSF origin, CSF function, CSF composition  Define or describe: meningeal spaces, brain herniation, hydrocephalus

Meningeal coverings

• Dura mater – pachymeninx • Arachnoid •Pia • Pia + Arachnoid = leptomeninges

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Dura Mater

• Provides mechanical strength • Separates different intracranial components • No space on either side of the dura (normally) • Contains venous sinuses (lined with endothelium) • Has its own blood supply • Pain sensitive

falx cerebri

tentorium cerebelli

Tentorial notch or incisure

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Arachnoid Mater

• Thin, avascular, several layers of cells adhering to the dura (barrier function) • Arachnoid trabeculae – strands of collagenous connective tissue and scattered cells (suspends the brain) • Bridges over CNS surface irregularities forming cisterns (subarachnoid cisterns) • Cerebral arteries and veins travel in subarachnoid space • Subarachnoid space (between arachnoid and pia) is filled with CSF • CSF enters the venous system through Arachnoid villi

Pia Mater

• Covers the surface of the brain – closely follows the external surface • Abuts against astrocyte feet at the surface of the CNS • Pia covering the spinal cord is thick in some places – Denticulate (Dentate) ligaments – anchor the spinal cord to the arachnoid – Filum terminale – anchors the caudal spinal cord to the caudal end of the spinal dural sheath

• Vessels enter and leave the brain within a “perivascular space” (Virchow-Robin space)

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Spinal canal meninges

• Inner layer of cranial dura is continuous with spinal dural sheath at foramen magnum • Spinal epidural space is between periosteum and dura • Spinal epidural space is filled with connective tissue and vertebral venous plexus • Spinal dura and arachnoid end at 2nd sacral vertebrae • Large subarachnoid cistern – lumbar cistern • Thickened pia components (Denticulate ligament, Filum terminale)

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CSF - production

Produced by active and passive transport

CSF Origin 60% - Choroid plexus 30% - Capillary bed 10% - metabolic

Choroid plexus

Choroid plexus (Blood-CSF barrier) 1. Capillary – fenestrated 2. Pia – scattered cells and collagen 3. Choroid epithelium – specialized ependyma, connected by tight junctions, numerous microvilli facing CSF, numerous mitochondria

CSF - production

Median aperture - Foramen of Magendie Lateral aperture - Foramen of Luschka

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Transverse cerebral fissure

https://www.msu.edu/~brains/brains/human/index.html

Choroidal fissure

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CSF Functions • Total of ~ 200 ml of CSF – 25 ml in the ventricles (2ml in 3rd and 4th ventricle) – Production of 250uL/min (500 ml/24 hours)

• Mechanical support (buoyancy) • Spatial “buffering” system • Free communication with extracellular fluid • “Sink” for substances made by the brain that need to be removed or reabsorbed • Route for spread of “neuroactive” hormones

Hydrocephalus

• Pathological state characterized by excessive accumulation of CSF within the ventricles or subarachnoid spaces. • “Classical hypothesis” – secondary to impaired CSF circulation, insufficient absorption or over secretion • (New hypothesis – depends on the hydrostatic and osmotic forces between the CSF, interstitial fluid and blood capillaries)

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Meningeal spaces & “Bleeding”

Bone epidural Dura subdural subarachnoid “subarachnoid cistern”

intraparenchymal (intracerebral) BRAIN

intraventricular

Brain Herniation

Castro, Merchut, Neafsey, Wurster; Neuroscience: An Outline Approach, 2002 http://calsprogram.org/manual/volume2/Section8_DisabilitySkills/02-DisSk1SkullTrephination13.html

10 Foundational Neuroscience Course Blood supply of the Brain August 8, 2012 G. Gruener, MD, MBA

BLOOD SUPPLY OF THE BRAIN

Date: August 8, 2012 – 10:30 AM Preparation Assignment: Essentials of the Human Brain by Nolte ; Chapter 6 Blood supply of the Brain presentation – Gruener

KEY CONCEPTS & LEARNING OBJECTIVES

I. After studying the assigned material and attending lecture you need to be able to: a.) Define the components or describe: cerebral circulation (major vessels), ganglionic arteries, perforated substance, Circle of Willis b.) Describe the mechanism of regulation of cerebral blood flow c.) List the blood brain barriers d.) Describe the function and components (endothelial cells, Pericytes, astrocytes, neuronal processes) of the BBB e.) Define or describe circumventricular organs and their role f.) Describe the drainage pattern of cerebral veins (deep and superficial groups) II. After review of the clinical correlation sessions, within small groups, you need to be able to demonstrate: a.) Identify vascular territory/distribution of strokes, intracerebral and subarachnoid hemorrhage on neuroimaging b.) Identify on neuroimaging and describe the pathophysiological difference between a subdural and epidural hematoma c.) Suggest a site of dysfunction that will explain signs and symptoms for a clinical case d.) Identify the (expected) site of abnormality on an MRI (or CT) scan of the brain e.) “Develop” three potential diagnoses, appropriate to the patients’ clinical scenario, course and medical history, which would explain the etiology of their presentation.

