Neuroscience - Exam 2

Visual System
Objectives
Point to and name the principle structures of the eye and recount how light is correctly focused onto the retina or refractive errors occur Recognize the retinal layers and name the main classes of neurons in the retina that are in each layer Outline key features in transduction of light energy to transmitter release in photoreceptors and describe differences between rods and cones individually as systems of rod-based and cone-based information. Describe how ON and OFF pathways contribute to RGC receptive field organization and how this relates to contrast enhancement at edges and contours Define the differences in the anatomical organization of peripheral and central retina and explain how these relate to the receptive field properties of the neurons in these regions and corresponding to the alerting and analysis functions of the cells Describe the differences between the properties and central projections of the P and M RGCs Name the central processing visual system structures and characterize how M and P pathways utilize separate projection routes and subregions of target structures. Also describe how the visual field is represented (visuotopic map) in visual pathways and main structures. Relate visual field deficits (scotomas) to sites of damage of visual pathways or nuclei Describe the concepts of binocularity and ocular dominance as they apply to neurons in visual cortex. Identify the cortical areas and layers where information from both eyes is kept separate and where it is combined Describe or draw a cortical processing unit composed of ocular dominance columns and orientation columns Give examples of how cortical processing streams distil information regarding perceptions of color, shape, and motion of visual images Recognize and describe the basic science issues that pertain to pathophysiological mechanisms of cataract, retinitis pigmentosa, optic neuritis resulting from glaucoma or multiple sclerosis, brain trauma or stroke or surgical lesions to optic radiations (Meyers loop example) or higher level cortex.

by Batmanuel

Diseases
Retinitis Pigmentosa Inherited eye disease that causes degeneration of photoreceptor cells in the retina causing progressive vision loss Problems seeing in low light, problems adapting to low light levels, restriction of visual field Rods are affected first Optic Neuritis Glaucoma - optic disc destroyed and enlarged Can have normal tension (these patients often have vasospastic diseases like migraine, Raynauds disease, hypotension etc.) How to test, since IOP isnt good test? Moving stimuli are detected less reliably on the peripheral retina in glaucoma patients of all sorts Multiple Sclerosis - myelin breakdown can distort appearance of optic disc and damage optic nerve Damage to Central Pathways (Meyers Loop)

Parallel Processing (of streams)

Detector arrays produce streams of information (information from neighboring detectors is usually similar) and higher order analyzers pick out different aspects of information from that stream (color, motion, shape etc.) These higher order analyzers then create their own streams Within each stream information can be processed sequentially too Eventually everything is merged together to make a whole

Light and Optics (Image Formation)

Light is refracted at the interface of two substances whose optical indicies are unequal Emmetropia - good focusing power Myopia - (near sighted) image focused in front of retina Hyperopia - (far sighted) image focused behind retina Presbyopia - hardening of lens so that it loses its ability to accomadate Visual Angle - used to define size or relative position of an image on the retina Line spread function - light spreads over a much broader visual angle in the eye due to diffusion (a line on a screen actually looks like a blur to the retina)

 Visual system compensates for this and sharpens the image Depth of Field - when small pupil then sharp focus at all depths, when large pupil then best focus in one plane Large pupil lets in a bunch of light and light scatter, thus adding to the line spread function and limits depth of field

Retina
Receptors outer nuclear layer outer plexiform layer inner nuclear layer (horizontal, bipolar and amacrine cells) inner plexiform layer ganglion cell layer RGC axons to optic nerve RGCs are the only ones that have axons Retinal - a Vitamin A aldehyde that is inactive in cis form and active in trans form (housed in rhodopsin protein) Visual Transduction - bright light causes lots of hyperpolarization Light is absorbed by rhodopsin and undergoes rapid transitions into an activated metabolite Activated retinal interacts with a G-protein called transducin Transducin activates an enzyme which depletes cGMP Sodium channels that require cGMP to stay open, close Sodium entry into rod is reduced and rod membrane potential hyperpolarizes Adaptation to light or dark conditions is mainly due to changes in available photopigment Color Vision Principle of Univariance - any single cone photopigment cannot be used to determine what color light is. Signals from multiple pigments must be compared via higher order processing. Color Blindness - L (long, red) and M (medium, green) cone pigments are adjacent to each other on the X chromosome so males are more likely to have red-green deficiency blue deficiencies are rare and not sex linked Color vision is best centrally at fovea where there are no rods and many cones Cones vs Rods Rods Cones Relative properties of individual photoreceptors
High sensitivity to light, specialized for night vision More disks and photopigment molcules, thus captures higher % of photons High amplification, single photon detection Lower temporal resolution; slow response; long integration time More sensitive to scattered light, thus poorer image formation ability Low acuity Peripheral retina dominant Highly convergent pathways Achromatic (only one type of pigment) Lower absolute sensitivity, specialized for daytime vision Less photopigment Less amplification Faster initial activation and shorter response duration provides better temporal resolution Most sensitive to direct axial light (wave guide properties), thus higher spatial resolution for sharper images High acuity Fovea and central retina dominant Non-convergent pathways Chromatic information pathways (3 types of cone pigments with different spectral absorbances = basis for color vision)

Characteristics of rod and cone systems (2nd, 3rd etc order neurons connected to R or C)

Retinal Neuron Circuits & Receptive Fields All photoreceptors respond to increased light intensity with hyperpolarization This signal is interpreted in opposite directions by either on-bipolar (metabotropic) or offbipolar (ionotropic) cells These cells send their signals to RGCs in a spatial pattern of concentric regions where the Center - depolarizes at either light onset or light offset (depending on if signal comes from on or off bipolar cells) Surround - antagonizes (does not inhibit) or cancels the center response On Pathways - activated by light, inhibited by dark

 Off Pathways - activated by dark, inhibited by light Ex - Off center ganglion cell receives dark spot and surround receives light large stimulation Same cell receives dark spot in center and surround does too surround antagonizes excitatory signal from center and stimulation is less Herman Grid Illusion (dark boxes, white lines) See picture this means that less activity in second case in middle so middle will look darker

Specialized Processing
M and P systems Both types of cells get bigger the farther away you get from the fovea P cells - smaller RGCs (smaller than M cells at any distance from fovea) Small receptive fields which allow for high resolution at fovea and central areas Color-selective, high visual acuity, less significant for movement and flicker detection Thinner axons and project to different areas in brain M cells - larger RGCs (more sensitive to small differences in contrast?) Larger receptive fields which are poor for high resolution but good for movement detection and fast flickering sensitivity (more in periphery) High speed, thick axons into the brain Grating Responses in terms of Center-Surround receptive field structure The grating bar (alternating dark/light) that lines up with the size of the center-surround receptive field best will stimulate the cell the most M cells have broader fields than P cells and so they respond better to larger grating bars

Central Visual Pathways

M & other superior colliculus (midbrain) motor pathways (pons & spinal cord) - for eye movements, head movements pulvinar (thalamus) - for visual attention M&P Pathway Retina (M & P) lateral geniculate nucleus (thalamus) primary visual cortex (V1) (coding of form, color, motion, position, depth) independence of M & P maintained Optic chiasm - axons from the nasal portion of each retina cross over to other side, while axons from the temporal side stay ipsalateral. This creates the left and right hemifields These axons end up in LGN and stay in centers divided into 6 layers by whether they are ipsa or contralateral within larger groups of whether they are M (layers 1 and 2) or P (layers 3-6) From LGN to V1, some axons go laterally into temporal lobe and are called Meyers Loop At V1 the visual field is represented topographically (upside down and reversed like retina) Left fovea on outermost part of right occipital lobe (left peripheral on medialmost) Upper fovea is below calcarine fissure (lower fovea is above calcarine fissure)

 Lesions and Scotomas Scotoma - blind area in visual field (homonopsia? Heteronopsia?) See Picture Geniculostriate Projection (LGN to V1) These projections end in layer 4C in alternating columns from the right and left eye From layer 4C, cells send axons to supragranular layers and this is the first time that information from the right and left eye is mixed allowing for the first bit of binocular vision Abnormal Visual Development Esotropia - one eye crossed inward (exotropia is one eye crossed outward) Monocular Deprivation - causes ocular dominace columns to develop Treatment can be to patch the non-deprived eye See Picture Monocular Cues for Depth Two eyes are not completely necessary for depth perception This section needs help Orientation Selectivity - some neurons in V1 are highly selective to the orientation of a moving bar of light (ie they only activate the most when the bar is at a certain angle)
Interestingly - if optic tract axons are forced to innervate the auditory thalamic nucleus instead of the LGN, the ATN will send visual stimulation to auditory cortex and it will process it

Cortical Processing Module - side-by-side ocular dominance columns comprised of numerous orientation columns Higher Order Visual Areas (Visual Processing Streams) From LGN V1 layer 4C V2 V3 V4 V5 Dorsal stream pathways - go from V1 to parietal cortex via MT These are for image movement and spatial relationships Ventral stream pathways - go from V1 to temporal cortex via V4 These are for color and perception with lots of specificity Face Recognition In monkeys the inferotemporal cortex is especially responsive to facial profile Seems to be same spot in humans? Prosopagnosia - inability to recognize faces (measure reaction time) Agnosias (dont know what we need to know) See picture

 Autonomic Nervous System

Objectives
Understand the basic functions of the autonomic nervous system underlying fight and flight and rest and digest behaviors Be able to identify the three main divisions of the ANS as well as their major functions, preganglionic inputs, postganglionic outputs, and targets Be able to describe the sensory componens of the ANS Be familiar with the chemistry of synaptic transmission in the ANS and its physiological implications Understand the concept of referred pain Be able to identify and explain the autonomic circuits that control heart rate, urination, and male sexual function

General Information
Autonomic nervous system is mainly a visceral motor system Main task is homeostasis Controlled by the hypothalamus via the dorsal longitudinal fasciculus Sympathetic Division - Fight and Flight Pathway = stress hypothalamus releases corticotropin-releasing hormone pituitary releases adrenocorticotropin into blood adrenal glands release epinephrine, norepinephrine and cortisol Epinephrine - blood pressure, HR, diverts blood to muscles Cortisol - releases glucose from body reserves General Effect - gut motility, dilation of the bronchioles, BP, sweating, pupillary dilation, piloerection, watery gland secretion (dry mouth) Normally feedback mechanisms turn it off when threat has passed Parasympathetic Division - Rest and Digest General Effect - maintaining basal heart rate, respiration, and metabolism under normal conditions

General Layout of ANS

Efferent Component Somatic Efferent System
Voluntary Innervates skeletal muscles Motor neuron cell bodies housed within CNS in cranial nerve nuclei and spinal cord ventral horn Monosynaptic pathway to effector All outputs are excitatory

Autonomic Efferent System

Involuntary Innervates smooth, cardiac and glandular cells Neuron cell bodies housed outside the CNS in peripheral autonomic ganglia Disynaptic pathway to effector, one synapse for preganglionic neuron, one for postganglionic Outputs are either excitatory or inhibitory depending on which subsystem

Afferent Component Somatic Afferent System

Conveys sensory info from head, neck, extremities, body wall to CNS Primary afferent cell bodies are in dorsal root, trigeminal, geniculate and superior ganglia Somatic nerves carry all types sensory info

Autonomic Afferent System

Conveys sensory info from viscera to CNS Primary afferent cell bodies are in DRGs or in sensory ganglia of CN IX and X Parasympathetic nerves - carry mechanosensory (often stretch) info Sympathetic nerves - generally carry pain and pressure info

Pain and pressure afferents travel in the same sympathetic nerve which provides efferent innervation to that organ Referred pain - both visceral sympathetic nerves (carrying pain and pressure) and somatic afferent cell bodies are located in the DRG and thus signals can get mixed

 Three Divisions of the ANS

Sympathetic Division Postganglionic Axons innervate Skin - sweat glands, blood vessels, piloerector muscles Head - eye, blood vessels, salivary, and lacrimal glands Viscera - smooth and cardiac muscles, digestive and urogenital organs Connections Preganglionic Neurons come from intermediolateral horn of T1-L2/L3 See picture Then there are Two choices spinal nerve white ramus synapse at paravertebral chain ganglia then exit via grey ramus upper levels usually do this one named ganglion is superior cervical ganglion - it supplies tarsal muscle to raise eyelid, lacrimal gland, dilates eye, salivary glands spinal nerve white ramus continue through paravertebral chain ganglia travel in splanchnic nerve synapse in prevertebral ganglia close to the target organs lower levels usually do this Exception - the only organ innervated by ANS that is not disynaptic is the adrenal medulla Receives innervation directly from spinal cord named ganglia include celiac plexus (supplies foregut), superior mesenteric plexus (supplies midgut), inferior mesenteric supplies hindgut Parasympathetic Division Postganglionic Innervation Head - eye, blood vessels, salivary glands Viscera - smooth and cardiac muscle, digestive and urogenital organs Connections Preganglionic neurons arise from either the brainstem or the sacral spinal cord and always project to ganglia near (or embedded in target organ) From Brain Stem
Midbrain Edinger-Westphal nucleus CN III cilliary ganglion cilliary and iris constrictor muscles Pons lacrimal nucleus CN VII pterygopalatine ganglion lacrimal gland Pons superior salivatory nucleus CN VII submandibular ganglion salivary gland Medulla inferior salivatory nucleus CN IX otic ganglion parotid gland (increased salivation) Medulla dorsal motor nucleus of vagal nerve CN X no ganglia viscera

From Sacral Spinal Cord From intermediolateral sacral cord at S2-S4 Preganglionic axons form the pelvic nerve and this innervates the descending colon, bladder, and external genitalia Erections = NO activates guanylate cyclase cGMP smooth muscle relaxation in corpus cavernosum Viagra - inhibits a phosphodiesterase that would normally degrade that cGMP Enteric Division Receives regulatory innervation from parasympathetic and sympathetic divisions of ANS Sympathetic innervation - occurs indirectly via the prevertebral ganglia and the postganglionic neurons innervate enteric neurons in the organs

 Parasympathetic innervation - occurs directly (without passing through a ganglion) from CN X and innervates enteric neurons in the organs Two interconnected plexi Myenteric (Auerbachs) plexus - lies between the external longitudinal and circular smooth muscle layers Submucous (Meissners) plexus - lies within the connective tissue of the supmucousa between the circular muscle and the mucosa

