Tiffany BrockeNSS: General Sensory and Motor Outline

SOMATOSENSORY SYSTEM: PERIPHERAL MECHANISMS OF PERCEPTION

I. Peripheral receptors are specialized to detect specific different types of energy, inputs travel by dedicated pathways to targets in the CNS. a. Thus there are modalities (chemical stimuli, vision) and submodalities

(within touch, vibration, temperature)b. Senses include exteroception (body with external world), proprioception

(posture and movements of body), and interoception (state of organ systems).

c. Detect form and texture, size and shape, vibration, grip and motion, also more complex interactions with affect, like emotional touch

d. Sensory neurons have a receptive field: the part of the body where a stimulus will elicit a response from that neuron, size varies

i. Determines spatial acuity (two-point discrimination)e. A population of one type of neurons responding to a stimulus gives the

overall response, a neural imagef. Can be slowly adapting (burst of APs then continued above baseline for

duration of stimulus), rapidly adapting (burst as stimulus applied, silent, burst as it stops), and Pacinian corpuscle (RA-type with bigger bursts at both ends): detect things changing over time

II. General somatosensory pathways have the primary sensory neuron with its cell body in a ganglion (face, trigeminal ganglion; body, dorsal root ganglia), second order neuron cell body in spinal cord or brainstem (axons cross here), third order neurons in thalamus, these project to primary somatosensory cortexa. Dorsal root ganglia neurons are derived from neural crest. Pseudounipolar

structure: no dendrites, rather axon with two branches (carrying APs), peripheral branch and central branch into spinal cord by dorsal root

i. 4 classes of DRG neurons: Aa are large cells, heavily myelinated from muscle spindles and Golgi tendon organs; AB are medium cells, large myelinated axons from skin mechanoreceptors; Ad and C are small cells with lightly myelinated or unmyelinated axons respectively, carrying cold/pricking pain and warm/burning pain/itch respectively

ii. Conduction speed and ease to depolarize reflects fiber size and myelination

b. Basis for submodality segregation is what receptor channels/sensory endings each afferent end has

c. Cutaneous low threshold mechanoreceptors: in glabrous (hairless) skin, Merkel (base of dermal papillae) is slowly adapting, Meissner (dermal papillae) is rapidly adapting, Pacinian (deeper dermis) is rapidly adapting, and some free nerve endings. Hairy skin also has Merkel cells associated with base of hairs.

i. RA do motion on the skin, SA do steady pressure

d. Mechanoreceptor ion channels are physically opened by touch, stimuli stretch or deform the cell membrane

e. Meissner corpuscles have lamellar cells derived from Schwann cells tethered to epidermal ridges, up to 80 of these go to one AB-RA1 fiber (defining receptive field), detecting initial contact and movement on skin surface

f. Merkel cells (derived from epidermis) have Piezo2 protein channels that open with applied membrane force, cause release of NT onto axon. Again one afferent fiber innervates multiple Merkel cells, Piezo2 channels also on neural fiber. Detect form and texture.

g. Ruffini receptors are deeper, detect stretch (hand shape, lateral force). h. Pacinian corpuscles are layers of lamellar cells and fluid around a central

axon, filter out slow vibrations so only high frequencies stimulate the axon. Key for use of tools.

III. Muscle and joint mechanoreceptors convey information about posture and movements. a. Intrinsic stretch receptors in muscle fibers are sensitive to changes in muscle

length and receive motor axons that act to maintain that length. b. Golgi tendon organs are found on muscle tendons, respond with feedback

inhibition to increasing force to protect muscle. IV. Free nerve endings mediate nociception and thermal sensation

a. Warm receptors fire above 45C, equally sensitive to rapid and slow warming. Cold receptors are much more sensitive to sudden cooling.

i. Warm fibers fire more with increasing temperature. Cold does not, fires in different chunky bursts to distinguish temperatures.

b. Via TRP ion channels, which also recognize some molecules that thus give cool or warm sensations (mint, capsaicin)