Additional References for the Interested

Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M. The Blood–Spinal Cord Barrier: Morphology and Clinical Implications. Ann Neurol 2011;70:194-206

Benarroch EE. Circumventricular organs: receptive and homeostatic functions and clinical implications . Neurology 2011;77:1198-1204

Dalkara T, Gursoy-Ozdemir Y, Yemisci M . Brain microvascular pericytes in health and disease . Acta Neuropathol 2011;122:1-9

Kwee RM, Kwee TC. Virchow_Robin spaces at MR imaging. RadioGraphics 2007; 27:1071–1086

Liebner S, Czupalla CJ, Wolburg H. Current concepts of blood-brain barrier development. Int J Dev Biol. 2011;55:467-476

FINAL COPY RECEIVED: 7/10/2012 1 7/10/2012

Blood supply of the CNS SSOM Foundational Neuroscience Course

August 8, 2012

Gregory Gruener, MD, MBA Senior Associate Dean, SSOM Department of Neurology, LUHS

Objectives

 Define the components or describe: cerebral circulation (major vessels), ganglionic arteries, perforated substance, Circle of Willis  Describe the mechanism of regulation of cerebral blood flow  List the blood brain barriers  Describe the function and components (endothelial cells, Pericytes, astrocytes, neuronal processes) of the BBB  Define or describe circumventricular organs and their role  Describe the drainage pattern of cerebral veins (deep and superficial groups)  Identify vascular territory/distribution of strokes, intracerebral and subarachnoid hemorrhage on neuroimaging  Identify on neuroimaging and describe the pathophysiological difference between a subdural and epidural hematoma

Cerebral circulation - Overview

• Internal cerebral arteries – supply most of cerebrum – Branches: ophthalmic artery, anterior choroidal artery, posterior communicating artery – Bifurcates into the anterior and middle cerebral artery

• Vertebrobasilar – supply brainstem, cerebellum, spinal cord – Vertebral branches: posterior and anterior spinal artery, posterior inferior cerebellar artery (PICA) – Vertebral arteries fuse to form Basilar artery • Basilar branches: anterior inferior cerebellar artery (AICA), superior cerebellar artery • Bifurcates into posterior cerebral arteries

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Cerebral circulation - Overview

• Small perforating arteries supply deep cerebral structures – Arteries around the base of the brain – give rise to small perforating (or ganglionic) arteries – MCA branches – lenticulostriates (supply deep structures of diencephalon, hypothalamus, and telencephalon) – Anterior and posterior perforated substance – visible entry points of perforating arteries on base of the brain

• Circle of Willis – Interconnects the anterior and posterior circulations – Other intracranial-extracranial anastamoses (external- internal carotid artery, carotid-basilar, carotid-vertebral)

Blood flow control to CNS • 2% of body weight, 15% cardiac output, 25% oxygen consumption • Normally 55ml of blood/100g CNS/minute – 20ml – neurons stop generating electrical signals – 10ml – necrosis of brain • Control of blood flow – Autoregulation – arterial and smooth muscle cell mediated – Metabolic – increased neuronal activity → glutamate released → astrocyte end feet receptors activated → vasodilator factors released at end-feet applied to vessels – (Neural control – cerebral vessels innervated by autonomic fibers)

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perforated substance

Duvernoy HM. The human brain: surface, blood supply and three-dimensional sectional anatomy, 2nd ed.; Springer Wien, NY, 199

Schuenke M, Schulte E, Schumacher U. Thieme Atlas of Anatomy, 2007

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Blood-Brain “Barriers”

• Arachnoid barrier • Blood-CSF barrier • Blood-Brain-Barrier (BBB) – Restricts ionic/fluid movements, supplies essential nutrients, mediates efflux of waste or toxic products • Blood-Spinal Cord-Barrier (different from BBB)

Blood-Brain Barrier Composition • Capillary endothelial cells: tight junctions, polarized expression of membrane transporters and receptors, enzymes that target neurotransmitters or precursors, large number of mitochondria • Pericytes: contractile function, endothelial cell regulation, angiogenesis, phagocytic activity, (pluripotent?) •Astrocytes • Neuronal processes