Physiology of the ANS

Synaptic Transmission Pre Post Uses acetylcholine for both sympathetic and parasympathetic systems Mainly uses nicotinic fast ACh receptors (sometimes uses slow muscarinic receptors) Post Effector Sympathetic - use norepinephrine Exception - sympathetic neurons innervating sweat glands use ACh Parasympathetic - use acetylcholine (NO is also released) Receptor cells use slow muscarinic ACh receptors and NO affects the cells directly Examples of Autonomic Control Cardiovascular Function Sympathetic Stimulation Caused by low levels of stimulation from mechanosensitive? baroreceptor afferents???? Norepinephrine from postganglionic neurons activates a G protein activates adenylate cyclase cAMP production activity of L-type Ca channels in the heart causing contractility and the interspike interval thus HR Parasympathetic Stimulation Caused by high levels of baroreceptor stimulation (mechanoreceptors) which signal BP ACh from postganglionic neurons activates muscarinic ACh receptors these activate K channels which causes hyperpolarization Ca thus contractility and interspike interval thus HR Bladder Sympathetic = T10-L2 preganglionics postganglionics internal sphincter contraction Inhibition of this allows internal sphincter to relax/open Parasympathectic = S2-S4 preganglionics postganglionics bladder wall contraction Afferents = bladder stretch afferent activity and excitation of parasympathetic preganglionic nuclei in S2-S4 this causes inhibition of sympathetic preganglionics in T10-T12 which relaxes internal sphincter Somatic = S2-S4 alpha motorneurons innervate striated muscle in external sphincter Tonic activation keeps this closed, tonic activity voluntarily inhibited during urination Sexual Function Afferents = erotic stimulation excites somatic sensory endings in penis parasympathetic Parasympathetic = S2-S4 preganglionics postganglionics dilates penile/clitoral arteries relaxes smooth muscles of venous sinusoids erection Sympathetic = T11-L2 preganglionics postganglionics vasoconstriction loss of erection Also innervates prostate and helps with ejaculation Somatic - lumbar and sacral alpha motor neurons help with ejaculation and orgasm

Clinical Correlations

Megacolon (Hirschsprungs disease) - caused by absence of ganglion cells in the myenteric plexus Results in extreme dilation and hypertrophy of the colon due to fecal retention Familial dysautonomia - caused by loss of neurons in autonomic and sensory ganglia Results in abnormal sweating, blood pressure instability, difficulty feeding due to inadequate muscle tone of GI tract and progressive sensory loss. Mainly affects Jewish children Raynauds Disease - idiopathic paroxysmal bilateral cyanosis of the digits due to aterial and arteriolar constriction caused by cold or emotion. Is painful and can be treated by preganglionic sympathectomy

 Introduction to Motor Systems and Reflexes

Objectives
Define the concept of motor unit Describe neural mechanisms regulating force production in muscles Recognize internal organization of motor pools (spinal cord & brainstem) and summarize somatotopic arrangement of motor neurons Describe classes of motor neurons Learn locations of interneurons and how they are combined into functional circuits Gain a general understanding of the contributions made to motorl control by motor cortex, premotor cortex, cerebellum and basal ganglia Recognize the various types of sensory receptors involved in spinal reflexes Describe the anatomic and functional pathways involved in the stretch reflex, withdrawl reflex and the Golgi tendon (lengthening) reflex Recognize the importance of supraspinal influences and Renshaw cell circuits which regulate spinal reflexes

Introduction
Motor systems contain multiple feedback pathways at all levels Feed-forward pathways - integration of sensory and other inputs into motor system planning operations Feed-back pathways - compare movements intended with those actually produced Motor systems have long term plasticity Basal Ganglia - involved in the initiation and maintenance of motor activity, particularly repetitive semi-automatic behaviors Also new motor tasks Cerebellum - involved in motor accuracy, learning and highly skilled movements that use sensory inputs to compare an intended motor pattern with feedback from movements that are taking place

Peripheral Motor Components

Curare - antagonist of the nicotinic ACh receptor Botulinum toxin - reduces muscle activity by blocking the release of ACh from nerve terminals Each skeletal muscle receives input from a single motor neuron but within that muscle, multiple fibers Motor Unit - a motor neuron and all of its muscle fibers Muscle fibers in a motor unit are spread out to distribute tension evenly An AP in a motor neuron always leads to a muscle action in the end fiber

Neural Mechanisms for Control of Force Within a Muscle

Recruitment Order (Size Principle) - Smaller motor units are first to become activated Smaller motor units usually have slow and non-fatiguing oxidative fibers, while larger motor units usually have fast twitch anaerobic fibers Number of Motor Units Activated - as force required so do the # of motor units AP Frequencies of Motor Neurons - frequency the force to an extent Partial Tetanus - summation of tension due to AP frequency and still some evidence of individual contraction seen Fused Tetanus - summation of tension due to AP frequency and no individual contractions seen

Location of Motor Neurons and Interneurons

Motor neuron pools - in the spinal cord, motor neurons that innervate a single muscle are clustered, often in columns Has somatotopic arrangement where at each level distal muscles are anterior and proximal muscles are located in medial portion of spinal cord Extensors are located ventrally and flexors are dorsal Interneurons - most are located in lamina VII and make inhibitory connections

Characteristics of Motor Neurons

-motor neurons - innervate skeletal muscles, which are extrafusal muscles receive many inputs (excitatory and inhibitory) and act as the final common pathway to innervation of the muscles Types of Circuit Inputs onto -Motor Neurons Divergence and Convergence Interneurons as Gates - another neuron will control opening or closing of gate Reverberating Circuit - involve negative feedback

 Rhythmic Alternation - a type of reverberating circuit using multiple interneurons and causes the flexor to be inhibited when the extensor is activated (and visa versa) -motor neurons - innervate intrafusal muscles located in muscle spindles Spinal Reflexes (Not Covered in Class) Monosynaptic Reflex - only two neural elements Polysynaptic Reflex - involves one or more interneurons Muscle Spindles A group of intrafusal muscle fibers with two types of sensory endings that detect velocity of stretching and absolute length of a muscle Arranged in parallel with extrafusal muscles Surrounded by a CT capsule connecting the spindle to the tendon and muscle Contain Nuclear bag fibers - larger fibers with many nuclei congregated in expanded center Nuclear chain fibers - thin fibers with nuclei arranged in series Primary sensory ending/annulospiral ending - on nuclear chain and bag fibers Give rise to large diameter, faster conducting axons End directly on synergistic muscles, connect via interneurons to antagonistic muscles Secondary sensory ending/flower spray ending - on nuclear chain fibers Give rise to small diameter, slower conducting axons, connect only via interneurons Reflexes Phasic/DeepTendon Stretch Reflex - tap tendon with hammer causes excitation of homonymous muscle via monosynaptic signal and inhibition of antagonistic muscle via polysynaptic signal knee jerk Phasic response occurs when muscle elongates Tonic Stretch Reflex - is a response to any maintained change in length of a muscle Is a polysynaptic reflex, responsible for muscle tone Tonic response occurs when stretch is maintained Golgi Tendon Organs Encapsulated sensory receptors with type Ib axons that are sensitive to tension and located within the tendon When muscle tension suddenly increases then large increase in APs (otherwise has static response) Lengthening/Golgi Tendon Reflex - prevents too much tension on the muscle by inhibiting synergistic muscles and fascilitating antagonistic muscles Is polysynaptic Withdrawl/Flexion Reflex - polysynaptic reflex caused by noxious stimuli (sensory input) Can be elicited even when spinal cord is transected above reflex center Flexion reflex disappears in deep unconsciousness Modulation of Reflexes -Motor Neuron Effects - can modulate the sensitivity of the intrafusal muscle fibers by producing tension changes in these fibers modify threshold for reflex contraction of somatic muscles this is called the gamma loop Renshaw Cells - inhibitory interneurons in the spinal cord that stabilize the discharge frequency of motor neuron pools

Motor System Syndromes

Upper Motor Neuron Syndrome - caused by a lesion to descending pathways to interneurons, which then causes an unbalance in excitation and inhibition in some motor circuits Results in changes in amplitude of reflexes and loss of motor control Lower Motor Neuron Syndrome - caused by damage to motor neurons and results in abnormal electrical activity, muscle degeneration, reduction in reflex activity of that muscle, and weakness

 Motor Systems and Spinal Cord Lesions

Objectives
Review location and inputs to lower motor neurons Describe the origin and termination for the four supraspinal descending motor tracts, make sure to include the details of their pathway Describe the differences in the sensory and motor loss for the following: peripheral nerve lesion, dorsal root lesion, ventral root lesion List the signs of a lower motor neuron lesion. Be sure you understand the underlying cause for each symptom listed List the signs of an upper motor neuron lesion. Be sure you understand the underlying cause for each symptom listed Describe the effect of the spinal cord lesions discussed in class. Make sure to explain both the sensory and motor changes for each lesion

Lower Motor Neurons (Alpha Motor Neurons)

Location Ventral Horn of Spinal Cord Has Somatotopic organization Medial - proximal motor neurons (axial core) Ventral - extensor motor neurons Anterior - distal motor neurons Dorsal portion of ventral horn - flexor motor neurons Cranial Nerve nuclei of Brainstem What can influence activity of LMN? Sensory Fibers Input from muscle spindles - can monosynaptically influence LMN Input from golgi tendon organs - use interneuron to influence LMN Renshaw Cells - inhibitory to LMN Directly influenced by axon collateral (an offshoot) of the LMN Upper Motor Neurons - descending motor systems 4 pathways, 3 use interneuron to talk to LMN and originate in brainstem (vestibulospinal, rubrospinal, reticulospinal) and the other influences LMN directly and originates in the cortex (coticospinal) Vestibulospinal Tract (has two subdivisions) Does not cross midline Origin of tract - medial or lateral vestibular nuclei Termination of tract Medial - cervical spinal cord Lateral - limb and trunk extensors Primary Function Medial - regulates head position, controls neck muscles Lateral - controls antigravity and posture muscles, coordination of head and body in space influenced by cerebellum Reticulospinal Tract Does not cross midline Origin of tract - reticular nuclei/formation in the core of the pons and medulla Termination of tract - on LMN throughout spinal cord so they excite trunk and limb extensors and inhibit their flexors Primary function - posture, anticipatory action, planning movements Can be influenced by hypothalamus, cerebrum, brainstem Rubrospinal Tract Decussates at midline Origin of tract - red nucleus

 Termination of tract - on LMN throughout spinal cord so they excite upper limb flexors and inhibit their extensors Primary function - modify newly acquired tasks of upper limb Can be influenced by cerebellum and cerebrum Corticospinal Tract Decussates in medulla at pyramidal decussation Origin - primary motor cortex, specifically Layer V axons premotor cortex contributes 30% of the axons premotor cortex receives multisensory input, provides appropriate actions in context, allows expression of emotion, coordinates eye movement Pathway - Know anatomy/pathway of this tract (SEE SHEET) Termination - mostly directly on LMN Function - distal musculature, fine and coordinated movements, highly skilled/agile actions All of the tracts have a general locations within a cross section of the spinal cord SEE SHEET Lesions Peripheral Nerve Lesion Sensory Loss - loss of all sensory modalities along corresponding dermatome Motor Loss - weakness (not complete loss) of every muscle innervated by that nerve Dorsal Root Lesion - same sensory loss, no motor loss Ventral Root Lesion - no sensory loss, same motor loss LMN Lesion (in the spinal cord) Sensory Loss - none Motor Loss weakness (not complete loss) of every muscle innervated by that nerve hyporeflexia (can be areflexia) of deep tendon reflex hypotonia - directly related to stretch reflex muscle atrophy UMN Lesion Sensory Loss - none Motor Loss Muscle weakness and less voluntary control Hyperreflexia - related to over-responsiveness of golgi tendon organ Spastic movements Clonis - rapid, repeating, alternating movements Babinski reflex - toes raise instead of curl downwards upon stimulation of sole of foot Spinal Cord Lesions Complete Transection of Spinal Cord Sensory Loss - bilateral loss of all modalities below level of lesion Motor Loss - bilateral UPN signs below lesion LMN signs at site of lesion Reflexes - hyperreflexia below lesion, hyporeflexia at site of lesion Hemisection of Spinal Cord Sensory Loss - ipsalateral loss of touch and proprioception ~ contralateral loss of pain and temp Motor Loss - ipsalateral UMN below lesion Ipsalateral LMN signs at site of lesion Reflexes - ipsalateral hyperreflexia below lesion, ipsalateral hyporeflexia at site of lesion Springomyelia - Lesion of central grey due to central canal getting bigger Sensory Loss - bilateral pain and temp loss at specific dermatomes Motor Loss - initially, no motor loss

Reflexes - initially, no change Poliomyelitis - Lesion to ventral horn cells of spinal cord (virus attacks LMN) Sensory Loss - none Motor Loss - LMN signs at site (loss of muscle tone) Reflexes - absent or decreased reflexes at site Amyotropic lateral sclerosis (Lou Gherigs) - Lesion of ventral horn and corticospinal tracts Attacks UMNs and LMNs, progressive and fatal Sensory Loss - none Motor Loss - mixed symptoms of LMN and UMN Reflexes - atrophy & hyporeflexia and spasticity & hyperreflexia Lesion of central spinal cord Caused by whiplash (hyperextension of cervical spine, generally dorsal columns are spared) Sensory Loss - bilateral pain and temp loss at cervical dermatome Motor Loss - LMN signs for affected levels of cord at lesion Can affect UMN signs with sacral sparing below lesion Reflexes - hyporeflexia at lesion Lesion of Anterior (Ventral) spinal cord only thing spared is dorsal column caused by thrombus in anterior spinal artery Sensory Loss - bilateral loss of pain and temp (in tact touch and proprioception since dorsal column spared) Motor Loss - bilateral UMN signs below lesion, bilateral LMN signs at lesion