SOMATOSENSORY SYSTEM: CENTRAL MECHANISMS OF TACTILE PERCEPTION

I. Remember the broad distinctions: large fibers carry touch and proprioception, small fibers carry nociception, temperature, and itch. Information is processed as the activity across the populations in a region. a. Also processed by time, as activity varies within populations temporally. b. Touch and proprioception pathway to cortex, body: afferents pass through

dorsal root ganglion, enters dorsal horn to dorsal columns (fasciculus gracilis for leg, fasciculus cuneatis for arm above T6, adding laterally) and rise to respective nuclei in the medulla, where they synapse. Fibers decussate and ascend in the medial lemniscus (leg now back on the lateral side). Synapse in the ventral posterior lateral part of the thalamus and rise to the somatosensory cortex (leg medial)

c. Touch and proprioception pathway to cortex, face: afferents pass through trigeminal ganglion, synapse right next door at main trigeminal sensory nucleus and cross to add to the medial side of the medial lemniscus and ascend with the body neurons. Synapses again in ventral posterior medial part of the thalamus, then most lateral of S1.

i. Recent evidence that descending input from cortex is integrated via interneuron processing in the dorsal horn of the spinal cord with the sensory afferents.

d. Pain and temperature pathway to cortex: afferents pass through dorsal root ganglion or trigeminal ganglion, primary central axons ascend or descend a few segments in Lissauer’s tract at the very tip of the dorsal horn. Synapse and cross at that level via the ventral white commissure to ascend in the spinothalamic (anterolateral) tract (crescent wing around ventral horn).

i. Face: pain/temp fibers enter in pons, descend in spinal trigeminal tract to C2 level of medulla, synapse in the spinal trigeminal nucleus, axons cross to add to the contralateral spinothalamic tract.

ii. Fibers terminate in VPL/VPM of thalamus to give conscious perception of pain. Then project to S1 and S2.

II. CNS somatosensory follows major organizing principles. a. Somatotopy: internal neural mapping of the body surface. Leg is medial

throughout spinal cord, decussation in pons gives legs lateral, then back to being medial on sensory cortex.

b. Cortex is organized in both layers and columns. Columns are structural units (like one digit), layers are functionally distinct: thalamic input to IV, projects to II-III which can go to other cortical areas, V goes to subcortical structures and VI goes back to thalamus.

i. 3a in floor of central sulcus receives proprioceptive input, then 3b codes spatial form by responding to particular orientations, then area 1 does motion with direction preference, area 2 gets both proprioception and touch depending on configuration.

ii. Projects then to S2, where neurons are more like responding to orientation of all digits – more complex, tuning depends on attention

c. Often surround inhibition for receptive fields: as sensory stimulation comes into the dorsal column nucleus, branches terminate on neurons that inhibit adjacent neurons, and second order neuron in thalamus also inhibits surrounding neurons, and cortical neurons can dampen inhibition or excitation lower down

d. Cortex is plastic, if part of the body is no longer sending afferent input that part of the cortex will be reassigned to respond to other nearby areas. Causes the phantom limb sensations after limb loss.

PAIN MECHANISMS

I. Pain is a multifactorial and emotional systemic perception of tissue damage, while nociception is detection of noxious stimuli. a. Nociceptive neurons depolarize in response to exogenous stimuli, while

cortical processing is what gives the subjective experience of pain. b. Compound action potential: any nerve is composed of axons carrying

different types of information (labeled lines). Ad fibers carry the initial component of pain, C fibers do delayed component, and AB fibers can be perceived as painful after nerve injury and tissue inflammation (allodynia)

c. The threshold for heat pain is 45C pretty universally in peopled. Ischemic tissue or neutrophils doing anaerobic respiration produce local

acidosis, broken cells release ATP, regulated release of histamine all noxious chemical stimuli; also some analgesic peptides cleaved from precursors

i. Remember prostaglandins come from membrane phospholipids when tissues are injured via phospholipases and COXs, noxious stimulus

e. Pain can be acute or chronic, encouraging protection vs. outliving damage. Can be inflammatory, neuropathic (peripheral neuron damage), or central (brain damage) in origin

f. Pain serves a purpose – congenital insensitivity to physical pain means person lacks negative reinforcement to protect their tissues.