Blood-Brain-Barrier

Neurology 2012;87:1268-76

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Circumventricular organs

• Areas of fenestrated capillaries that allow communication between blood and extracellular fluid • Near/contact with 3rd and 4th ventricle – Pineal gland, median eminence of hypothalamus, posterior lobe of pituitary gland, subfornical area, vascular organ of lamina terminalis, area postrema • Cell bodies “monitor” extracellular fluid and project to other parts of the CNS • Tanycytes – specialized ependymal cells that overlie circumventricular organs; barrier between organ and ventricular CSF

Venous System

• Cerebral veins – valveless with numerous anastamoses • Emissary veins – connect extracranial veins with dural sinuses • Cerebral veins drain → dural venous sinuses → internal jugular veins + basilar venous plexus (base of the brain, communicates with epidural venous plexus of spinal cord) • Two major divisions – Superficial veins • Superior group: Empty into superior and inferior sagittal sinuses • Inferior group: Empty with transverse and cavernous sinus – Deep veins • Cerebellar and brainstem – Collection of veins that drain into the deep (Great vein of Galen), straight, transverse and petrosal sinus

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Schuenke M, Schulte E, Schumacher U. Thieme Atlas of Anatomy, 2007

Osborn AG. Introduction to cerebral angiography. Harper & Row, Hagerstown, 1980

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http://calsprogram.org/manual/volume2/Section8_DisabilitySkills/02-DisSk1SkullTrephination13.html

Sulci

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Foundational Neuroscience Coursecourse

Objectives

1. Be able to describe the function: Merkel’s disks, Meissner's corpuscles, Pacinian corpuscles, free nerve endings, muscle spindles, Golgi tendon organs, hair follicle receptors; medial and lateral divisions of the dorsal root

2. Be able to define: alpha and gamma motoneurons, motor unit; (size principle of motoneuron recruitment; two muscle fiber types)

3. Be able to describe: muscle spindle and myotatic stretch reflex circuit; alpha‐gamma coactivation

CHAPTER 9

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Each Sensory Receptor Has an Adequate Stimulus, Allowing it to Encode the Nature of a Stimulus

Sensory receptors transduce some aspect of the external environment into a graded electrical signal known as a receptor potential

Adequate stimulus Chemoreceptors Photoreceptors Thermoreceptors Mechanoreceptors

Many Sensory Receptors have a Receptive Field, Allowing Them to Encode the Location of a Stimulus

Visceral Receptors

BP glucose head position muscle length

Receptor potentials Encode the Intensity and Duration of Stimuli

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Most Sensory Receptors Cats know Adapt to Maintained when the Stimuli, Some More big earthquake Rapidly Than Others is coming

Figure 9‐8 Some of the sensory endings found in glabrous skin. A, Schematic overview. M, Meissner corpuscle; Me, Merkel cell; PC, Pacinian corpuscle; R, Ruffini ending. B, Light micrograph of two Pacinian corpuscles from monkey skin, sectioned transversely. Multiple thin layers of each capsule surround a central mechanosensitive ending (arrows). C, Section of biopsied skin from a human fingertip, stained to show epidermis (blue fluorescence), myelin (red fluorescence), and nerve fibers (green fluorescence). Myelinated and unmyelinated axons course horizontally in a dermal plexus (thick arrows), giving off branches that end in Meissner corpuscles (thin arrows) and as Merkel endings (arrowheads). D, Higher‐ magnification view of a human Meissner corpuscle (actual size about 30 × 80 μm), stained as in C. A myelinated axon (thick arrow) enters the corpuscle, loses its myelin, and winds back and forth (thin arrows) between the stacked Schwann cells. Other unmyelinated fibers (arrowhead) head off into the epidermis to form free nerve endings. (B, courtesy Dr. Nathaniel T. McMullen, University of Arizona College of Medicine. C and D, courtesy Dr. Maria Nolano, Salvatore Maugeri Foundation, Terme, Italy.)

Most Sensory Receptors Adapt to Maintained Stimuli, Some More Rapidly Than Others

Sensory Receptors All Share Some Organizational Features

Figure 9‐4 General organization of sensory receptors, as illustrated by a somatosensory receptor (Pacinian corpuscle, A), a hair cell of the inner ear (B), and a retinal rod photoreceptor (C). Each has a receptive area (orange) and mitochondria nearby. The receptive ending of the Pacinian corpuscle has no obvious anatomical specializations but is surrounded by a layered capsule. The microvillar projections of the hair cell contain mechanosensitive channels (see Chapter 14), and the receptive area of the rod contains a collection of pigment‐studded membranous disks (see Chapter 17). Somatosensory receptors make synapses far away in the CNS, whereas hair cells and photoreceptors make synapses nearby on peripheral endings of vestibulocochlear nerve fibers (CN 8) or on retinal interneurons (RI), respectively. DRG, dorsal root ganglion.