 Clinical Electrophysiology and Neuromuscular Disease

Objectives
Get a brief overview of diseases affecting the peripheral nervous system (muscle and nerve diseases) Understand the basis for recording electrical activity from muscle and nerve Learn how various disease states affect this electrical activity Understand how electromyography and nerve conduction studies help clinicians diagnose diseases of the PNS

Peripheral Neuropathy
Injury to cell body can lead to pathological changes in the axon Schwann cells envelop a single axon in the PNS and myelinate it Death of axon results in breakdown of myelin, but not of Schwan cell Symptoms occur distally first - this is characteristic of neuropathy Cranial nerves can be affected too Types Axonal Neuropathy Main characteristic is that conduction velocity of the nerve is normal or low normal Trophic influence of nerve on mucle is lost so the muscle atrophies Distal part of axon starts dying back first Long, large diameter fibers affected first Causes
Metabolic - uremia, diabetes, endocrine Vitamine Deficiency - thiamine, pyridoxine, B12 Toxins (common) - hexane, lead, arsenic Drugs - phenytoin, vincristine

Demyelination Neuropathy/Myelinopathy Main characteristic is conduction velocity due to abnormality of Schwann cell Axon is still in tact Examples - Lyme disease, HIV, Guillian Barre - immune mediated attack on PNS myelin Asymmetric Neuropathy and Mononeuropathy Usually due to compression of a nerve axon or bundle of them Examples - median nerve at wrist, ulnar nerve at elbow, sciatic nerve Neuromuscular Junction Disease Myasthenia Gravis - antibodies attack acetylcholine receptor of NMJ Symptoms - typically affects small muscles (eye muscles causing diplopia, eyelid causing ptosis, difficulty talking and swallowing Weakness is episodic and precipitated by exertion, relieved by rest

Muscle Diseases
Involve problems with larger muscles, proximal muscles of arms and legs Cant get up stairs, get up from a chair etc. Types Inherited - long duration, typical distribution of weakness Dystrophies - ex. Duchenne muscular dystrophy (X linked) Acquired - shorter duration, no family history, can be drug induced Causes - poliomyelitis (inflammatory), drugs (steroids and cholesterol lowering drugs), potassium deficiency Endocrine problems - Cushings disease, hyperthyroidism, hypothyroidism Root Disease - Root being compressed Asymmetric involvement Root pains and motor and sensory defect in distribution of a specific root

Electrodiagnosis
Use electrodiagnosis along with imaging studies to get the best diagnosis Types of Procedures

 Motor Nerve Conduction - nerve stimulated at a specific point and the amount of time the stimulation takes to get to the muscle is measured Then you calculate conduction velocity (normal = 40-60 m/s) Sensory Nerve Condution - same as motor nerve conduction, but more difficult Late Responses (F wave) - measures proximal PNS response by stimulating distal PNS If you give enough stimulation, you will see the response that goes up nerve, to ventral root then back down to distal limb as an F wave EMG (electromyography) - stick an electrode in the muscle and you can detect changes induced by denervation or primary muscle disease due to alterations in muscle membrane excitability and motor unit architecture Abnormalities to look for Changes in Spontaneous Activity Normal muscle shows no activity at rest Denervated (injured muscle) shows spontaneous activity at rest 10-14 days after injury Fibrillations - abnormal activity from a single muscle fiber, seen at acute stage Fasiculations - abnormal activity from fiber bundles, seen in chronic stage (seen without EMG) Changes in Motor Unit Potential If Myopathic Injury then there will be a smaller motor unit that causes a smaller peak If Neurogenic Injury then there will be a large peak because the nerve? recruits a lot of muscle fibers

The Neurological Examination

Objectives
Learn how to plan a clinical examination of the CNS Become familiar with the various areas to be examined (mental and speech functions, cranial nerves, motor and sensory system, reflexes, gait and coordination etc.) Learn the correct technique for performing the neurological examination

Get Notes noor.pirzada@utoledo.edu

 Cranial Nerves I-VI

Objectives
Describe how to examine each cranial nerve Localize cranial nerve or pathway lesions based on the functional deficits produced Use your knowledge of cranial nerve anatomy to solve neurological cases

Clinical Significance of Cranial Nerves

Provide direct window into brain function CN reflexes are often presereved in coma Help determine prognosis for recovery

Olfactory Nerve Lesion (I)

Has no thalamic relay, goes direct to cortex Much of taste is actually smell, so people with olfactory nerve lesions could lose weight Major Projections
Stria medullaris thalami - olfactory areas to habenula Stria terminalis - amygdala to anterior hypothalamus Medial Forebrain bundle - connects olfactory areas to hypothalamus Habenula and hypothalamus then project to the reticular formation, salivatory nuclei, DMN of X for visceral responses

Lesion can be caused by blunt force and this blunt force can fracture skull and cause CSF to leak, this poses risk of infection How to Test CN I Test each nostril separately with scratch-n-sniff cards

Optic Nerve Lesion (II)

Is a direct extension of the brain Pattern of visual disturbance helps localize the lesion The lens inverts and reverses the image onto the retina optic nerve and tract preserves retinotopic organization Optic Radiations (Pathways to Optic Cortex) Parietal Radiation - carries fibers for the inferior visual field Meyers Loop - carries fibers for the superior visual field Homonymous - if visual field loss is symmetrical in both eyes
Ex - lesion to right optic tract causes left homonymous hemianopia Ex - lesion to right optic nerve causes right eye blindness Ex - lesion to optic chiasm causes bitemporal hemianopia

hole in center vision can be an early sign of demyelination of CN II due to multiple sclerosis How to test CN II Test visual acuity (often with just a near card) Test visual field - hold up fingers on both sides while patient looks straight ahead Fundoscopy Pupillary Reflex Normal - shine a light in one eye both pupils contract shine a light in the other eye both pupils contract have patient focus on near object pupils contract (Edinger Westfall nucleus (EWN) also can cause relaxation of suspensory ligaments of lens) Afferent Loop - light info sent to midbrain (superior colliculus), then to EWN Efferent Loop - EWN sends parasympathetic signal to constrict pupillary sphincter muscle of both eyes causing consensual constriction Afferent Loop Lesion - less light detected in eye with lesion shine a light in good eye both pupils contract shine a light in the bad eye neither pupil contracts have patient focus on near object pupils contract pupils contract with accomadation because it is a stronger stimulus than light Efferent Loop Lesion - light detected, but lesion prevents constriction on that side

 shine a light in good eye pupil of good eye contracts, pupil of bad eye doesnt shine a light in the bad eye pupil of good eye contracts, pupil of bad eye doesnt have patient focus on near object pupil of good eye contracts, pupil of bad eye doesnt

Oculomotor Lesion (III)

Controls all extraocular muscles (except for superior oblique (IV) and lateral rectus (VI)) See picture when eye is laterally directed the inferior oblique extorts the eye when eye is medially directed the inferior oblique raises the eye Nuclei - in medial midbrain, ventral to cerebral aquaduct. Has multiple subnuclei From the Edinger Westfall nucleus, parasympathetics control constrictor pupillae and the cilliary muscles (how is this possible?? Doesnt CN II do this??) Symptoms Eye is down and out/abducted due to unopposed IV (superior oblique) and VI (lateral rectus) Mydriasis - dilated pupil Ptosis - lid droop Causes

Midbrain strokes - Weber syndrome (midbrain stroke with contralateral weakness), Benedict syndrome (midbrain stroke with contralateral tremor) Infection or thrombosis of cavernous sinus Infacrt of IIIrd nerve (due to diabetes) - here you get pupil sparing since parasympathetic fibers travel superficially in nerve

Trochlear Nerve Lesion (IV)

Controls contralateral superior oblique When eye is laterally directed the superior oblique intorts the eye When eye is medially directed the superior oblique lowers the eye Nucleus - in midbrain, caudal to III Exits dorsal midbrain just below inferior colliculus Crosses arteries and thus is vulnerable to aneurysms Symptoms Extorsion of eye due to pull of other muscles, loss of downgaze in medial position Patients tilt head toward the unaffected side to compensate Head tilts away from nerve lesion, toward brainstem lesion (since the nerve decussates) Tilting head gets rid of double vision

Trigeminal Nerve Lesion (V)

Sensory - Ophthalmic (V1) and Maxillary (V2) Travel in cavernous sinuses?? and receive sensory info from face Ophthalmic nerve exits skull at superior orbital fissure Maxillary nerve exits skull at foramen rotundum Sensory fibers synapse in trigeminal ganglion Sensory nucleus is very large, extends from midbrain to C2 of spinal cord Contains subnuclei?? Mesencephalic nucleus, pontine nucleus, nucleus of spinal tract of V Motor - Mandibular (V3) Innervates muscles of mastication, tensor tympani, etc. masticator nucleus is in mid pons If unilateral lesion, chewing isnt affected because you only need one sides muscles Motor and Sensory - Mandibular (V3)

 Motor and sensory branches from mandibular nerve Exits skull at foramen ovale Symptoms Trigeminal Neuralgia (Tic Doloureux) - causes severe stabbing pain in maxillary nerve area Unknown cause, could be due to pressure on CN V from arteries when it exits pons Controlled with anticonvulsants because they decrease excessive nerve firing

Abducens Nerve Lesion (VI)

Controls lateral rectus muscle Nucleus - in dorsal pons, near midline Axons of facial nerve loop around abducens nucleus and create the facial colliculus on the floor of the 4th ventricle Axons exit brainstem at pontomedullary junction Symptoms - diplopia (when attempting lateral gaze) due to lateral rectus weakness (inability to abduct (move away from midline)) Strabismus - inability to direct both eyes to a target Causes - aneurysms, tumors, inflammation, infection, fractures Coordination of Lateral Gaze Initiated in Brodmanns Area 8 Fibers cross in pons, innervate lateral gaze center (PPRF) in pons at level of abducens nucleus Fibers travel in median longitudinal fasciculus PPRF sends excitatory input to ipsilateral VI nucleus, which causes abduction of the ipsilateral eye PPRF sends excitatory input to contralateral III nucleus, which causes adduction in contralateral eye

Rules of Diplopia
False image is always the outer image False image always comes from the affected eye You have to cover each eye to see which one generates the false (outer) image

Cranial Nerves VII - XII

Objectives
Know the major modalities and anatomical pathways of the cranial nerves Describe how to examine each cranial nerve Localize cranial nerve or pathway lesions based on the functional deficits produced

Facial Nerve Lesion (VII)

Components Visceral motor - to lacrimal, submandibular, sublingual glands (of mouth), mucous membranes of nose Sensory - small part of external ear Special Sense - taste from anterior 2/3 of tongue via chorda tympani Branchial motor - to stapedius, facial expression muscles Facial expression initiated in motor cortex Different cortical innervation (from facial nucleus) for upper and lower face Bilateral input for upper face Contralateral input for lower face Lesions Unilateral UMN lesions - cause only lower facial weakness (forehead and eye closure intact) Unilateral LMN lesions - cause weakness to entire side Bells Palsy - idiopathic form of this, sometimes caused by herpes zoster Reflexes affected by problems with branchial motor component Blink reflex to light, corneal stimulation, and noise Stapedius reflex (which tenses eardrum) upon loud noise

 Problems with this cause sounds to be louder Suck and snout reflexes to oral stimulation in infants

Vestibulocochlear Nerve Lesion (VIII)

Auditory and vestibular components travel together Cochlea spiral ganglion cochlear nuclei in lower lateral pons Vestibular apparatus vestibular ganglia vestibular nuclei in lower lateral pons Auditory Component Tonotopic organization High frequencies absorbed at base of cochlea fibers synapse at dorsal cochlear nuclei Low frequencies generated at apex of cochlea fibers synapse at ventral cochlear nuclei Central Auditory Pathways
(probably dont need to memorize pathways because they are more complex than what I am writing) Most cochlear neurons contralateral lateral lemniscus superior olivary nucleus Other fibers (from ventral cochlea) form trapezoid body then join lateral lemniscus Lateral lemniscus inferior colliculus inferior brachium medial geniculate nucleus of thalamus superior temporal gyrus

Pathways are bilateral above level of cochlear nuclei Lesions above vestibulocochlear nuclei rarely result in hearing loss Testing Hearing Rub Fingers next to each ear, see if heard equally Weber Test - place tuning fork on vertex of head, if normal then heard equally in both ears Tests for sensorineural hearing loss Rinne Test - (test if bone hearing or air hearing is better) place tuning fork on vetex of head, when they cant hear it anymore move it to just outside ear and they should be able to hear it Tests for conductive hearing loss The Weber and Rinne tests are only interpretable together If Weber test says fork louder in affected ear (due to less masking that would happen if the conductive system was working properly) and the Rinne test has bone conduction being louder than air conduction in affected ear conductive loss in that ear If Weber test says fork louder in unaffected ear and Rinne test has air conduction being louder than bone conduction in affected ear sensorineural loss in that ear Vestibular (balance) Component Vestibular nuclei project to cerebellum via inferior cerebellar peduncle Lateral Nucleus - projects to spinal cord via vestibulospinal tract Influences tone of antigravity muscles Projects to MLF to influence III, IV and VI to help coordinate eye movements with body Testing Vestibular Nuclei in Coma Dolls eyes - turning head produces eye movement to keep eyes gazing in same direction Cold Calorics - put cold water in ear eyes will move toward the cold water

Glossopharyngeal Nerve Lesion (IX)

Mostly to tongue and pharynx Emerges from medulla between inferior olive and inferior cerebellar peduncle Components Brachial Motor - to stylopharyngeus (from nucleus ambiguous) Elevates pharynx during swallowing, speech, gag reflex Visceral Motor - to parotid gland (salivatory) and otic ganglion (from nucleus ambiguous) Otic ganglion involved with mucous membranes of middle ear, auditory tube, mastoid air cells Visceral Sensory - from carotid body and carotid sinus (to solitary nucleus) Sensory - from posterior 1/3 of tongue (to spinal nucleus of trigeminal nerve) Special Sensory - from posterior 1/3 of tongue (to solitary nucleus) Symptoms

 Fainting - can be due to stimulation of brainstem nuclei that regulate blood pressure causing BP Issues swallowing or gagging - swallowing causes brainstem to inhibit gag reflex Glossopharyngeal Neuralgia - like trigeminal neuralgia in that excessive nerve firing causes pain Cause is usually unknown, anticonvulsants help Testing Glossopharyngeal Nerve - test gag reflex