II. Hyperalgesia is increased pain in response to a formerly noxious stimulus – both primary becoming more sensitive to heat and touch within the injured region and secondary more sensitive to touch nearby (more severe pain per stimulus)a. Allodynia is pain in response to formerly nonpainful stimuli, like light touch

(left-shift of force for you to start feeling pain)b. Hyperalgesia can result from increased peripheral or central sensitizationc. Visceral pain may be referred, as visceral and cutaneous neurons converge at

a particular part of the spinal cordIII. Spinal cord laminar anatomy: III and IV can be sensitized at the level of an injury;

I, II, and V receive nociceptors but II is interneurons only while I and V go to braina. Lamina V tends to do sensory discriminative aspects, like localization,

intensity; going through anterior spinothalamic tract to lateral thalamus and somatosensory and insular cortex

b. Lamina I has other processing like homeostasis and emotional content of pain, to lateral spinothalamic tract and medial thalamus to anterior cingulate cortex and insular cortex

IV. Receptors for noxious stimuli a. May be in the acid-sensing ion channel (ASIC) family, where low pH opens a

sodium channel. ASIC 3 is enriched in nociceptive neurons in muscle, more robustly activated by combined protons and lactate to detect muscle struggling to perform.

b. Heat-gated ion channels are like TRPV1, enriched in nociceptive neurons and which binds capsaicin, TRP channel family does all heat sensations.

c. Voltage gated sodium channels include NaVs 8 and 9, on nociceptors and important for initiation of pain APs.

i. Distinct from NaVs 1-7 because 8 and 9 aren’t blocked by tetrodotoxinii. Yet all are involved in pain sensation, as well as voltage-gated calcium

channels in spinal cord. iii. Local anesthetics and tricyclic antidepressants block 1-9, 1.7 mutated

in congenital insensitivity to pain. d. Potassium channels are analgesic, open and diminish nociceptor excitabilitye. May also act at GPCRs: highly expressed in nociceptive neurons and when

their ligands bind, they promote pain sensation and sensitivity by phosphorylating excitatory ion channels

i. But analgesics like endogenous opioids (enkephalins, endorphins, dynorphins) and exongenous (morphine) also act through GPCRs

f. Neurotrophins are in the NGF and GDNF families, each family has a common domain and a distinct track functional domain, affect gene expression to regulate nociceptor anatomy and function

i. Promote nociceptor class differentiation during development, nociceptor survival, nociceptor gene expression, signaling cascades that sensitize ion channels, and activate selective trafficking of ion channels to the peripheral terminal.

g. Signaling is plastic – activity-dependent, microglia, spinal interneurons all change efficiency of NT release

i. Descending modulatory pathway from cortex to periaqueductal gray to rostral ventral medulla to spinal cord influences efficiency of inputs affecting firing of spinal projection neuron

ii. Where opiate drugs act, analgesic opiate receptors throughout (mostly target mu subtype): decreasing excitability, controls pain but deleterious side effects, naloxone antagonist

h. Endogenous opiates are produced throughout CNS by cleavage from polypeptide precursors

i. May get genetically altered sensitivity to pain by lacking nociceptive neurons from defective neurotrophins, hypofunctional NaV1.7, polymorphic drug transporters or cytP450s giving altered metabolism

MOTOR SYSTEM: DESCENDING PATHWAYS

I. Peripherally, motor system ends with muscle, composed of fascicles, each fascicle containing multiple muscle fibers (cells), each with multiple myofibrils (force-generating protein unit)a. Proximally, motor neurons synapse with muscle fibers at neuromuscular

junctions, mediated by acetylcholine; depolarizing gives generation of forceb. Amount of force generated depends on the rate of action potentials: above a

frequency threshold, twitches become a smooth contractionc. Motor unit: a motor neuron and all the muscle fibers it innervates. Each

muscle fiber is innervated by only one motor neuron from the ventral horn of the spinal cord. 70% of motor neurons are alpha type driving contraction.

d. Three types of muscle fiber, based on three protein isoforms: type I is slow-contracting and fatigue resistant, IIa is fast-contracting and fatigue resistant, and IIx is fast-contracting and easily fatigued. All muscle fibers in a given motor unit are the same type.

i. Fiber types can convert with use to give different muscle compositione. Muscles generate more force by recruiting more motor units to firef. Remember intrafusal fibers detect stretch within the muscle spindle,

measuring length and rate of change of length; Golgi tendon organs sense force on the muscle

i. Muscle contracts, spindle fiber becomes slack, gamma motor neurons modulate length of this fiber to give sensitivity to stretch