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Sensory Receptors Use Ionotropic and Metabotropic mechanisms to Produce Receptor Potentials

All Sensory Receptors Produce Receptor Potentials, But Some Do Not Produce Action Potentials

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Somatosensory Receptors Detect Mechanical, Chemical, or Thermal Changes

Relationship between the number of cutaneous receptors and the ability to distinguish between two points

Figure 9‐9 Correlation of spatial resolution and number of cutaneous receptors in different areas of the human hand. Spatial resolution (the reciprocal of the two‐point discrimination threshold) was determined in psychophysical experiments by touching humans with two points and determining the minimum separation needed for them to be recognized as two separate points; this separation is less than 2 mm for fingertips but more than 8 mm for the palm of the hand. Correspondingly, there are many more Meissner corpuscles and Merkel endings per cm2 in the fingertips than in the palm. (Modified from Vallbo ÅB, Johansson RS: Hum Neurobiol 3:3, 1984.)

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Nociceptors Have Both Afferent and Efferent Functions

Axon Reflex:

Only known reflex involving only one neuron and no part of the CNS

Figure 9‐13 Production of flare and edema by axon reflexes. Injuring a localized area of skin (1) causes a receptor potential in nociceptive endings located there (2). If the receptor potential depolarizes the receptor's trigger zone (3) to threshold, action potentials travel in both directions, propagating toward the spinal cord (4) and spreading distally into nearby branches of the same nociceptor (5). Impulses reaching the spinal cord cause the release of glutamate (6) and neuropeptides (7) onto second‐order neurons. Impulses spreading into sensory endings also cause the peripheral release of glutamate (8) and neuropeptides (9). Thus two different branches of a single neuron form the afferent and efferent limbs of the axon reflex circuit. The neuropeptides are vasoactive and cause flare and edema; the effects of peripherally released glutamate are less well understood.

Receptors in Muscles and Joints Detect muscle Status and Limb Position

Muscle Spindle

Figure 9‐14 Simplified diagram of a muscle spindle. A single nuclear bag fiber and a single nuclear chain fiber are shown. A single afferent fiber (group Ia) supplies all the intrafusal fibers with primary endings. Several smaller afferents (group II) provide secondary endings, mostly to nuclear chain fibers. Small motor axons (of gamma motor neurons) of two different types innervate the contractile portions of nuclear bag and nuclear chain fibers. (The Ia‐II‐gamma terminology is explained later in this chapter.) The upper and lower insets show the response properties of axons from primary and secondary endings in human finger extensors, stretched by passive bending at the metacarpophalangeal joint. For each inset, the upper trace shows the metacarpophalangeal joint angle, the middle trace shows the firing rate of the axon (impulses/sec), and the lower trace shows the actual action potentials recorded. (Drawing, modified from Warwick R, Williams PL, editors: Gray's anatomy, Br ed 35, Philadelphia, 1975, WB Saunders. Insets, from Edin BB, Vallbo ÅB: J Neurophysiol 63:1297, 1990.)

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Interaction of Muscle Spindles and firing of Gamma Motor Neurons

Figure 9‐15 Mechanism of action of gamma motor neurons. Muscle spindles in a contracted muscle (in this case, the biceps) are unstretched and thus electrically silent (A). As a result, slight stretching of the muscle causes little or no response (B). Activity of gamma motor neurons "prestretches" the central receptive region of the muscle spindle, causing some background activity when the biceps is contracted (C) and many more action potentials when it is stretched (D).

Golgi Tendon Organ (gto)

Figure 9‐16 A, Golgi tendon organ. One or more large‐diameter afferent fibers enter a capsule around part of the myotendinous junction and then break up into many branches that interweave with bundles of collagen. B, Responses of a single afferent fiber from a Golgi tendon organ to a pull on the tendon that stretched it by 50 μm. The firing rate of the afferent, indicated by dots in the middle trace, closely tracks the tension developed in the tendon. (A, adapted from Krstić RV: General histology of the mammal, Berlin, 1985, Springer‐Verlag. B, from Fukami Y, Wilkinson RS: J Physiol 265:673, 1977.)

Comparison of Firing Patterns of Muscle Spindles and GTO’s

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Visceral Structures Contain a Variety of Receptive Endings— but little is known about them‐‐‐‐

Epineurium

Perinerium (blood‐nerve barrier)

Endoneurium

Figure 9‐19 Continuity of spinal meninges and the sheaths of peripheral nerves. The continuity between spinal subarachnoid space and extracellular space within nerve fascicles is indicated by the arrow emerging from both the cut end of the nerve and the vicinity of a dorsal root ganglion (DRG). The pia mater is reflected from the exit zone of the ventral rootlets for clarity. DR, dorsal root; SG, sympathetic ganglion; VR, ventral root. (Adapted from Krstić RV: General histology of the mammal, Berlin, 1985, Springer‐Verlag.)