Vagus Nerve Lesions (X)

Components Brachial Motor - to striated muscle of pharynx, palatoglossus, larynx from nucleus ambiguous Lesion to pharynx innervation causes droop of palate on affected side Lesion to larynx muscles causes vocal cord paralysis, hoarseness Visceral Motor - to smooth muscle of pharynx, larynx, thoracic and abdominal viscera from dorsal motor nucleus of Vagus (on floor of 4th ventricle) Parasympathetic innervation (used to cut this to reduce ulcers) Slow heart rate, bronchioconstriction (which can cause coughing and shortness of breath) Visceral Sensory - from larynx trachea, esophagus, thoracic & abd viscera, stretch and chemoreceptors of aortic arch to inferior vagal ganglion then solitary nucleus Sensory - from skin of back of ear, external surface of tympanic membrane, pharynx To superior vagal ganglion then to spinal nucleus of trigeminal nerve Paths Exits via jugular fossa superior or inferior ganglia descends in carotid sheath between carotid and jugular splits into right and left side Testing IX and X Generally tested together because they are hard to distinguish Test gag reflex by swabbing back of pharynx See if soft palate elevates upon phonation (say ahhh) Vagus nerve stimulation can be used to control seizures for some reason

Spinal Accessory Nerve Lesions (XI)

Innervates trapezius and sternocleidomastoid muscles Nuclei - cell bodies in lateral spinal cord anterior gray (same cell column as nucleus ambiguous?) Fibers exit lateral cord at C1-C5 and ascend through foramen magnum, join IX, X Symptoms Cant turn head away from side of nerve lesion Ipsilateral shoulder drop Tests - test shoulder shrug, test ability to turn head against resistance Can be affected by neck surgery, pressure on trapezius etc. Affected by UMN lesions of opposite cortex

Hypoglossal Nerve Lesions (XII)

Supplies all but one tongue muscle Nuclei - in medulla at dorsal midline, medial to the dorsal motor nucleus of X Symptoms LMN lesion causes tongue deviation toward side of lesion UPN lesion causes tongue deviation away from side of lesion

 Cerebellum Objectives
Describe the macroscopic and microscopic anatomy of the cerebellum. Know the divisions of the cerebellum, the names and locations of the cerebellar nuclei, and the main input and output pathways concerned with the clinical relevance of the cerebellum Understand the location, function and interconnections between the various cerebellar neurons with regard to cerebellar modulation of motor pathways List the typical clinical syndromes of cerebellar dysfunction and usual associated clinical signs

Allows you to learn repeated movement tasks like how far & fast to move Right side of cerebellum affects right side of body because pathways cross twice (contralateral input and contralateral output)

Clinical Anatomy
Vermis - midline region of cerebellum Cerebellar hemispheres - the lateral portions
Anterior lobe primary fissure posterior lobe posterolateral fissure flocculonodular lobe

Cerebellar Nuclei Listed medial to lateral = fastigial, interpositus (made of globose and emboliform) and dentate Corresponds to medial, intermediate and lateral zone (defined by the nuclei) Around midline of cerebellum Receive input from cerebellar cortex and afferents. Are mains source of cerebellar efferents. Flatten cerebellum Vestibulocerebllum - includes flocculus and nodulus Receives input from the vestibular nuclei in the brainstem Mostly involved in posture and equilibrium Spinocerebellum - includes vermis as well as part of the intermediate zone Vermis - proximal muscle movement and vestibuloocular responses Median spinocerebellum - only area to receive direct input from the spinal cord Lateral spinocerebellum - involved in larger movements of walking and running Cerebrocerebellum - lateral aspects of both the anterior and posterior lobes and includes the dentate nucleus Allows for tasks of fine dexterity, makes us human Connections to Brainstem Inferior Cerebellar Peduncle Connects to the medulla and carries afferent and efferent fibers Contains dorsal spinocerebellar tract (originates in Clarkes nucleus) - receives proprioceptive input from the trunk and ipsilateral leg Contains cuneocerebellar, olivocerebellar, vestibulocerebellar and reticulocerebellar tracts Middle Cerebellar Peduncle Connects to the pons and carries only afferent (input) fibers Contains pontocerebellar tract - gets impulses from contralateral pontine nuclei, which come from cerebral cortex Superior Cerebellar Peduncle Connects to the midbrain and carries some afferent but mostly efferent fibers Afferent anterior spinocerebellar tract - proprioception from trunk and legs

 tectocerebellar tract - integrates auditory and visual information from inferior and superior colliculi Efferent Dentatorubral tract - to contralateral red nucleus Dentothalamic tract - to contralateral VL nucleus of thalamus

Microanatomy and Physiology

This section needs help Name Originates in
Mossy Fibers Pontine nuclei and spinocerebellar pathways Inferior olivary nuclei Granular cell layer Upper granular cell layer Purkinje cell layer Purkinje and lower molecular cell layers Molecular cell layer

Outflow to Granule Cell Layer

Granule cells and deep cerebellar nuclei neurons (do fine tasks?) Purkinje cells Parallel fibers contact a multitude of Purkinje cells Dendrites of granule cells

Net Effect
Activates granule cells and efferent cerebellar nuclei Localized bursting of Purkinje cell activity Activates Purkinje cells Inhibits granule cells Inhibit deep cerebellar nuclear outflow Inhibit nearby Purkinje cells

Climbing Fibers Granule Cells Golgi Cells Purkinje cells Basket cells

Purkinje Cell Layer

Deep cerebellar nuclear cells Purkinje cells (periphery)

Molecular Cell Layer

Stellate Purkinje cells Inhibit nearby Purkinje cells

See Picture every time you practive a movement/task, the synapses of the stellate and basket cells get more and more mature and numerous and better at shutting down the surrounding area, allowing a more focused areas of Purkinje cells to be activated selectively Main inputs into cerebellum are Mossy fibers from spinocerebellar pathways Mossy fibers from pons Climbing fibers from inferior olive
Activation of a bundle of parallel fibers will lead to activation of a row of Purkinje cells just above. Simultaneously, the Purkinje cells in the flanking areas will be inhibited by the action of basket and stellate cells (which are also activated by parallel fibers). These populations of activated and inhibited Purkinje cells will cause, respectively, inhibition and disinhibition of cerebellar nuclear cells via the corticonuclear pathway

Cerebellar Syndromes
Midline cerebellar syndrome - typically seen in alcoholic cerebellar degeneration Symptoms - wide based stance and gait Ataxia of gait, but intact finger-nose-finger and heel-knee-shin testing Occasional hypotonia, nystagmus and dysarthria Hemispheric cerebellar syndrome - typically seen in infarcts, hemorrhages, tumors, MS Symptoms - incoordination of ipsilateral arm and leg movements Ataxia, dysmetria, dysarthria, tremor, nystagmus, dysrhythmia, etc. Pancerebellar syndrome - typically seen in infections, parainfections, paraneoplastic and neurodegenerative disorders Symptoms - all of the above

 Basal Ganglia
Objectives
Describe the macroscopic and microscopic anatomy of the basal ganglia Know the neurotransmitters and the main receptor classes involved in the basal ganglia circuitry with thalamus and cerebral cortex Understand the differential effects of dopamine at D1 versus D2 receptors and the mechanism whereby these differential effects lead to balance between the direct and indirect pathways Understand the physiological/neurochemical imbalances in the direct/indirect pathways that lead to and/or produce the syndromes/symptoms of the Parkinsons, Huntingtons and hemiballismus

Allows you to initiate novel movement tasks Anything that affects the basal ganglia will affect the whole person (emotions, movement, etc.) Exists in parallel with the cerebellum to modify motor activity Both cerebellum and basal ganglia connections go through the thalamus

Macroscopic Anatomy of the Basal Ganglia

Dorsal Striatum - includes caudate nucleus and putamen Ventral Striatum - includes the nucleus accumbens, olfactory tubercle and amygdala Globus Pallidus - consists of an external (lateral) (GPe) and an internal (medial) (GPi) segment Subthalamic Nucleus Substantia nigra pars compacta (SNpc) - contains highly pigmented dopaminergic neurons Substantia nigra pars reticulata (SNpr) -

Microscopic and neurochemical anatomy of the basal ganglia

Components of striatum Striasomes - islands of cells enriched in medium spiny neurons (MSN), expressing D1 receptors Uses GABA, substance P and dynorphin Matrix - surrounds striasomes, enriched in MSNs expressing D2 receptors Uses GABA and enkephalin as the neuropeptide Giant aspiny neurons - use acetylcholine as their neurotransmitter The modulatory effects of the striatopalladial pathways are dependent on the differential effects of dopamine at D1 and D2 and the subsequent stimulation/inhibition that results downstream Glutamate also affects things

Input and Output of the Basal Ganglia

Areas that have direct input to the striatum - prefrontal cortex, premotor cortex, motor cortex, parietotemporo-occipital cortex and cingulate cortex Direct Pathway Uses GABA as the neurotransmitter (thus is inhibitory) Substance P and dynorphin are associated neuropeptides SNpc D1 receptors in Striatum GPi/SNpr complex thalamus Net result is to inhibit the thalamic inhibition (net increase in thalamic activity) Indirect Pathway Uses GABA (thus is inhibitory) unless noted otherwise SNpc D2 receptors in Striatum (Matrix?) GPe Subthalamic nucleus excitatory input to GPi/SNpr complex via glutamate inhibitory signal via GABA (again) to thalamus Net result is to increase thalamic inhibition (net decrease in thalamic activity)

Diseases
Parkinsons Disease (A hypokinetic disorder) Someone with severe Parkinsons can still catch a ball spontaneously because this signal goes directly to cerebellum and bypasses basal ganglia Main problem - SNpc has diminished or no significant release of dopamine into striatum Causes - lack of stimulation to D1 receptors, lack of inhibition of D2 receptors Direct pathway is thus is overactivity of GPi/SNpr complex

 Indirect pathway is thus overinhibition of GPe causing less inhibition of subthalamic nucleus which then overexcites the GPi/SNpr complex causing large inhibition of thalamus Excessive inhibition thalamus bradykinesia (decreased spontaneous movement), rigidity on passive manipulation, resting tremor, postural instability If given too much dopamine as treatment for Parkinsons then Huntingtons symptoms can occur Huntingtons Disease (A hyperkinetic disorder) Main problem - deficiency of striatal neurons expressing D2 Causes - problem with indirect pathway D2 in striatum signal is weak GPe less inhibited by D2 cells GPe becomes overactive overinhibition of subthalamic nucleus less excitation signals from STN to GPi/SNpr complex less inhibition signal sent out from complex to thalamus thalamus overactive Overactivity of thalamus choreiform activity Hemiballismus Main Problem - injury to subthalamic nucleus Causes too little excitatory output from STN GPi/SNpr complex does not produce enough inhibitory signals thalamus overactive This type of overactivity of thalamus results in intense flailing movements of one side of body

 Cortical Motor Systems and Eye Movements

Objectives
Explain corticospinal projections to motor neurons (remember that most actually terminate on interneurons) Explain the functional organization of the primary motor cortex including gross topography, fine structure, coding of movement direction and amplitude Explain corticospinal areas in addition to M1, (the projections and the division of labor in organizing and sequencing movements) Explain pyramidal and extrapyramidal cooperation Describe the sensory input required, movement characteristics, and contributions of cortical and subcortical control centers for the vestibulo-ocular response, optokinetic nystagmus, saccades, and visual pursuit

Corticospinal Tracts
Pyramidal Tracts Lateral corticospinal tract - to motor neuron pools Ventral (anterior) corticospinal tract - to axial muscles They originate from three areas in roughly similar propotions Primary motor cortex, premotor and supplementary motor cortex, and somatosensory cortex Depending on where the projections originate from, this will determine which lamina on the grey matter in the spinal cord they terminate on Motor related projections (primary motor cortex, proprioceptive somatosensory) end on middle lamina (interneurons and motor neurons) Sensory related projections (tactile somatosensory, parietal association cortex) end on upper lamina (control sensory processing and reflex afferents) Corticobulbar tract - to brainstem nuclei

Random Notes
A descending axon can activate multiple motor neuron pools at different spinal segments Smart animals have direct connections from brain to motor neuron pools better control Dumb animals have indirect connections (using interneurons) Certain neurons in the motor cortex are active before and during actions in one direction, but silent if the movement is in another direction Each neuron has a preferred direction Motor cortex somatotopy is not as simple as we were lead to believe Originally it was mapped by just stimulating the outer portion of cortex Really, cells controlling any particular area have pools that are dispersed through the cortex The map is organized more by movement pattern/function rather than single muscles fMRI patterns before and after learning a movement sequence in the motor cortex the trained sequence lights up more of the brain than the new sequence premotor and supplementary motor cortex also light up?? Supplementary Motor Cortex - involved in motor planning (and imagined movement) Organizes movements cued internally and not involving specific visual signal or spatial guidance Premotor Cortex - active when preparing a muscle to move? active before responding to signal to move; are directional Organizes visual information about spatial relationships and external timing to control movements Red Nucleus - receives inputs from motor cortex that then go to cerebellum and spinal cord? Eye Movement Control (Not covered in class) Basic Facts Saccades are controlled by the superior colliculus Vestibular nuclei have important connections with the oculomotor nuclei and they are all tied in at the medial longitudinal fasciculus Retina lateral geniculate nucleus (LGN) V1 M pathway dorsal stream motor cortex information about moving targets and spatial relationships