II. CNS organization: somatotopy is retained in the descending system, as motor neurons going to the same muscle will be near each other, distal muscles laterally in the ventral horna. Corticospinal tract is the only tract with monosynaptic connections from the

cortex to the spinal cordi. Starts in cortex (M1, PMd, other), decussates in medullary pyramids,

down through spinal cord to synapse directly onto spinal motor neurons

ii. Vast majority decussates to the ventral corticospinal tract, just a small amount stays in the ipsilateral lateral corticospinal tract (trunk)

b. Reticulospinal tracts originate from reticular formation across brainstem, control posture and balance. Pontine part is excitatory, medullary part is inhibitory.

c. Tectospinal goes from tectum, decussation of pyramids, cervical musclesd. Rubrospinal goes from red nucleus to arm extensors, vestibulospinal goes

from lateral vestibular nucleus to leg extensorsi. Lesion the corticospinal tract and get deficit in fine finger movements;

lesion the reticulospinal tract or vestibulospinal tract and get postural deficits

ii. CST gets enhanced and distinct in more advanced primatese. Simple (early, R1) reflexes are mediated by spinal cord pathways: tap the

tendon, muscle lengthens, spindle detects, sensory neuron triggers motor neuron for that muscle, corrects by contracting. Also stimulates inhibitory interneuron to antagonist muscle, so the opposing muscle will relax.

i. Later reflexes (R2, R3, longer than 50 ms) use a transcortical pathway to integrate information across multiple joints

f. Generating force with any muscle unbalances the body, via reticulospinal tract brain coordinates movement to counteract

MOTOR SYSTEM II: CORTEX

I. The cortex exists to support movement. Especially key are the primary motor cortex at the precentral gyrus, then supplementary motor area and premotor cortex anterior to that. The posterior parietal cortex is posterior to S1. a. Remember the motor system is layer V of the cortex, projecting to brainstem

and spinal cordb. Via electrical mapping, found contralateral somatotopic organization of M1,

with feet and toes medially and face laterally. More subtle intracortical microstimulation gives some disjointedness for each body part.

i. Could also track by rabies virus traveling retrograde transynapticallyii. Multiple site outputs converge onto one muscle; neighboring site

outputs diverge onto different musclesc. M1 activity for particular motor tasks has some relative overlap between

people but the patterns themselves are not shared. d. Individual M1 neurons are tuned for even particular types of movements, so

motor cortex constructs movements by summing the vectors of each neuron

i. So with more force required, firing rate increasesii. Tuning direction changes with changes in posture

e. M1 is highly plastic, brain areas changing to reflect changes in body and very quickly. Also becomes more sensitive to new tasks that you learn, so usage dictates representation.

II. Premotor cortex (PMd) is found laterally between the prefrontal cortex and primary motor cortex. Divided into ventral and dorsal regions, encodes the precursors to motor commands generated by M1. a. Does abstract movement plans (preparatory activity), as tuning direction is

invariant to changes in posture. b. Thought that if the target is not fully known, movement plans are encoded in

parallelIII. Supplementary motor area is sensitive to particular sequences of movement or

in transitions between sequence elementsa. SMA is selectively active during memory-guided movement, vs. PMd active

during visually guided movement. M1 is the same movement no matter what. b. Posterior parietal cortex is active during movement but doesn’t vary by load

on the muscle – an abstract sensory representation, tuned to the spatial location of movement goals

i. Thought to integrate information from proprioception and vision into a single coordinate system for M1 to engage with

ii. Lesions here can lead to neglect of the contralateral visual spaceiii. Lesions to left parietal cortex give apraxia, an inability to imitate or

use tools with strength and dexterity intact

THALAMUS AND CEREBRAL CORTEX

I. The thalamus is composed of individual nuclei to keep the information segregated, does not refine its input but can strengthen it so that the cortex pays more attention to it. Gyri are subdivided into functional unit cortical areas. a. Can define thalamic and cortical regions by structure, connectivity, and

functionb. The cortical mantle has five lobes, the frontal, parietal, temporal, occipital,

and insular, each different functional regions, so location of damage dictates loss of function.

c. Ventral occipital lobe does visual things: guidance of navigation, perception of color and faces and emotional response to those

d. The left hemisphere is dominant. Broca’s area (inferior frontal gyrus) does motor aspects of language, so damage there gives nonfluent aphasia and deficits in perception

i. Wernicke’s area (superior temporal gyrus) gives fluent aphasia, not aware they don’t make sense. Similar damage on right side will give visual hemispatial neglect until attention is drawn to that side.