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More on The Coverings of Nerves and Nerve Fibers

The Diameter of a Nerve Fiber is Correlated with its Function

Classification of Peripheral Nerve Fibers

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a. Slowly adapting b. Rapidly adapting

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Objectives

1. Be able to identify within the cross section of a spinal cord: cervical/thoracic/lumbar level, dorsal horn, ventral horn, intermediate gray, intermediolateral cell column, substantia gelatinosa; nucleus proprius; nucleus dorsalis; dorsal columns 2. Be able to “identify” and describe the function of the major ascending sensory pathways: dorsal‐column/medial lemniscus system, spinothalamic tract, spinocerebellar tract 3. Be able to “identify” and describe the function of the major descending motor pathways: pyramidal (corticospinal) tract, corticobulbar fibers, and rubrospinal tract, 4. Be able to describe/contrast: preganglionic and postganglionic; parasympathetic and sympathetic; referred pain; blood supply of the spinal cord

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The spinal cord is segmented

The spinal cord is segmented‐‐‐

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Muscles and their function as related to the spinal roots that innervate them (not a true myotome)

A true myotome = all the muscles innervated by a given ventral root

Differences between a myotome and a dermatome

Figure 10‐4 Cutaneous territories innervated by spinal nerves (dermatomes) and the trigeminal nerve (V1, V2, V3). Co, coccygeal segment. (Based on Bonica JJ: Applied anatomy relevant to pain. In Bonica JJ, editor: The management of pain, ed 2, Philadelphia, 1990, Lea & Febiger.)

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Dermatome = skin innervated by a single dorsal root

All Levels of the Spinal Cord Have a Similar Cross‐Sectional Structure

Figure 10‐8 Cross sections of the spinal cord at various levels; note the large lateral extensions of the anterior horns in C5, C8, and L5. C, Clarke's nucleus; DR, dorsal root; FC, fasciculus cuneatus; FG, fasciculus gracilis; IL, intermediolateral cell column; L, Lissauer's tract; SG, substantia gelatinosa.

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Stretch Reflex or Deep Tendon Reflex

Tapping the patellar tendon stretches the quads, causes the spindle to “fire”, makes the quads reflexively shorten (contract), makes the spindle nuclear bag sag, and finally causes gamma fibers to fire and tense up or reset the spindle bag.

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Pain can cause a flexor withdrawal response which can involve several segments and reciprocal muscle groups

If the left arm is extended when the right is withdrawn, it is called a crossed reflex

The Posterior (Dorsal) Column – Medial lemniscus pathway

This one crosses in the medulla

Seems hard—not so bad

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The Spinothalamic Tract‐‐OWY

This one crosses in the cord

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The Spinocerebellar Tracts

Dorsal (posterior) Ventral (anterior) Cuneo

Figure 10‐23 Spinocerebellar and cuneocerebellar tracts. Mechanoreceptive afferents from the lower extremity ascend through fasciculus gracilis (FG) to reach Clarke's nucleus, whose cells give rise to the ipsilateral posterior spinocerebellar tract (PSCT), which enters the inferior cerebellar peduncle and ends ipsilaterally in the vermis of the anterior lobe. A larger variety of afferents end on other cells of the spinal gray matter, whose axons form the contralateral anterior spinocerebellar tract (ASCT); this tract ascends to the pons, loops over the superior cerebellar peduncle, and recrosses in the vermis of the anterior lobe. Mechanoreceptive afferents from the upper extremity ascend to the medulla in the fasciculus cuneatus (FC) and end in the lateral cuneate nucleus (analogous to Clarke's nucleus); these cells give rise to the cuneocerebellar tract (CCT), which enters the inferior cerebellar peduncle and ends ipsilaterally in the vermis of the anterior lobe. The rostral spinocerebellar tract is not shown in this diagram.

Descending Pathways Influence the Activity of Lower Motor Neurons

The Corticospinal Tract (CST)

Upper motor neuron Lower motor neuron

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The Autonomic Nervous System Monitors and Controls Visceral Activity

preganglionics postganglionics location

Referred Pain

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Major Tracts in Spinal Cord

Spinal Cord Lesions

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23 Neuroscience Spinal Cord Disorders August 10, 2012 M. Merchut, M.D.