 Also to premotor cortex to cue grasping and reaching movements Conjugate Eye Movements Vestibulo-Ocular Reflexes (VOR) Sensory Input - vestibular, thus can occur in dark Movement Characteristics - causes the eyes to turn at the same speed as head rotation, but in the opposite direction Circuitry - vestibular nuclei MLF activate contralateral abducens and ipsalateral oculomotor nucleus inhibit ipsalateral abducens and contralateral oculomotor nucleus Shows accommodation if turning is continuous and endolymph doesnt register movement Is the Dolls Eyes thing Optokinetic Nystagmus (OKN) Sensory Input - visual Movement Characteristics - person is not moving, but visual scene is (looking out car window) Eyes track in the same direction as the moving scene at the same speed and quickly snap back (saccade) when they cant move any more Circuitry - not known Does not accommodate and only works for relatively slow rotations Saccades Sensory input - voluntary or reflex Voluntary saccades - can be done in the dark without visual stimulus Reflex saccades - produced by superior colliculus, and do require sensory stimulus, which could be auditory, visual, somatosensory etc. Movement Characteristics - rapid shifts of gaze to fix the fovea on specific targets Circuitry - Frontal Eye Field (in frontal lobe) superior colliculus (or can bypass this) decussates paramedian pontine reticular formation (PPRF) abducens nucleus Visual sensitivity is reduced during saccades so that there is no blur Visual Pursuit Sensory Input - mainly voluntary since you pick what moving object to track, but once you pick the object, the visual pursuit is reflexive Movement Characteristics - follow a specific target against a fixed background Circuitry - not known

 Limbic System
Objectives
Identify the major components and circuitry of the limbic system Be able to explain the role of the limbic system and the amygdaloid nucleus in emotional behaviors Be able to explain the circuitry thought to contribute to our experiences of fear and anxiety Be familiar with the organization of the hippocampus and the role of the hippocampus in declarative memory formation

Introduction
Structures - hippocampal formation, mammillary bodies, anterior thalamic nuclei, cingulate gyrus, amygdaloid nucleus and septal nuclei Functions Coordinates the activity of the hypothalamus providing higer level control of the ANS Provides strong emotional experience and expression Can be thought of as related to ANS since this often involves sweating, piloerection, etc. Formation of long-term declarative memories in contexts of space and time

Circuitry and Functions

Experiement - remove cat cortex, basal ganglia, and white matter cats display rage in absence of any stimuli termed sham rage Sham rage not seen if caudal hypothalamus and mammillary bodies were also removed Conclusion hypothalamus is critical for expression of rage-like emotional behaviors that are modulated by cortical activity Original Limbic Circuit (NOW OUTDATED) Hippocampus via fornix mammillary bodies via mammillothalamic tract anterior nucleus of thalamus cingulate gyrus hippocampus Cortical Components Cingulate Gyrus - connects limbic system to cortex Receives reciprocally from - frontal, parietal, and temporal association cortecies Also hippocampus, septal nuclei and thalamus Projects unidirectionally to amygdala Autonomic Role General stimulation reduces rates of breathing, HR, BP, dilates pupils (like parasympathetic) No direct connections to hypothalamus, effects are mediated via hippocampus, amygdala and septal nuclei which do have direct connections to hypothalamus Behavioral Role Stimulation of anterior region produces aggressive reactions Removal of that region makes animals tamer Amygdaloid Nucleus Links cortical structures that process sensory information (association cortex) with hypothalamic and brainstem effector systems Thus it receives processed sensory information and integrates that into an emotional response Major Subnuclei Centromedial (CM) subnucleus Smaller and lies close to the olfactory cortex Projects to - visceral nuclei of brainstem Receives from - brainstem nuclei, olfactory bulb, olfactory cortex and hypothalamus Autonomic functions Basolateral (BL) subnucleus Larger and deals with conscious processes related to the frontal and temporal lobes Associated with arousal and increased signs of attention Strong stimulation produces behavioral signs of rage and fear Projects to - thalamus, septal nucleus, hippocampus

 Receives from - thalamus, sensory association cortex, cingulate gyrus Learned Behaviors Related to Fear Quickly learned fear-related behaviors are reflected in plastic changes in the properties of neurons in the BL that are driven by inputs from the medial geniculate nucleus Increased activity in BL during conditioned fear acquisition Person without amygdala basically has no fear response Hippocampal Formation Associated with acquisition of memories If damaged anterograde amnesia - cant form new declarative memories Encodes information about spatial position 3 structures arranged in layers Subiculum - in parahippocampal gyrus Hippocampus - part of allocortex (3 layers) Contains pyramidal cells whose axons leave via the fimbria Dentate gyrus - part of allocortex (3 layers) Located along medial aspect of hippocampus Most neurons are granule cells which project to pyramidal neurons in the hippocampus Inputs Entorhinal Cortex - provides glutaminergic innervation Provides link between association cortex and limbic system, via subiculum Septal Nuclei - inputs travel via fornix Cingulate cortex Outputs Cortex - most connections go to entorhinal cortex via subiculum and septal nuclei then to cortex Thus the connections are reciprocal Precommissural Fornix - carries pyramidal axons from hippocampus septal nuclei Postcommissural Fornix - carries axons from subiculum hypothalamus mammillary bodies Septal Nuclei Lesions in rats produces transient rage reactions, hyperemotionality, hyperactivity Stimulation produces pleasure and HR

Clinical Correlations
Kluver-Bucy Syndrome - caused by surgical removal of both medial temporal lobes in monkeys Causes - hyperactivity, hypersexuality, dramatic changes in emotional behavior, they become docile, do not respond with appropriate fearful or aggressive behaviors Amnestic syndrome - caused by bilateral infarct to hippocampus Causes - anterograde amnesia

 Hippocampus
Objectives
List the major cell types, intrinsic pathways and structural features of the hippocampus Know the mechanisms and significance of long term potentiation as a form of synaptic memory Understand the role of the hippocampus in memory formation and the types of memory deficits caused by temporal lobe disease Describe the role of the hippocampus in human epilepsy and animal models of epilepsy

Part of allocortex (thus has 3 layers) Derived from medial pallium

Function
Memory - forms associations between significant stimuli and allows for memories Linkage between internal drives and environmental stimuli Also links cortical and subcortical regions Regulates aggression, eating and mating behaviors mediates things

Structure
Two interlocking horseshoe cell layers Dentate Gyrus - mainly granule cells and are not spontaneously active Contains molecular layer, granule cell layer and plexiform layer (hilum) Hippocampus Proper - CA3, CA2 and CA1 pyramidal cell regions CA3 and CA1 pyramidal neurons generate bursts of APs CA3 bursts are higher frequency and more sustained CA1 bursts accommodate (slow with time) Subicular Complex Entorhinal Cortex - place for major cortical inputs May function as a gate since only high frequency, concentrated input stimulates it Most of its input comes from association cortex, which responds strongly to novel stimuli

Major Synaptic Connections

Excitatory synapses (with inhibitory interneurons) Entorhinal cortex via perforant path dentate gyrus via mossy fibers CA3 via Schaffer collaterals CA1 subiculum back to entorhinal cortex

Long Term Potentiation

A form of synaptic plasticity related to experience Hebbian synapse - synapses that can fire a post-synaptic cell become strengthened Ex. stimulate once small EPSP, then stimulate a little later larger EPSP due to LTP LTP is induced rapidly and can last days A stimulus intensity threshold is needed for LTP to occur Multiple weak inputs can cause LTP in the receiving cell Associative Potentiation - when LTP occurs from one hemisphere to the other? Mechanism of LTP Glutamate binds AMPA receptors Na enters causes EPSP Glutamate also binds to nearby NMDA receptors channel blocked by Mg EPSP from multiple AMPA channels depolarize membrane and displaces Mg NMDA channel allows Ca entry Causes activation of multiple enzymes including PKC, CAM kinase II, and nitric oxide sythase Effects sensitization via phosphorylation or expression of AMPA receptors postsynaptic cell to get more excited presynaptic glutamate release - caused by nitric oxide release in postsynaptic terminal Late Phases - require protein synthesis for new synapse formation NMDA receptor activation requires cooperative or associative activation of multiple/strong inputs

 LTP and Memory Poor LTP poor memory; blocking LTP with drugs (NMDA antagonists like ketamine) can block memory Learning situations can induce LTP Oddities LTP always decays Rats can still learn withough NMDA receptors, just slower LTP still occurs in CA3 even with NMDA receptor blockade

Hippocampus and Memory

Lack of hippocampus anterograde amnesia (lack of declarative memory) Preservation of procedural memory Lack of hippocampus problems with spatial memory Seems that certain cells in hippocampus only light up when a certain location is thought about

Seizures
Brain response to abnormal physiological or disease states in cortical neurons May result from features related to abnormal information processing and memory storage Requires that some degree of hyperexcitability and hypersynchrony occur Hypersynchrony - abnormal tendency of a population of neurons to discharge together independently of other neurons Spike and Wave pattern seen on EEG Caused by Paroxysmal Depolarization Shift (PDS) intracellularly? Failure of surround and feedforward inhibition results in spread of seizure activity? Blockade of GABA inhibition leads to propagation of bursts from CA3 to CA1 then to cortex Low Mg or high K triggers prolonged PDS in CA1 and propagates to CA3 can lead to seizures? Dentate Gyrus and Seizures Dentate gyrus can be thought of as gatekeeper for hippocampal seizures because it plays big role in surround inhibition Dentate gyrus activates mossy cells which activate CA3 and inhibitory basket cells The basket cells inhibit the dentate granule cells If surround inhibition can be overcome then seizure can occur Dormant Basket Cell Hypothesis - chronic seizure activity can result in mossy fiber loss surround inhibition due to stimulation of basket cells - seizures Axonal Sprouting Hypothesis - chronic seizure activity can result in mossy fiber loss mossy cells try to grow back, but connect back to dentate gyrus excitation of dentate gyrus seizures Kainic Acid Animal Model of Seizures - overactivates glutamate receptors and allows too much Ca in cell death especially in CA3 and CA1 causes seizures Kindling hypothesis - repeated stimuli to areas that can cause seizures can cause seizures of severity Epilepsy - recurrent, unprovoked seizures not due to any other cause Often one temporal lobe is larger than other Anterior temporal lobectomy - very effective, but only if seizures come from only one side because you can only remove one temporal lobe. Use Wada Test to disable one hemisphere and test other

 Learning and Memory

Objectives
Point out categories of learning and memory that are based on type of information and time after learning Describe methods that are used to identify brain structures that contribute to learning and memory Describe structures that are involved in declarative memory and procedural memory Point out examples of findings about memory that come from clinical studies of medial temporal lobe lesions Point out examples of findings about memory that come from MRI and MEG studies of cortex Describe cellular and molecular mechanisms that contribute to short-term and long-term synaptic changes Explain CREB1 and CREB2 contributions to long-term synaptic changes Point out different types of memory problems and examples of causes of these problems Describe one approach being used to deal with developmental dyslexia

What is learning and memory?

Learning - neural processes that are involved in acquiring new information in the nervous system Memory - neural processes that are involved in storing and retrieving that information Engram - physical embodiment of a memory in neural tissue Declarative Memories - events and facts, can be declared verbally, usually available to conciousness Uses hippocampal formation, frontal lobes and diencephalon Procedural Memories - motor skills and procedures; is reflexive or unconscious Uses sensory and motor corticies, basal ganglia and cerebellum Immediate memory - sense of present Note - localized electrical stimulation of memory structures in the brain can evoke flashbacks, while more widespread stimulation can lead to amnesia

Where does learning and memory occur?

Declarative Memory What we know from lesion studies Hippocampal formation is important for declarative, but not procedural memory Bilateral damage of CA1 is sufficient to produce anterograde amnesia The severity of declarative memory impairment roughly correlates with the extent and location of hippocampal formation damage Hippocampal lesions often have impact on forming new memories, not recalling old ones What we know from fMRI studies Early declarative memory formation involves the hippocampal formation and the dorsal frontal cortex There is hemispheric specialization for verbal (left) and nonverbal (right) information Procedural Memory Acquisition of Motor Skills Trained motor activities involving procedural memory are related to increased neural activity of the motor cortex in activity levels of primary motor cortex are related to developing procedural memory? Somatosensory cortical differences in musicians procedural memory involves increased activity to both motor and somatosensory cortices in some cases (in musicians because lots of touch and proprioception)

Cellular and Molecular Mechanisms

General Idea Synaptic changes can occur via mechanisms that act presynaptically and/or postsynaptically Fast/short-lasting synaptic changes can involve changes mediated by Ca and kinase phosphorylation of channel or receptor proteins at existing synapses Long-term synaptic changes can involve gene activation and new protein synthesis that leads to prolongation of short term effects and formation of new synapses Jointly controlled by memory enhancing and memory suppressing gene mechanisms Long Term Potentiation

 Occurs especially by CA3 neurons using their Schaffer collateral axons to send tetanus stimulation to CA1 neurons Short Term Changes Serotonin on the presynaptic terminal involved in LTP can transmitter release PKA Cascade Serotonin binds receptor receptor activates G-protein adenylyl cyclase activated cAMP activates PKA phosphorylates K channels K efflux duration of AP depolarization thus influx of Ca results in release of transmitter PKC Cascade Serotonin binds receptor receptor activates G-protein activates phospholipase and DAG DAG activates PKC PKC phosphorylates Ca channels influx of Ca transmitter Long Term Changes Involve gene activity and new protein synthesis Still start with serotonin and are thought to be involved with converting short-term memories into long-term ones Prolonged PKA Cascade Serotonin binds receptor eventually PKA activated phosphorylates CREB1 transcription factor eventually activate downstream genes and encode new proteins ubiquitin hydroxylase - one of the proteins made prolongs activity of PKA C/EBP CAAT ApCAM growth of new synapses CREB1 is normally suppressed by CREB2 PKA activates MAPK, which phosphorylates CREB2 and frees CREB1 Thus things that activate CREB1 are long-term memory enhancers and things that activate CREB2 are long-term memory suppressors

How is memory stored by changes in synaptic strength?