e. Spaces with more territory dedicated to them are more likely to get strokes that affect only them, whereas trunk is so small on cortex that will present with other problems

f. Brodmann’s areas are separated by changes in the size and packing density of cell bodies in the cerebral cortex.

i. Layer I is superficial, dominant is layer IV which receives most thalamic input to its pyramidal cells. Structural differences in these layers indicate functionally distinct regions.

ii. Association areas of cortex are homotypical (medium amount of cell bodies), can be granular (primary sensory) or agranular (motor) with more and less.

g. Pyramidal cells communicate within and outside the cortex but mostly with their neighbors, all are glutamatergic (excitatory, spiny dendrites). Stellate cells have local axons and release GABA. Layer IV stellate cells have spiny dendrites and are powerfully excitatory, dominate cortical response.

II. All ventral thalamic nuclei go to the primary sensory or motor regions. Thalamic nuclei are named relative to the internal medullary lamina. Lateral geniculate nucleus does visual relay and medial does auditory relay. a. Thalamic nuclei have two-way relationships with cortical regions. Anterior

nuclei go to the cingulate gyrus, medial nuclei go to the prefrontal cortex, lateral group goes to the association areas

b. Also a thalamic reticular nucleus that releases GABA onto its thalamic targets, giving inhibition of those neurons followed by rebound: thus rhythmic thalamic and cortical activity and sleep.

c. Ascending reticular activating system is brainstem neurons that go broadly to thalamus and cerebral cortex to release Ach, DA, NE, serotonin: activate forebrain neurons and do arousal. Not discriminatory information, just volume neurotransmission to become responsive to excitatory inputs.

i. Ex. Locus ceruleus in the pons sends NE axons to the whole cortexii. Cholinergic input to thalamus from reticular formation and cortex

from basal nucleus, key for cortical plasticity. The first to die in Alzheimer’s disease

SYNAPTIC PLASTICITY

I. Synaptic plasticity underlies both good behaviors like learning and maladaptive behaviors like drug abuse. a. Noted: after tetanic stimulation, upon return to single volleys, a more intense

EPSP than before is noted, and the change persists for weeks. This is long-term potentiation in synaptic response.

b. Increased stimulation of the presynaptic neuron causes LTP by both increased NT release and increased postsynaptic response to NT.

c. Remember post-synaptic receptors can be ionotropic (binding opens ion channel) or metabotropic (binding stimulates G protein); ionotropic glutamate receptors include AMPA and NMDA.

i. AMPA-R is gated by glutamate only and permeable to Na and Kii. NMDA-Rs are gated by glutamate in combination with depolarization

(without depolarization, channel blocked by Mg ions) and permeable to Na, K, and Ca

iii. Thus during tetanus, the post-synaptic dendrite depolarizes long enough to activate NMDA-Rs, giving calcium influx and insertion of more AMPA-Rs into the post-synaptic density. Thus next NT volley gives a greater amplitude response.

d. Thought to be some ceiling on each synapse’s ability to potentiate: can’t keep adding indefinitely. But generally, stimulating a pathway makes it easier to activate in the future.

i. But can be bad, like seizures make more seizures easier. e. Potentiation is generally synapse-specific, since glia ensheathe synapses so

that others don’t get the local glutamate. However, can be cell-specific if a weakly active input is activated at the same time as a strong tetanic input, so that the dendrite depolarizes globally and the weak glutamate can still give NMDA-R activation there.

i. Think associativity potentiation, like PavlovII. Fragile X syndrome is one of the most common inherited intellectual disabilities

a. Fragile X mental retardation protein (FMRP) blocks translation in the dendritic spines that is driven by metabotropic glutamate receptors. Defective FMRP gives excessive translation and maladaptive plasticity: low-level NMDA-R activation gives long-term depression of that synapse. Thus, get only transient plasticity.

b. Unclear whether this is a developmental or ongoing defect – if decreasing mGluR activation would rescue the cognitive defects.