CLINICAL CORRELATION: SPINAL CORD DISORDERS

Date: August 10, 2012 – 9:30 AM Reading Assignment: refer to posted handout in LUMEN calendar

KEY CONCEPTS AND LEARNING OBJECTIVES

1. List the clinical signs found with upper motor neuron (UMN) lesions versus lower motor neuron (LMN) lesions, and then use these findings to localize lesions to cervical, thoracic, or lumbar levels of the spinal cord.

2. Recognize that any expected UMN signs from acute, severe spinal cord trauma may be temporarily absent due to spinal or neurogenic shock, where only LMN signs are present.

3. For a radiculopathy, be able to predict which root level is involved based on the dermatomal distribution of radicular pain and pattern of muscle weakness and reflex loss.

4. Recognize that an extramedullary spinal cord lesion is usually associated with radicular pain and sensory impairment of pain and temperature up to the level of the lesion without sacral sparing.

5. Recognize that an intramedullary spinal cord lesion is usually associated with diffuse or no pain, with a suspended impairment of pain and temperature sensation with sacral sparing.

6. List the signs and symptoms of the following spinal cord syndromes, based on the involvement or sparing of spinal roots, lower motor neurons, upper motor neurons, posterior (dorsal) column pathways, or the spinothalamic tract: ---spinal cord transection or transverse myelopathy (myelitis) ---spinal cord hemisection (Brown-Sequard syndrome) ---syringomyelia or syrinx ---anterior spinal artery syndrome ---posterolateral syndrome or subacute combined degeneration ---amyotrophic lateral sclerosis ---tabes dorsalis

7. List the common causes of the following spinal cord syndromes: ---spinal cord transection or transverse myelopathy (myelitis) from trauma, extramedullary tumors, spinal stenosis, viral infections, multiple sclerosis

FINAL COPY RECEIVED: 7/11 1 Neuroscience Spinal Cord Disorders August 10, 2012 M. Merchut, M.D.

---spinal cord hemisection (Brown-Sequard syndrome) from trauma, extramedullary tumors, degenerative spine disease including herniated intervertebral discs ---syringomyelia or syrinx from prior trauma, intramedullary tumors ---anterior spinal artery syndrome from aortic atherosclerosis or aortic surgery ---posterolateral syndrome or subacute combined degeneration from vitamin B12 deficiency ---amyotrophic lateral sclerosis (motor neuron disease of unknown cause) ---tabes dorsalis from syphilis

FINAL COPY RECEIVED: 7/11 2 6/27/2012

Spinal Cord Disorders

Michael P. Merchut, MD (lecture slides with Frank Netter slides, copyrighted materials, videos and patient material removed)

Lower motor neuron signs---are found in a limb that has muscles innervated by anterior horn cells affected at the level of the spinal cord lesion.

Upper motor neuron signs---are found in a limb when a spinal cord lesion involves the corticospinal tract rostral to the anterior horn cells that innervate the muscles of that limb.

What are the expected physical signs in a patient with a complete, severe spinal cord injury at the C8 level?

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“Lower motor neuron signs” are found when the LMN is adversely affected at different places: anterior horn cell, spinal root, plexus or peripheral nerve.

(Signs and symptoms of neuromuscular junction disorders were Slide discussed. Myopathies will be “Diseases of Motor-Sensory discussed later.) Unit: Regional Classification” (Frank H. Netter MD, The CIBA Collection of Medical “Upper motor neuron signs” are Illustrations. Vol 1 Nervous found in the limbs ipsilateral to System, Part II, 1986, p. 204) a corticospinal tract lesion in the spinal cord, or from contralateral corticospinal tract involvement in the brain or brain stem.

Radicular (root) pain---lightning, stabbing, shooting pain in the dermatomal distribution of a dorsal root. ---from inflammation or extramedullary compression (e.g., herniated disc) of a dorsal root Slide Other motor, reflex or sensory “Cervical Disc Herniation: abnormalities may correlate with Clinical Manifestations” a specific radiculopathy (root (Frank Netter Collection, lesion). p. 193)

A dull, local pain may occur from the extramedullary lesion itself. An intramedullary spinal cord lesion may produce diffuse pain or none at all.

Sensory signs in spinal cord lesions

The clinical sensory deficit corres- ponds to the spinal cord, not vertebral, level.

The vertebral column becomes longer than the spinal cord during development.