Input signal goes into 2 cells via strong synapses cells receiving info send input to many weak synapses that behave in a Hebbian way and then output their info Basic idea - memory is not held in one cell, but instead is distributed across many synapses

Common learning and memory problems

Forgetting - is normal, especially old information Aging - in memory with aging, could be related to in brain size Learning Disabilities Types - developmental speech and language disorders, academic skills disorders, coordination and attention disorders Causes - factors that disrupt synaptic structure and function and number of synapses formed during development Dyslexia Thought to reflect brain function problems that impair abilities to learn verbal sounds and speech Phonological processing skills like rhyming and sounding out words are impaired Remedy - have people use a program that has them process this information at their speed and practice getting faster Result - left temporal-parietal and left inferior frontal cortical areas showed activity (that was below normal prior to the remedy) and also scores on language tests Amnesia Can be related to time - recent memories gone after electroshock therapy, but not old ones Causes - multiple, including B1 deficiency associated with alcoholism (Korsakoffs disease)

 Epilepsy, EEG and Sleep

Objectives
Understand the fundamental principles of EEG Understand the clinical utility of EEG Describe the neuroanatomy & neurophysiology of attention and arousal Describe the neuropharmacology of sleep and arousal

Electroencephalography (EEG)
The study of electrical activity of the brain that is cortical in origin and arises from EPSPs and IPSPs generated from pyramidal cells Electrical field generated by 6 cm2 of similarly oriented pyramidal cells and detected by scalp electrode Scalp electrodes placed over all lobes of brain in a montage arrangement Individual APs do not contribute to EEGs Not useful for assessing brainstem or subcortical function Normal EEG Patterns Alpha - 8-12 Hz, awake, seen posteriorly, originate in cerebral cortex Beta - 12-30 Hz, awake, mainly frontal, originate in thalamus Gamma - >30 Hz, seizure related Theta - 4-7 Hz, during drowsiness, originate in hippocampus Delta - 1-3 Hz, during sleep, originate in thalamus EEG and Seizures Can help identify risk of recurrence Types of Seizures Tonic-Clonic Seizure - stereotypic seizure seen in movies, not that common though Frontal Lobe Seizure - bizarre, stereotypical movements including thrashing, bicycling and tonic/dystonic posturing May occur in clusters, frequently confused with non-epileptic events, possiblty with aura Invasive monitoring is possible but has disadvantages

Awake State
Responsive and active, alpha and beta Neurophysiology Ascending Reticular Activating System - critical for maintaining consciousness and projects to: Intralaminar and midline thalamic nuclei via dorsal pathway Hypothalamus and basal forebrain via ventral pathway Neurotransmitters include Norepinephrine - locus ceruleus ACh - pontomesencephalic tegmentum Dopamine - ventral mesencephalic tegmentum Consciousness - awarness of self and requires Alertness - dependent on reticular activating system and intralaminar & midline thalamic nuclei Awareness - requires sensation and perception, thus sensory and association cortex Attention - ability to select response based on various alternatives, based on cognitive strategy Requires - anterior cingulate gyrus, prefrontal cortex, inferior parietal lobule, visual, auditory, somatosensory & association corticies, ventral postlateral nucleus of the thalamus and the reticular formation Neurotransmitters involved
Norepinephrine - modulates attention and arousal by dense cortical and hippocampal innervation ACh - nicotinic visuospatial, muscarinic alertness and arousal Dopamine - important for working memory and ability to shift attention

Disorders Unilateral inattention - cant respond to one visual hemisphere?

 Global inattention - inability to concentrate or focus, like in Alzheimers Coma - state of unarousable unresponsiveness Can be localized to specific brain structures?

Sleep
Behaviorally quiet state in which response to sensory stimuli and movement greatly reduced EEG activity is slow (theta and delta) Eye movements absent, muscle tone reduced Reduction in ascending reticular activating system Change in pattern of firing in thalamocortical neurons GABA is main neurotransmitter involved? Stages of Sleep Non-REM Sleep Stage 1 - low V, 2-7 Hz, vertex sharp waves, slow rolling eye movements, slight in tone Stage 2 - everything in Stage 1 plus sleep spindles (which are large beta waves?) Stage 3 - 20-50% of activity is delta greater than 75 uV Stage 4 - >50% of activity is delta REM/Paradoxical Sleep Rapid eye movements, large in muscle tone, sawtooth waves, EEG fast and low voltage almost like awake state Pontomedullary tegmentum important for REM sleep Cholinergic neurons fire during REM sleep Circadian Rhythms - controlled by suprachiasmatic nucleus which gets info from visual system REM latency is usually around 90 minutes (goes through all stages of sleep, then back up first) Shorter latency in narcolepsy, neonates and those with excessive sleep deprivation Age and Sleep Neonates go into REM sleep directly in stage 3 & 4 with in 1 & 2 with age Disorders Narcolepsy - Excessive sleepiness, cataplexy, hypnogogic hallucinations and sleep paralysis Has genetic basis, related to low or absent hypocretin/orexin (a neuropeptide hormone in hypothalamus that helps induce wakefulness) Treatment - methamphetamine, modafinil Sleep Apnea - cessation of air movement due to relaxed muscles in throat Patient complains of daytime sleepiness Parasomnias - talking during sleep, sleep walking, sleep terrors Patient actually asleep Summary Wakefulness Non-REM sleep REM sleep Inactive Active with PGO spikes Cholinergic nuclei Active Active Inactive Inactive Locus coeruleus (norepinephrine) Active inactive Inactive Raphe nucleus (serotonin)

 Development of the Nervous System

Objectives
Describe the basic germ layers and tissues that contribute to the formation of structures found within the peripheral portion of the nervous system and the central portion of the nervous system Describe the formation of the neural plate, neural groove and neural tube. What induces or controls the development of these structures? How does the general development of the cranial portion of the tube differ from the development of the caudal portion of the tube Describe the development of the three developmental layers of the neural tube What major areas of the nervous system are derived from each? Describe the formation of the alar plate and the basal plate What major functional areas of the nervous system are derived from each? Describe the positional changes that occur during the development of the spinal cord and vertebral column Describe the development of the regions of the lower portion of the brainstem Rhombencephalon - hindbrain Myelencephalon - medulla oblongata Metencephalon - pons and cerebellum Mesencephalon - midbrain Describe the major features of the development of the prosencephalon-diencephalon and telencephalon Cerebral hemispheres and cortex; Commissures; Basal Ganglia and internal capsule Summarize the functional components of the cranial nerves and localize (theoretically) their respective nuclei in the brainstem Define and/or describe the elements of the choroid plexus, the tela choroidea and arachnoid villi Differentiate between the tectum and the tegmentum of the brainstem How does the structure of the cerebellum reflect its phylogenetic development? What is the origin of the cells of the sympathetic nervous system and how does this contrast to the origin of the parasympathetic system? Describe the morphological defects and developmental errors associated with Hydrocephalus and Spina Bifida

This is a Yeasting lecture so it is disorganized and bad Ectoderm - skin, nails etc.; Mesoderm - everything in between; Endoderm - lining of gut Notochord - midline structure, controlling factor for spinal cord and brainstem Extends from primitive node to oropharyngeal membrane Underneath ectoderm An organizer, sends out chemical messengers to help determine what other tissues become Chemical messengers create a concentration gradient Protective - cells receiving signals from notochord will not be able to respond to signals from endoderm or other tissues, therefore it isnt stimulatory Oropharyngeal Plate/Prechordal Plate - controls development of the cerebral portion

Formation of Neural Tube

Distal ectoderm is squamous, medial ectoderm is columnar Neural crest - comes together and causes an invagination of columnar cells Neural plate - columnar cells of ectoderm that get invaginated Once invaginated forms neural groove then neural tube Neural tube breaks free from ectoderm and migrates down Initially the neural tube is open, but at D24 the cranial neuropore and caudal neuropore close -fetal protein - a protein produced by inside of neural tube if neural tube does not close, then -fetal protein will leak into amniotic fluid can be tested for by amniocentesis Neural crest cells break free and migrate laterally Spina Bifida - complete closure of neural tube, but mesoderm does not migrate over it, causing weakened covering Spina bifida cystica - unfused portion of spinal column protrudes through spine Spina bifida with spinal cord defect - if neural tube is involved in malformation Occult spina bifida - hidden, you cant tell you have a weakened covering Development of Neural Tube Neural tube becomes pseudostratified and mitosis occurs at the luminal side then nuclei move away from lumen Cells (neuroblasts) then move away from lumen and are guided by radial glial cells, which span the entire length These cells are responsible for the organization of neurons into parallel packets of columns, since groups of neurons will travel up one radial glial cell and some neurons stop in different lamina

 These cells give rise to neurons and glial cells (oligodendrocytes and astrocytes), not microglia (they are lymphoid cells) Layers of the Neural Tube Ependymal Cell Layer - right around the ventricle Mantle Zone - contains grey matter and protoplasmic astrocytes Alar Plate (dorsal) - neurons that stay completely within CNS and receive input from primary sensory neurons Ex. dorsal horn interneurons receiving input from primary sensory neurons Basal Plate (ventral) - efferent neurons that leave CNS and go to PNS Ex. can be motor, preganglionic autonomic and even interneurons Marginal Layer (outer) - contains white matter and oligodendrocytes Ascending and descending nerve fibers Neural Tube and Growth Factors Shh is released by the notochord and nearby structures are affected, the closest structure is the basal plate, and Shh causes the cell bodies to grow? Bone morphogenic proteins are released by ectodermal sites and affect development of alar plate

Development of the Neural Crest

Give rise to CT in head and neck, dorsal root cells, primary sensory cells, postganglionic autonomic neurons, cells of adrenal medulla, pigment cells (melanocytes), Schwann and satellite cells

Spinal Cord
After birth the spinal cord stops elongating, but the vertebral column continues to grow Roots form cauda equina which ends up starting at L2

Regeneration
Peripheral nerves can regenerate at 1 mm a day, they follow CT Central nerve axons dont regenerate because there is no CT in the CNS (besides blood vessels)

Development of the Brain

Prosencephalon - forebrain Telencephalon cerebral hemispheres Diencephalon thalamus, hypothalamus, epithalamus Mesencephalon midbrain Rhombencephalon - hindbrain Metencephalon pons, cerebellum Myelencephalon medulla Note - the notochord only influences up to the midbrain (especially the basal plate stuff) All other brain structures influenced by prechordal plate (made from alar plate?)

Development of Metencephalon
Cranial portion of dorsal margin becomes cerebellum Cells migrate from mantel region toward surface to make extracellular granular layer and purkinje cells The granular cells migrate further inward than the purkinje cells This stuff came from the alar plate

Development of Brainstem
Basal plate derivatives stay near midline (motor efferents, nucleus ambiguous, CN V, CN VII etc) Alar plate derivatives move laterally (somatic efferents, visceral afferents, solitary nucleus) Sulcus limitans - forms floor of 4th ventricle?

Development of Cerebrum
Telencephalon grows back over and makes contact with diencephalon These portions then fuse together, this fusion makes the caudate nucleus and other deep cerebral grey matter structures Internal capsule fibers go through this fusion point to make a connection? Internal Hydrocephalus - if cerebral aqueduct closes, CSF builds up and ventricles can expand

 Higher Cognitive Functions

Objectives
Outline examples of major cognitive functions of the human brain that are thought to be largely produced by events in the cer ebral cortex Describe gross structural features of the cerebral cortex Identify examples of anatomical and functional asymmetries in the two cerebral hemispheres Explain why primary and nonprimary cortical areas are different Outline Brodmanns cortical areas that contribute to visual, somatosensory, auditory, olfactory, gustatory, vestibular, and polymodal perceptions Outline Brodmanns cortical areas that contribute to learning, motor planning and performance, thinking, personality characteristics, and decision making and social conduct Describe the posterior to anterior mapping of different mental functions in a hemisphere Point out examples of cross modal specialization changes and their implications Present concepts that contribute to understanding consciousness Describe some ingredients that go into thinking about how cortex makes a visual image Explain the internal observer issue

Hemispheric Asymmetry and Specialization

Anatomical asymmetry Planum temporale - region of temporal lobe that includes Wernickes area, left side is larger in most people, even in infants Functional asymmetry Contralateral control - most sensory and motor functions carried out by contralateral hemisphere Language dominance - mainly in left hemisphere, test by Wada test (where one side is disabled) Related to handedness - right handed people are more likely to have language on left side Nondominant hemisphere usually better at nonverbal tasks People with cut corpus callosum Present object to left hemisphere right hemisphere processes it Cant identify object with with words, can point to it with left hand Why Asymmetry? Decussating nerve fibers Number of synapses available within one hemisphere is greater than across a hemisphere (less fibers cross the hemisphere)

Maps of mental and cognitive functions within a hemisphere

Primary vs. Nonprimary cortical areas Primary cortical areas - dedicated to one function, inputs directly from thalamic projections from the subcortical sensory system or to motor sytems Nonprimary cortical areas - mainly communicate with other cortical areas Perception Mainly located in caudal regions Notice that some cortical areas are polymodal Visual Perception - begins at primary visual cortex and then goes to two paths Ventral subsystem - below calcarine sulcus and into temporal areas Involved in perceptual recognition of shape and color to identify what something is Dorsal subsystem - above calcarine sulcus and into posterior parietal areas Involved in perceptual recognition of motion, depth, location to identiry where something is Somatosensory perception - secondary processing occurs in posterior parietal cortex and also within the lateral sulcus (S-II, insular cortex and retroinsular cortex) Auditory perception - begins in primary auditory cortex, which is in top of temporal lobe Secondary processing around the primary area in the temporal lobe Dominant side controls verbal, non-dominant controls non-verbal Olfactory perception - on ventral surface of frontal and temporal lobes Gustatory perception - on operculum of postcentral gyrus (right near lateral fissure) and in the insular cortex Vestibular perception - deals with our perception of where we are in gravitational field At end of lateral fissure Planning and Performance of Motor Behavior

 Premotor cortex and frontal eye field (which is important for saccadic eye movements) Language and Speech Temporal, parietal and frontal lobes Wernickes area - important for speech comprehension, in temporal lobe Arcuate fasciculus - connects Wernickes area to Brocas area Brocas area - important for programming language expression Higher order Located in rostral and medial areas Learning and Memory Anterograde memory - (new factual info) caudal temporal lobe Retrograde memory - (previously learned) rostral temporal lobe Creative and Original Thinking - prefrontal area Personality, emotional state, motivation, arousal - midline frontal lobe areas Judgement, decision making, social conduct - medial and inferior surfaces of the rostral frontal lobe

Cross-Modal Cortical Changes

When one modality of input is processed in cortex of another modality (often because the other modality isnt being used anymore, like in a person that lost their eyes at birth) Ex. blind people can end up using their visual cortex for somatosensory purposes like reading Braille Shows that functional specialization of the cortex can occur after birth