INTRODUCTION TO CLINICAL LOCALIZATION

I. Remember apraxia is the lack of ability to carry out learned purposeful movements despite intact strength and coordination; agnosia is lack of recognition with the primary sensory modality intact; aphasia is a disturbance in formulation and comprehension of language despite intact articulation and hearing; dysarthria is inability to physically move tongue to make speech. a. Remember the dorsal column – medial lemniscal system does position,

vibration, and fine touch; the anterolateral system does heat and temperature

b. Aphasia, neglect, apraxia, and agnosia indicate cerebral cortical involvementc. Visual dysfunction implies involvement within the orbit or in pathways

ending in the occipital cortexd. Disorders of alertness imply a systemic metabolic problem, brainstem lesion,

or bilateral cerebral cortical lesionse. If a cranial nerve palsy is present, spinal pathology is unlikely if there is only

one lesion. f. Ischemic stroke is typically acute in onset with symptoms maximal at time of

onset. Intracranial hemorrhage presents more progressively (hours to days) as the hematoma expands. Insidious onset (days to months) is more consistent with neoplasm or abscess.

II. Remember spinal anatomy: spinal nerve carrying mixed sensory and motor information to dorsal and ventral rami

a. One anterior spinal artery feeding the central cord, two posterior spinal arteries

b. Dermatome levels: C6 is thumb, T4 is nipples, T10 is umbilicus, S1 is sole of the foot

c. Test the dorsal column – medial lemniscal system with proprioception and tuning fork; test the anterolateral system with sharp touch and cold tuning fork; test the corticospinal tract with extension and flexion confrontation

d. Remember reflexes happen at the level of the nerve of interest. Lesions at the spinal level that innervates the muscle may affect the lower motor neuron, giving hyporeflexia. Inhibition of spinal reflexes is done by descending corticospinal tract, so lesion above the level that innervates that muscle will give hyperreflexia.

i. Biceps and brachioradialis reflexes are C5, C6; triceps reflex is C7, C8; patellar reflex is L2, 3, 4; ankle jerk is S1.

e. Brown-Sequard syndrome: because of where different fibers decussate, may get ipsilateral vibration loss but contralateral pain and temperature loss to where the lesion actually is.

i. Note anterolateral system decussates over a few levels so may catch some ipsilateral pain and temperature loss at level of injury.

III. For brain, remember that each hemiretina observes the opposite side of the visual field (lateral of left and medial of right both see the right side of each visual field). Partial decussation in optic chiasm so left-sided optic chiasm, lateral geniculate nucleus, and optic radiation carry visual information from the right side of each eye’s visual field. a. Know where things decussate – corticospinal tracts at the medullary

pyramids, corticobulbar tracts at the level of cranial nerve innervationb. Contiguity: things near each other tend to be involved, like CNs IX, X, XI

exiting through the jugular foramen c. Remember somatotopy within pathways, the vascular territories (like PICA

supplies dorsal lateral medulla and inferior medial cerebellum)d. Consider another unifying feature may be cellular specificity or selective

vulnerability, like all dopaminergic neurons

WEAKNESS AND DISEASES OF THE MOTOR UNIT

I. Diseases of different parts of the motor unit have different presentations. a. Motor neuron disease (neuronopathy) includes amyotrophic lateral sclerosis

(ALS, Lou Gehrig’s disease), poliomyelitis, and spinal muscular atrophyi. Poliomyelitis is post-polio syndrome of accelerated weakness as they

age, no longer common in the USb. Most motor neuron disease in the US is ALS: mostly sporadic, inherited form

is autosomal dominant mutation in superoxide dismutasec. Criteria for ALS diagnosis are upper motor neuron signs by exam, lower

motor neuron signs by clinical, electrophysiological, or pathological exam, normal sensation, autonomic function spared, no visual involvement, and progression to other muscles

i. Progresses over time, LMN involvement expect weakness, atrophy, fasciculation (little twitches); UMN findings reflect hyperreflexia and cortical findings

d. Spinal muscular atrophy also known as Werdnig-Hoffmann syndrome: lower motor neuron involvement only, often from mutated SMN1 gene. Typically a disease of newborns (floppy baby – hypotonia) with diffuse and severe weakness, like trouble feeding and breathing, normal intellect

i. Antisense oligonucleotide drug (spiranza) has babies now living into toddlerhood, previously 95% mortality by 17 mos

II. Radiculopathy means a problem with the nerve root (like sciatica), often pinched by a slipped diska. Steppage gait: trouble dorsiflexing, so picking the whole leg up higher to

clear the floor with the toesb. A very focal phenomenon: weakness and pain in the distribution of the

slipped diskIII. Mononeuropathies are like radial neuropathy, manifesting with wrist drop.

a. Usually caused by local trauma, just needs days to week to get over a night’s pinch from sleeping wrong.