(e.g., a metastatic tumor in the L1 vertebrae would expand and com- press the spinal cord at its L5, S1 or S2 levels)

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Sensory signs in spinal cord lesions

---spinothalamic tract lesion: * contralateral deficit;

* suspended pattern of deficit with sacral sparing in intramedullary lesion;

* deficit up to a derma- Slide tomal level in extramed- “Cervical Spine Injury: ullary lesion; Incomplete Spinal Cord Syndromes” (Frank Netter Collection, S p. 106) T T

---dorsal column tract lesion: * ipsilateral deficit;

Spinal Cord Syndromes: Transection or transverse myelopathy

* LMN signs and level of sensory loss localize the spinal level of the lesion;

* UMN signs develop in limb muscles innervated by anterior horn cells below the level of the lesion;

* an acute, severe, traumatic lesion may present with spinal shock;

* etiology ---trauma ---inflammation (viral, MS, autoimmune) ---compression (tumor, spinal stenosis) ---ischemia

Syringomyelia * cavity (syrinx) in the central gray matter, which may expand;

* initial suspended (vestlike) spinothalamic sensory loss with sacral sparing;

Slide * position sense, vibration spared; “Syringomyelia” (Frank Netter * cavity may then disrupt Collection, p. 190) anterior horn cells (LMN signs), or may cause paraparesis if corticospinal tract involved;

* etiology: ---abnormal CSF flow or pressure with congenital (Chiari) malformations; ---tumor; ---residual of trauma;

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Autopsy specimen of extensive syringomyelia (central cavity).

Occlusion of the anterior spinal artery

Slide “Acute Spinal Cord Syndromes: Pathology, Etiology and Diagnosis” (Frank Netter Collection p. 185)

* sudden hyperreflexic, spastic paraparesis, loss of pain and temperature below the lesion level (lower thoracic or upper lumbar); * preserved vibration and position sense (intact dorsal columns); * etiology ---atherosclerotic aortic disease or dissection ---aortic surgery

Subacute combined degeneration of spinal cord (postero lateral syndrome)

* lesions in posterior and lateral columns, usually thoracic level; Slide “Subacute Combined * loss of vibration and position Degeneration” sense in the lower limbs, but (Frank Netter Collection, pain and temperature preserved; p. 191) * UMN signs (corticospinal tract lesion) in lower limbs;

* etiology ---usually vitamin B12 deficiency ---copper deficiency ---HIV

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Autopsy specimen, thoracic spinal cord, showing subacute combined degeneration. In this myelin stain, normal myelin appears dark, while demyelinated areas appear pale.

Amyotrophic lateral sclerosis (ALS) * progressive degeneration of UMN (pyramidal neurons, corticospinal tract) and LMN (anterior horn cells, cranial nerve motor nuclei);

* initially asymmetrical, later more Slide generalized LMN signs, often with “Motor Neuron Disease: diffuse fasciculations; Early Clinical Manifestations” (Frank Netter Collection p. 208) * normal sensation;

* coexistence of UMN signs; may first seem to be a cervical spinal cord lesion;

* outcome eventually fatal; * etiology unknown; * no curative treatment;

ALS patient: severe shoulder and upper limb atrophy.

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ALS patient: atrophic interosseus muscles of left hand (close-up of left hand held on top of the knee).

Tabes dorsalis * lightning pains from initial dorsal root lesions;

* subsequent dorsal column degeneration leads to loss of vibration, Slide position sense, then all “Neurosyphilis” (Frank Netter Collection p. 163) sensory modalities;

* areflexic;

* preserved strength;

* etiology ---neurosyphilis

Charcot joints: severe, traumatic injury and deformation of ankle joints due to loss of sensation from tabes dorsalis

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Ankle X-ray:

Severely destroyed Charcot joint from tabes dorsalis.

Videotaped patient

Patient xx: pin and temperature loss at shaded lines; reflex grading shown by numbers; Babinski sign shown as upgoing arrow.

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Spinal Cord Syndromes: Spinal cord hemisection (Brown-Sequard syndrome)

* contralateral spinothalamic deficit of pin, temperature;

* ipsilateral weakness (corticospinal tract), ipsilateral dorsal column deficit of vibration and position sense;

* etiology ---tumor (extramedullary) ---trauma ---herniated disc

8 Neuroscience Neuromuscular Junction Disorders August 10, 2012 M. Merchut, M.D.

CLINICAL CORRELATION: NEUROMUSCULAR JUNCTION DISORDERS

Date: August 08, 2011 - 9:30 AM Reading Assignment: refer to posted handout in LUMEN calendar

KEY CONCEPTS AND LEARNING OBJECTIVES

1. Explain the postsynaptic problem in myasthenia gravis (MG) and how acetylcholinesterase inhibiting drugs help these patients.

2. Explain the presynaptic problem in Lambert-Eaton myasthenic syndrome (LEMS) and botulism.

3. Recognize that the most common symptoms in myasthenia include ptosis, diplopia, dysarthria, and dysphagia, although all skeletal muscles may become weak or fatigable.