Consciousness
State of awareness of self and surrounding environment and responsiveness to external stimulation and internal need State of awareness of ones mental functioning and relation to past experiences and memories Theories of consciousness Electrical activity - consciousness is a function of electrical activity in the brain
Global spatial theories - it is a function of large, diffuse groups of neurons and it may not be possible to localize exactly which neurons contribute since they contribute differently over time Local spatial theories - is a function of activity in identifiable, localizable neuronal subsystems Temporal theories - is a function of large numbers of interconnected, synchronized neurons and the groups of neurons can change depending on what the brain is doing at the time

Cortical Matrix processes - conciousness is the processes of the brain Levels of Consciousness Simultaneous levels of awareness - awareness and aware that you are aware Blindsight - lesion to primary visual cortex can cause a level of recognition without awareness Prosopagnosia - temporal lobe damage causing inability to recognize faces Level of awareness without recognition Split-brain patients - see above Developmental states of consciousness - conscious changes from neonate to older Levels of awareness - sleep, drowsiness, etc. Cortical EEG and States of Consciousness Awake - desynchronized, low amplitude voltage, high frequency beta waves Asleep - synchronized, high amplitude voltage, low frequency delta waves (low activity, few cells) Coma - flat EEG waves in deep coma, high amplitude low frequency waves in less deep coma Brain Death - no EEG waves greater than 2 microvolts in amplitude, irreversible Brainstem Circuits and Awake States Reticular Activating System - activate cortical neurons directly via diffuse projections to widespread areas of cortex or indirectly via projections to thalamic nuclei then to cortex Includes cholinergic neurons near pons-midbrain junction (LDT and PPT nuclei) Includes serotonergic neurons in the raphe nuclei Includes noradrenergic neurons in the locus ceruleus Disruptions of the RAS - If the RAS is disrupted then consciousness will be disrupted

 Internal Observer - there aint none in the brain, image isnt processed then viewed on a screen Physical images are probably embedded by specific activation patterns of large populations of neurons across multiple cortical areas

 Stroke
Definitions
Stroke - sudden onset of neurological deficit caused by alteration in blood flow to a portion of the brain Transient Ischemic Attack - TIA, stroke-like episode with symptoms resolving within 24 hours (most within 60 minutes) <10% that have TIA will have stroke within 1 year 25-50% of large vessel strokes are preceded by TIA

Stroke Subtypes
Primary Hemorrhagic (20%) Subarachnoid Hemorrhage sudden onset, often with loss of consciousness Causes - rupture of berry aneurysm, arteriovenous malformation (AVM) Intracerebral Hemorrhage - bleed within the brain tissue progressive over hours, sometimes with headache Causes - most often caused by hypertension Can also be caused by drugs (cocaine etc.), cerebral amyloidosis and AVM Primary Ischemic (80%) Large Vessel Occlusion - blockage of large cerebral vessel due to pathologic process such as atherogenesis (most common cause), dissection, vasospasm, hypercoagulable/hyperviscous progressive over hours or fluctuating often preceded by TIAs more common in women, more common in anterior cerebral circulation Small Vessel Occlusion Variable presentation, often cant be seen with imaging Often subcortical white matter or deep grey matter or brainstem Symptoms often very specific (pure motor, pure sensory, clumsy hand) Causes - lipohyalinosis (thick blood vessel wall?), atheroma of lacunar vessels? Embolic - blockage of vessel by material that originated elsewhere Most frequently travel through the middle cerebral artery Sources - cardiac (often cause large strokes), carotid arteries Risk factor could be patent foramen ovale Show up as wedge shaped areas upon imaging

Stroke Pathogenesis - The Ischemic Cascade

Oxygen ATP loss of K from cell membrane depolarization depolarization causes voltage sensitive Ca channels to open extracellular glutamate glutamate overstimulates more Ca entry more ATP Nitric oxide synthetase and enzymes that degrade protein, DNA, and phospholipids cause free radical formation Reperfusion also causes free radical formation Free radicals cause cell death Core Region - infarcted, irreversibly injured brain tissue Penumbral Region - reversibly injured, may recover, may evolve into infarction, may die (apoptosis)

Clinical Presentation
Neurological deficit depends on brain area involved General - loss of unilateral strength/sensation, sudden dizziness, loss of vision, speaking, sudden head Middle Cerebral Artery Stroke Contralateral sensory loss & weakness of face + arm >> leg Aphasia if stroke in that hemisphere Anterior Cerebral Artery Stroke

 More rare and usually associated with MCA stroke Contralateral sensory loss & weakness of face + arm << leg Posterior Cerebral Artery Stroke Contralateral visual field deficit (homonymous hemianopia) May have mild contralateral motor and sensory deficit (if posterior thalamus?) Vertebrovasilar Stroke - can cause dysarthria (poor articulation), diplopia, vertigo, ataxia, dysphagia (trouble swallowing), depression of conciousness, unilateral hearing loss, nystagmus, weakness, sensory loss

Diagnosis and Treatment

Procedure Establish it really is a stroke Determine the stroke subtype (hemorrhagic etc.) Then attempt to determine the cause for that subtype (ex. hemorrhage due to dissection) Treat stroke and prevent recurrence Tests - CT, DWI MRI, MR or CT angiography, echocardiogram (looks for sources of emboli), EKG (since emboli could come from heart) Treatment (SHE DIDNT GO OVER THIS IN CLASS) Decrease Risk Factors - best way to prevent forest fires Tissue plasminogen activator - effective treatment for acute nonhemorrhagic ischemic stroke if given within 3 hours of onset Aspirin and Heparin can be helpful Invasive procedures can be helpful for embolus removal or to decompress edema Prevent Recurrance (SHE DIDNT GO OVER THIS IN CLASS) Antiplatelet Agents - aspirin, Plavix, etc. Anticoagulants - warfarin Statins and antihypertensives Invasive - remove atherosclerotic disease from carotid artery, do angioplasty or stenting on problem vessels

Case Studies
Mr. Treat Woke up in middle of the night, noticed his right foot was dragging, then noticed slurred speech, had just started Lipitor a few days before, things then got worse before they got better. Strength is fine, it is the coordination that is really tough Hyperreflexia in affected side Stroke to the posterior limb of the internal capsule and found a patent foramen ovale 35 yo woman left hand numbness, clumsiness, left facial droop Found Moyamoya (puff of smoke) - progressive intracranial vascular stenoses of the circle of Willis, resulting in successive ischemic events Treatment involved transplanting vessels 73 yo man left finger numbness, left facial droop, slurred speech, trouble reading, history of coronary artery disease

 Higher Cortical Dysfunction

Causes of cortical dysfunction
Infectious disease - sudden and diffuse (viral, bacterial, fungal) Vascular disease - sudden and focal (thrombosis, embolism, hemorrhage, A-V malformation) Other - neoplasm (benign, malignant, metastatic), neurodegenerative (Alzheimers, Parkinsons, toxic), congenital (dysgenesis, cortical anomalies), toxic/metabolic (poisons, thyroid, diabetes), trauma (open, damage to poles of brain where it hits the skull)

Effects of Frontal Lobe Diseases

Unilateral frontal disease Contralateral spastic hemiplegia Slight elevation in mood, talkativeness, tendency to joke, lack of tact, adaptation, initiative If only prefrontal then no hemiplegia, and grasp and suck reflexes may be released Anosmia - if smell regions affected Right frontal disease Left hemiplegia Slight elevation in mood, talkativeness, tendency to joke, lack of tact, adaptation, initiative Left frontal disease (assuming it is the dominant side) Right hemiplegia Slight elevation in mood, talkativeness, tendency to joke, lack of tact, adaptation, initiative Brocas area defect - motor speech disorder with agraphia (cant write), with or without apraxia of lips and tongue (can cause poor articulation) Loss of verbal associative fluency? If it catches corpus callosum - when trying to move both sides then apraxia ( voluntary movements) seen in left side Bifrontal disease Bilateral hemiplegia Pseudobulbar palsy - dysphagia (trouble swallowing), dysphonia, dysarthria (difficulty forming words due to muscle control), weak tongue and facial muscles, emotional control If prefrontal - abulia (lack of will power), akinetic mutism (cant move but can perceive), cant sustain attention, cant solve complex problems, decomposition of gait, incontinence

Effects of Temporal Lobe Diseases

Unilateral disease of dominant temporal lobe Homonymous upper quadrantanopia (due to Meyers loop?) Wernickes dysphasia - decreased comprehension and incoherent speech with normal articulation Impairment of verbal comprehension if presented auditorily Can have, amusia - inability to recognize musical tones, Dysnomia - problem with names Unilateral disease of nondominant temporal lobe Homonymous upper quadrantanopia (due to Meyers loop) Non-verbal impairment - inability to judge spatial relationships, impairment on tests of visually presented nonverbal material Agnosia (ignorance or altered knowledge) for sounds and some qualities of music Disease of either hemisphere Auditory delusions or hallucinations (not to be confused with schizophrenia) Pyschotic behavior, especially aggressivity Bilateral disease Korsakoff amnestic defect - memory, hallucinations, agitation due to alcoholism and thiamine Kluver-Bucy syndrome - removed temporal lobe apathy, sexual activity

Effects of Parietal Lobe Diseases

Unilateral disease

 sensation, or sensory extinction (if simultaneous stimulation to both sides then wont feel affected side) Mild hemiparesis, unilateral muscular atrophy in children ?? Visual - homonymous incongruent (not symmetrical) hemianopsia, visual inattention, anosognosia (denial there is a problem), or neglect of half of the body Loss of nystagmus on one side Unilateral disease on dominant side Disorders of language (especially alexia, cant read good) Gerstmann Syndrome - lesion between angular gyrus and occipital lobe causing finger agnosia, agraphia (inability to write), right-left confusion, acalculi Tactile agnosia - ignorance of stimulus; astereognosia (poor judgement of stimulus by touch) Bilateral ideamotor and ideational apraxia? Unilateral disease on nondominant side Topographic memory loss - cant remember where they are or where they are going Anosognosia (and neglect of one side?)

Effects of Occipital Lobe Disease

Unilateral Disease Contralateral (congruent/symmetrical) homonymous hemianopsia (central or peripheral) Visual hallucinations Left Occipital Disease Right homonymous hemianopsia, object agnosia If deep lesion - alexia (reading problems) and color naming problems Right Occipital Disease Left homonymous hemianopsia, loss of topographic memory and visual orientation If deep lesion - visual illusions and hallucinations Bilateral Occipital Disease Cortical blindness (but pupils reactive), Antons syndrome (anosognosia that they cant see) Loss of perception of color, prosopagnosia Balint syndrome - visual inattention to periphery, saccadic eye movements into peripheral field Disconnection Syndromes - marked by conduction aphasia, pure word deafness?

 Fundamentals of Pain Mechanisms

Objectives
Describe pathways for normal pain feelings and distinguish these pathways from pathways for nonpainful feelings Distinguish how normal pain differs from pathological pain Describe how pathological pain results from abnormal activation of pain pathways which, in turn, is caused by sensitization mechanisms that operate at peripheral and/or central levels Describe mechanisms that cause peripheral sensitization Describe mechanisms that cause central sensitization Discuss emerging thinking about brain structures that produce different dimensions of pain Discuss thinking behind mechanism-based pain treatment strategies Point out how pharmacological fMRI is being developed as part of mechanism-based pain treatment

Normal Pain
Triggered by noxious (high intensity) stimuli, signals imminent or actual damage, elicits responses to minimize damage and promote healing, C and A fibers, anterolateral or trigeminothalamic pathways Nonpainful sensations - low intensity stimuli, dorsal column medial lemniscal or trigeminal lemniscal pathways There is some convergence between the two types of stimuli

Pathological Pain
Increased activity to pain pathways due to sensitization mechanisms Can be triggered by noxious or non-noxious stimuli

Peripheral Sensitization Mechanisms

Abnormal activation or synaptic release in peripheral pain neurons (C and A fibers) Changes in receptor potentials or action potential generation Injury or inflammation to C and A fibers receptor potentials # of APs from any given stimuli increased pain from any given stimuli Or Inflammation PGE2 activates PKA phosphorylates Na channels on pain fiber facilitates channel opening and probability of AP firing Phenotype Changes Nerve or tissue injury can cause a normal nonpain neuron (A fiber) to release substance P, which is normally only released by pain neurons Tissue injury NGF (nerve growth factor) activates TrkA receptors cause gene expression and synthesis of substance P can now release substance P and signal pain Changes in Autonomic Interactions Injury or inflammation can cause abnormal expression of norepinephrine receptors in pain fibers Then postganglionic sympathetic neurons can activate these receptors and cause pain Pain not caused by sensory input This is called sympathetically maintained pain/reflex sympathetic dystrophy

Central Sensitization Mechanisms

Phosphorylation of Receptors resulting in activity of Spinothalamic Neurons Spinothalamic neurons in spinal cord receive inputs from pain and nonpain neurons After injury, spinothalamic neuron activity after pain input, nonpain input and with no input Mechanism - due to phosphorylation of excitatory and inhibitory amino acid receptors Painful stimulus glutamate and substance P release activates G protein eventually activates PKC which Phosphorylates NMDA receptors which mediate cell excitation makes neuron hypersensitive to glutamate leading to excitatory responses and Phosphorylates GABA and Glycine receptors which mediate cell inhibition makes neuron less sensitive to GABA and glycine leading to inhibitory response

 Sprouting of Nonpain Fiber Terminations in the Spinal Cord After peripheral injury and the degeneration of pain fibers in the spinal cord, nonpain fibers will fill in the synaptic connections that the pain fibers vacated This causes pain pathways to be activated by nonpain inputs

Cerebral Structures Involved with Pain

Sensory/discriminative dimensions of pain - insula, thalamus, somatosensory areas, & ipsi cerebellum Affective/emotional aspects of pain - frontal lobe orbital gyrus cortex, anterior cingulate cortex gyrus, nucleus accumbens (in basal ganglia), sublenticular extended amygdala

Mechanism-Based Pain Treatment

Different patients with the same disease/injury can have different sensitization mechanisms Converse is also true Thus it is better to treat the sensitization mechanism since that is the acutal cause of the pain Pharmacological fMRI (phMRI) - Monitor brain before, during and after administration of analgesic (that provides relief) and see which structure becomes less activated while the analgesic is active

Pain and Phantom Pain

Objectives

Understand how a physician looks at pain in one of his patients Understand how a patient comes to terms with chronic pain Understand how the medical community often overlooks and fails to respond to patients who require treatment for acute and/or chronic pain

Mr. Spangler
16 years ago a steel plate fell on his leg and crushed it, leg then amputated. Started out having phantom limb pain (phantom limb got shorter over time, this is characteristic) Also has stump pain, called neuropathic pain Medications - anti-epileptics, narcotics, nerve blocks, antiinflammatories Medications allow him to work and generally function well Has allodynia - normal stimulus produces abnormal response Tests - pain rated as a 3 or 4 (on Visual Analogue Scale), poke with pin to determine where the most pain was Maybe include notes from supplemental readings Gate Theory - ?