b. Carpal tunnel syndrome is median neuropathy at the wrist, often worse at night when people flex their wrists in sleep.

i. Often idiopathic, or more common with hypothyroidism, pregnancy, diabetes

c. Or ulnar neuropathy at the elbow from trauma, soft tissue masses, just entrapment at the muscle insertion

IV. Neuromuscular junction disorders tend to manifest with more proximal weakness (trunk muscles and large joints like hips and shoulders), vs. like having trouble turning keys in locks would get at distal weakness. a. Can evaluate subtle facial weakness by asking to blow up a balloon, compare

to older picture of themselvesb. Myasthenia gravis results from autoantibodies against the Ach receptor,

resulting in loss or dysfunction: flattened postsynaptic foldsi. Get fatigue following exertion as activity is less efficient, worse in

afternoon and evening: diplopia watching TV at nightii. Also dysarthria (floppy palate giving nasally speech), dysphagia

(trouble swallowing from pharyngeal weakness), dyspneaiii. Diplopia and asymmetric ptosis precipitated with sustained upgaze,

facial weakness, limb weakness from sustained actioniv. Treat with immunosuppressants (steroids are fast, azathioprine take

longer). AChase inhibitors like pyridostigmines act fast on symptoms but not everyone responds. Myasthenia crisis is presenting with respiratory failure, may require intubation and IV Ig

V. Myopathy presents with symmetric weakness, preserved reflexes, absent sensory signs and symptoms, normal autonomic function, and generally proximal involvementa. Many etiologies; toxic myopathy commonly caused by statins

b. Polymyositis is CD8 T cells mediating damage: commonly elevated creatine kinase and dysphagia, lymphocytic infiltrate visible on biopsy

c. Dermatomyositis is more humoral mediated with complement deposition on capillaries, get heliotrope rash on eyelids and sunburn/shawl pattern, warty Gotron’s papules on knuckles, possible calcinosis, proximal weakness and elevated CK

i. Perifascicular atrophy on histologyd. Inclusion body myositis is more in older men, weakness of wrist flexors and

quadriceps, refractory to corticosteroid therapy: vacuoles and inclusions on histology

e. Steroid-induced myopathy is common anywhere in the hospital: proximal weakness associated with prolonged steroid use

f. Acute quadriplegic myopathy is more in ICU and associated with high dose corticosteroid use; rapidly occurring but better recovery

VI. Sensory neuropathy indicates sensory involvement with or without motor involvementa. May be multiple mononeuropathies, strokes of peripheral nervesb. More commonly distal symmetric polyneuropathies, commonly from

diabetes starting in feet with longest neuronsc. Ganglionopathy is commonly like shingles, loss of proprioceptiond. Common causes include diabetes, alcoholism, autoimmune disease,

medication, infection, trauma, tumors, vitamin deficienciese. Axonal neuropathy has more sensory than motor and more distal than

proximal with ankle jerks absent. Demyelinating neuropathy has more motor than sensory and more proximal than distal, all reflexes absent. Sensory neuropathy is DRG, pure sensory and equal distal and proximal, all reflexes absent.

CASE CONFERENCE: MOTOR SYSTEM

I. Neural tube defects occur 3-4 weeks after conception. If it fails to close, can range from open or closed spina bifida caudally to anencephaly or encephalocele rostrally. a. A Chiari malformation is when the hindbrain herniates into the spine, often

producing hydrocephalus that may require a ventricle-peritoneal shunt placed.

b. Found that repairing the myelomeningocele could be done intra-uterine with better outcomes, and especially fetoscopically was better for pre-term births

c. Remember brain development occurs throughout childhood and adolescence, as myelination occurs and neural connections are formed and then pruned away in a manner driven by interactions with the world.

i. Frontal cortex thickens and myelinates, giving executive function and logical reasoning, like the Piaget water amount test and Stroop color-word test

d. Neurosurgeons try to protect the eloquent regions: somatosensory cortex, Broca’s area, Wernicke’s area, and the supplementary motor cortex, as damage here may be permanent.

e. For operations in very sensitive areas near stuff you want to keep, can have pt awake and interacting to make sure you’re not about to wreck anything