4. Contrast the restricted ocular form of myasthenia versus the generalized form.

5. Explain how the diagnosis of MG is made, and recognize that the most specific test is presence of serum acetylcholine receptor antibodies.

6. List the treatment options for MG, including treatment of myasthenic crisis.

7. Recognize that the proximal weakness typical of LEMS is similar to that of a myopathy, and most of these patients have an underlying small cell carcinoma of the lung.

FINAL COPY RECEIVED: 6/26/12 1 6/27/2012

Neuromuscular Junction (NMJ) Disorders

Michael P. Merchut, MD (lecture slides with Frank Netter slides, copyrighted materials, videos and patient material removed)

Normal neuromuscular transmission

---AP depolarizes motor nerve terminal, Ca influx facilitates release of ACh, ACh binds at specific sarcolemmal nicotinic AChR ---If enough AChR is bound, end plate depolarizes (EPP), and EPP exceeds threshold for single muscle fiber to contract ---Co-activation of many muscle fibers causes muscle to contract ---AChE limits action of ACh ---Slight decrease in ACh release with exercise is insignificant, since more than enough ACh is normally released (“safety factor”)

Slide “Myasthenia Gravis: Etiologic and Pathophysiologic Concepts” (Frank Netter Collection p. 225)

NMJ Disorders • Postsynaptic: myasthenia gravis – Immune target is nAChR • Presynaptic: Lambert-Eaton myasthenic syndrome (LEMS) – Immune target is voltage-gated Ca channel • Presynaptic: botulism – Exotoxin inhibits ACh release • Diverse inborn errors in NMJ: congenital myasthenic syndromes (rare)

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Myasthenia Gravis (MG) • Begins at any age • Ocular MG (10-20%) – ptosis, diplopia only symptoms after 2-3 years • Generalized MG (80-90%) – ptosis, diplopia, dysarthria, dysphagia; respiratory, facial, neck and limb weakness • Preserved sensation and reflexes • Symptom severity varies from patient to patient, remission may occur • Fatigue occurs with certain activities

Diplopia from dysconjugate right lateral gaze.

Bilateral ptosis, with compensatory contraction of frontalis ms.

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Slide “Myasthenia Gravis: Clinical Manifestations” (Frank Netter Collection p. 224)

Neuromuscular junction in Myasthenia Gravis (MG)

• Antibodies to AChR (from B-cells helped by T- cells) block receptors and increase degradation and turnover • Loss of functional AChR leads to weakness • Myasthenic fatigue occurs when the normally mild reduction of ACh released with exercise leads to a critical loss of end plate, and hence muscle fiber, depolarization

Slide “Myasthenia Gravis: Etiologic and Pathophysiologic Concepts” (Frank Netter Collection p. 225)

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EM: Normal NMJ in animal model, motor nerve terminal at top, junctional folds of muscle membrane below.

EM: Myasthenic NMJ in animal model, motor nerve terminal at top, junctional folds of muscle membrane below.

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Diagnosis of Myasthenia Gravis (MG)

• Typical clinical features • Positive Tensilon (edrophonium) test – IV injection of short-acting AChE inhibitor • EMG evidence of abnormal NMJ transmission – repetitive nerve stimulation, single fiber jitter tests • Elevated serum antibody titer to AChR – the most specific test of all – in 80-90 % generalized, 50% ocular MG

The Tensilon test.

Treatment of Myasthenia Gravis (MG)

• Anticholinesterase drugs – inhibit AChE, enhancing effect of released ACh – improve symptoms, not autoimmune pathology • Thymectomy – contains AChR-like material, where autoimmune response initiated? – hyperplastic thymus or thymoma (rarer) occur in MG • Immunosuppressant drugs

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Immunotherapy for MG

• Thymectomy • Corticosteroids • Azathioprine or mycophenolate mofetil • Cyclosporine • Other immunosuppressants • Transient, but potent “quick fixes” – plasmapheresis or IV immunoglobulin

Slide “Myasthenia Gravis: Electromyography” (Frank Netter Collection p. 226)

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Clinical – fatigable weakness of proximal limbs, trunk--- mimics a myopathy – exertion briefly improves power and hyporeflexia – autonomic symptoms (dry mouth, orthostasis) • Autoimmune attack vs presynaptic calcium channels, often related to small cell lung cancer • Diagnosis by nerve stimulation tests, EMG; occasional detection of specific antibodies

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Slide “Lambert-Eaton Syndrome” (Frank Netter Collection p. 227)

Treatment of Lambert-Eaton Myasthenic Syndrome

• Find and treat any underlying cancer, which will improve neurological symptoms • Drugs which enhance ACh release – guanidine – 3,4-diaminopyridine • Immunosuppressive therapy – with suboptimal success

Videotaped patients