 Hypothalamus
Objectives
Understand the location and precise boundaries of the hypothalamus In general terms, learn the names and general positions (zones) of the hypothalamus and know their associated functions Have an understanding of the main afferent and efferent connections of the hypothalamus Learn the details of the hypothalamohypophyseal tract and the pituitary portal system Review the hypothalamic-anterior pituitary-targe as a reference for understanding feedback loops Understand the mechanisms for hypothalamic actions (and cite examples) Review hypothalamic control of the ANS Describe the influence of emotion on hypothalamic mechanisms Describe the cascade of events and the role of the hypothalamus in response to stress

Ill-defined (because surrounding area doesnt have more myelin, thus nuclei are hard to distinguish?) collection of nuclei on the ventral aspect of the diencephalon

Functions
Maintaining Homeostasis - blood volume, BP, HR, drinking eating & sexual behavior, sleep/wake Endocrine - master gland, controls anterior and posterior pituitary Autonomic - central control for autonomic system (both para and sympathetic) Emotion - influences behavior relative to changes in emotion

Location and Boundaries

Rostral extreme - lamina terminalis Ventral extreme - optic chiasm, median eminence (contains fenestrated capillaries and no blood/brain barrier) to mammillary bodies Posterior border - mammillary bodies to pineal stalk Anterior border - hypothalamic sulcus (separates hypothalamus from thalamus)

Zones of Nuclei

Periventricular Zone - surrounds 3rd ventricle, controls anterior and posterior pituitary Suprachiasmatic nucleus - has direct retinal afferents, helps control sleep/wake cycle and the hormones involved in circadian rhythms Paraventricular nucleus - controls autonomics and BP controls anterior pituitary for stress response and ACTH site of production of posterior pituitary hormones Arcuate (infundibular) nucleus - controls anterior pituitary hormones Medial Zone - medial to fornix, site for limbic input as well as visceral sensory input Ventromedial nucleus - reception of info from amygdala, role in feeding behavior satiety center Dorsomedial nucleus - reception of limbic input then responsible for autonomic output Controls anterior pituitary growth hormone??? Mammillary nuclear complex - fornix terminates here (carries info from hippocampus), output to thalamus Lateral Zone - lateral to fornix, mediates autonomic response Receives sensory response and outputs to autonomics Anterior hypothalamic area - cooling center - activated in response to heat Lateral hypothalamic area - hunger center, feeding behavior Posterior hypothalamic area - heating center - activated in response to cold Random Supraoptic nucleus - posterior pituitary control and control of vasopressin (ADH) Preoptic Area - controls sexual behavior Contains the sexually dimorphic nucleus (larger in males) The hypothalamus is an integration center Extrinsic Connections - solely neuronal

Connections of the Hypothalamus

 Afferents Retino-hypothalamic tract (unidirectional) - info about light and dark from retina superchiasmatic nucleus Fornix (mainly unidirectional) - from hippocampus mammillary bodies Stria terminalis (unidirectional) - from amygdala ventralmedial nucleus Cortico-hypothalamic tract (bidirectional) - info about emotional state from frontal cortex Medial forebrain bundle (bidirectional) - from reticular formation (in brainstem), midbrain, and olfactory regions of forebrain Diffuse ascending pathway (unidirectional) - sensory input not from other tracts From spinal cord brainstem midbrain hypothalamus Efferents Mammillothalamic tract (unidirectional) - to anterior thalamic nucleus (limbic) Hypothalmospinal tract (unidirectional) - to spinal cord to influence autonomics Diffuse descending tract (unidirectional) - to other autonomic nuclei From hypothalamus midbrain brainstem spinal cord Intrinsic Connections - deal with neuroendocrine control Hypothalmohypophysial tract - formed by axons of two nuclei (Supraoptic nucleus and Paraventricular nucleus) and controls posterior pituitary Both nuclei release Vassopressin (ADH) - promotes water reabsorption from kidney, thus involved in blood volume, BP, and drinking behavior Oxytocin - stimulates contraction of uterine wall during labor and delivery Also milk ejection from breast Tuberoinfundibular tract - formed by axons of arcuate nucleus and ends at median eminence Controls anterior pituitary via releasing hormones into capillary plexi Primary capillary plexus - in median eminence and connected to secondary plexus Secondary capillary plexus - at end of anterior pituitary, connected to venous drainage of posterior pituitary (here hormones are released into the blood)
Dont memorize - Five Nuclei - release releasing or inhibitory hormones into primary capillary plexus (periventricular, arcuate, paraventricular, ventromedial, preoptic area)

Mechanisms of Hypothalamic Neuroendocrine control of Anterior Pituitary

Long Feedback Loop - target cells influencing hypothalamus Short Feedback Loop - anterior pituitary hormone influencing hypothalamus Ultrashort Feedback Loop - hypothalamic neurons influencing their own release

Hypothalamic Reflexes
Hypothalamic Control of Autonomics Temperature Reflex (Response to Heat) Info from temp receptors on skin ascends through spinothalamic tract to reticular formation diffuse ascending pathway anterior hypothalamic area Sympathetic sweat response via hypothalamospinal tract (T1-L2 lateral horn of spinal cord) Vasodilation - done passively by having core area constrict (via sympathetics) Blood Pressure Reflex Info from carotid sinus glossopharyngeal nerve IX solitary tract nucleus in brainstem paraventricular nucleus in hypothalamus If high BP Influence sympathetics to vasoconstrict in core causes passive vasodilation elsewhere Influence posterior pituitary to drinking behavior BV and BP Hypothalamic Control of Reproductive Activity Ejection of Milk Reflex Tactile stimulus to breast pressure info to dorsal columns brainstem reticular formation paraventricular and supraoptic nuclei send info to posterior pituitary release of oxytocin stimulates smooth muscle of breast and allows milk release

 Interplay between Hypothalamus and Limbic System

If not stressed then hypothalamic responses will be good If stressed then some hypothalamic responses can be compromised

Role of Hypothalamus in the Stress Response

Stressor - something that disrupts homeostasis Hormonal Circuit - hypothalamus pituitary adrenal gland (cortex) Release cortisol? and initiates stress response Neural Circuit - diffuse ascending pathway diffuse descending pathway Ends in spinal cord, where main output is to autonomic nuclei which can be involved in stress

Hypothalamus - Self Study

Objectives

Define the temperature range compatible with human life and the limits of control of the thermoregulatory system; explain the concept of thermal balance Explain the mechanisms of heat transfer between the body and the environment. Include bot evaporative and non-evaporative means of transfer. Compare the percent of heat lost or gained by evaporative and non-evaporative methods at cold and hot temperatures Discuss the physiological and behavioral responses to short-term heat stress. Include a listing of mechanisms of heat loss and heat production. List the ways by which humans respond to cold stress, including decreasing heat loss and increasing heat production Review the role of the central and autonomic nervous system in temperature regulation Describe the characteristics of heat exhaustion, hypothermia, and hyperthermia. Differentiate between heat stroke and fever. Contrast the vulnerability of infants, adults and the elderly to temperature stress. Define hunger, appetite and satiety Discuss the behavioral and physiological factors involved in regulation of body weight on a day-to-day and long-term basis Explain the function of the hunger and satiety centers in the hypothalamus. Include the afferent mechanisms signaling the hypothalamus to regulate food intake Discuss the bodys responses to overfeeding and the challenges presented by obesity Summarize the major factors involved in maintenance of fluid balance Compare hypovolemic and osmotic thirst as triggers for fluid intake Recognize common factors in the regulation of body temperature, feeding, and fluid balance

Most of these mechanisms are negative feedback mechanisms

Control of Temperature
Body tries to keep temperature within 97.6-99.9 F (thermal balance) Heat Production - influenced by in metabolism, food intake, skeletal muscle activity Can occur by radiation, conduction, and convection Heat Loss - influenced by in metabolism, food intake, skeletal muscle activity Can occur by radiation, conduction, convection and evaporation Sweating is regulated by the sympathetic nervous system Receptors - peripheral thermoreceptors beneath skin; central thermoreceptors in hypothalamus are sensitive to changes in core and blood temperature Preoptic nucleus (in anterior hypothalamus) - initiates cooling response Receptors in posterior hypothalamus - initiate warming response Conditions Heat Exhaustion - state of collapse due to hypotension caused by excessive sweating and vasodilation Heat Stroke - severely elevated body temperature that damages body Risk of thermal dysregulation depends on age

Control of Body Weight

Visceral fat is closely associated with morbidity and mortality Ventromedial Nucleus - satiety center desire for food Lateral Hypothalamus - feeding and hunger center desire for food Short-term regulation of feeding Gastrointestinal Filling - when GI tract distends, polypeptides are released and act on the hypothalamus to inhibit food intake (ex. cholecystokinin) Ghrelin - released when stomach empty?/hungry? Prolonged chewing decreases desire for food

 Glucostatic Effect - blood glucose produces sense of satiety in body temperature appetite (and visa versa) Long-term regulation of feeding Adipose tissue releases an amount of the hormone leptin proportionate to its number of cells Leptin receptors in hypothalamus and causes decrease in food intake seem to cause sympathetic nervous activity and metabolic rate? Obese people seem to become resistant to leptin Appetite stimulation occurs via NPY, orexin, cortisol, insulin It seems that those who keep a nice body weight have a higher non-exercise activity thermogenesis

Body Fluid Regulation

Fluid intake is driven by blood osmolality and blood volume Hypovolemic thirst - cue to water intake Detected as in blood volume by blood flow through kidneys kidneys release rennin angiotensin I angiotensin II blood vessels constrict and BP Drinking also triggered and vasopressin released from posterior pituitary vessel constriction blood volume causes tension on arterial walls carotid sinus barroreceptors detect this solitary nucleus medulla autonomic reflexes to cause blood vessel constriction extracellular solute osmotic thirst some cells in hypothalamus are osmoreceptors

 Neuronal Degeneration and Regeneration

Neuronal Degeneration
Direct damage to cell body - hypertrophy of cell body and in metabolic activity; possible atrophy Indirect damage - caused by free radicals peroxidation of membrane altered structure, fluidity and permeability Secondary Cell Death - damaged neurons release bad things that cause other neurons to die Trauma activation of Ca dependent proteases these can disrupt axoplasmic transport Trauma (esp. ischemia) extra glutamate release stimulation of cells excitotoxicity Apoptosis - proceeds through activation of proteolytic caspase cascade Impaired apoptosis plays a role in failure of regression of embryologic structures, cancer, etc. Occurs in single cells, characterized by abrupt cell shrinkage, chromatin condensation, nuclear fragmentation and eventually to membrane-enclosed apoptotic bodies Chromatolysis - process in apoptosis where cell body hypertrophies, nucleus moves to edge (ie eccentricly located), Nissl bodies go to periphery

Peripheral Nerve Injuries

Neurapraxia - like a concussion, physiological interruption of function Axonotmesis - axon is cut Neurotmesis - nerve is cut Wallerian Degeneration - degeration and phagocytosis of the distal portion of the axon (anterograde) Guillain-Barre - immune attack on random Schwann cells causing segmental demyelination No sensory involvement, mainly affects large muscles, possible face diplegia

Neuronal Regneration
Dependent on a lot of molecules Agrin - a proteoglycan synthesized in motor neurons and released in growing nerve fibers Binds to postsynaptic receptors and stimulates synaptogenesis Therefore is a presynaptically derived molecule that promotes postsynaptic differentiation Synaptic rearrangement during growth Each axon innervates more cells at birth than at maturity and during maturation, there is not a net loss of synapses, but instead a focusing of each axons synapses on fewer target cells? Neurotrophins - survival and growth of different neuronal populations in both the PNS and CNS is dependent on different neurotrophins Neural regeneration is mainly the regrowth of axons, not cellular replacement PNS axons can regrow after injury (in favorable conditions they will find their target), CNS axons dont because the cellular mechanisms are suppressed If an injured PNS nerve is transplanted to an area of CNS in need of axonal regrowth the CNS can take advantage of the stuff released from the PNS nerve and regrow some axons Cells that reside in the periphery or those that project to periphery are more likely to regenerate

Neurosurgical Intervention
Did he really skip the stem cell stuff?? Normal Pressure Hydrocephalus - symptoms are wet (urinary incontinence), wacky (mental decline) and wobbly (gait problems) Ventricles will be larger, just need to put a shunt in to drain excess CSF Cells from Subventricular Zone cells harvested grown in lab transformed into functional neurons and host brain receiving cells influences their behavior

Neurosurgical Advances
Intraoperative MRI, Stereotactic Free-Hand Guidance Systems MRI Spectroscopy - allows for preoperative tentative diagnosis of tumor, abscess etc.

 Neurodegenerative Diseases
Objectives
Identify the basic clinical features of dementia Identify the basic pathological features of Alzheimers disease Explain the mid-century transition of Alzheimers disease from a rare to a common disease Explain the cholinergic hypothesis and the amyloid cascade hypothesis Explain the roles of amyloid, of tau protein and of microglia in Alzheimers disease Describe the origin of and the evidence for the idea of an infectious protein Contrast the facilitated refolding model and the seed crystal model for prion propagation List and explain the various ways in which prion diseases may be acquired Describe the origins of Mad Cow disease in the UK and in the US What is variant Creutzfeldt-Jakob disease and what is its origin