AMYOTROPHIC LATERAL SCLEROSIS

I. ALS is a progressive slow wasting and weakness of skeletal muscle. It begins focally and becomes generalized to all muscles. a. It is always fatal, usually within 2-5 years of diagnosis, as people become

unable to eat and breathe. b. 50% of pts have mild cognitive dysfunction, and a small subset has severe

frontotemporal dementia. c. Muscle wasting results from degeneration of both upper and lower motor

neurons and interneurons: see fasciculations (involuntary twitches) from LMN disruption from the muscle, and spasticity (increased tone and exaggerated deep tendon reflexes) from UMN loss.

i. On post-mortem biopsy, lateral corticospinal tract is enhanced (neurons are dead), interneurons dead, and alpha motor neurons gone

ii. Will also see atrophy of ventral motor roots, with sensory dorsal roots generally unaffected

d. Concomitant changes in muscle when motor axons degenerate, visible denervation atrophy on histology: clumped small angular muscle fibers with peripheral nuclei retained

e. Cytopathology: loss of Betz cells (cortical motor neurons). When axons degenerate, bundles of neurofilaments polymerize and become large inclusions. Small eosinophilic cytoplasmic inclusions called Bunina bodies, not thought to be too important. Focal gliosis (activation of local microglia), and TDP43 cytoplasmic aggregates.

i. TDP43 is a nuclear protein involved in RNA metabolism, yet seen as cytoplasmic aggregates in almost all ALS pts: leads to death and dysfunction of those cells, and found in other degenerative diseases

II. Genetics of ALS: sporadic (unknown origin) in vast majority of cases, familial in just 5-10% of cases. Some increased incidence accompanied by Parkinson’s and dementia in Japan and Guam, but otherwise same risk worldwide. a. Median age of onset is 54 yo, slightly more prevalent in men than women

(argues against autoimmune cause) b. Most sporadic ALS is classical, involving both upper and lower motor

neurons. This is the fatal kind. i. Also primary lateral sclerosis (UMN symptoms only – severe

spasticity, progressing slowly over decades)ii. Progressive muscular atrophy is purely a lower motor neuron disease,

the adult version of spinal muscular atrophy

c. In most people the disease spreads, often in a windmill fashion (right hand to left hand to left leg etc). Asymmetric presentation is common in distal limbs, yet both sides of the tongue are always affected.

d. 50% of pts die in 3-4 yrs, some familial forms in just monthse. Remember signs are muscle atrophy, fasciculations, hyperreflexia (tapping

with fingers can elicit brisk reflexes), spasticity (velocity-dependent resistance to passive movement; Hoffmann and Babinski signs are UMN)

III. Riluzole can extend life by 3 mos to 1 yr; all other drugs keep failing clinical trials, despite many having been tried. We need to know where it’s coming from to be able to generate effective therapies. a. Trying to study with mouse models (reliable but not clinically good), human

induced pluripotent cells, zebrafish, othersb. Superoxide dismutase 1 is found in every cell in the body, yet any mutation

will produce only ALS. Autosomal dominant inheritance accounting for 15% of familial ALS, clinically identical to sporadic ALS.

c. More than 25 genes now discovered to have contributions to ALS. d. Recently: the GGGGCC repeat in the C9ORF72 found in half of familial ALS

and 10% of sporadic ALS, most common cause yet foundi. Still don’t know what it’s doing, but repeat expansion mutations can

give ALS in some people and frontotemporal dementia in othersii. Knockouts don’t produce disease, so not thought to result from

haploinsufficiency of this factoriii. Large repeat RNA stretches may be sequestering RNA-binding

proteinsiv. Also demonstrated repeat-associated translation: without a start

codon, still generating dipeptide repeat polypeptide aggregates, may produce toxicity

v. Overexpression of RanGAP1 in C9ORF72 mutants has been shown to suppress neurodegeneration. Pathophysiology of RanGAP1 (a nuclear transport protein) is key. Mutations in various of the 30 nuclear pore proteins produces neurodegenerative diseases. May also cause TDP43 mislocalization.

e. The proteins mutated in neurodegenerative disease are almost always ubiquitous. Established that non-neuronal cells, especially oligodendroglia, drive the disease in motor neurons, which produce the clinical phenotype.

f. Studies of UMN disease called lathyrism developed link suggesting one pathogenic mechanism may be glutamate toxicity, and indeed ALS pts show increased glutamate levels in CSF and decreased glutamate transporters

g. Remember TDP43, a pathology found in non-SOD1 fALS, ALS-FTD, and sALS: normally nuclear, here localized to cytoplasm in motor cortex, spinal cord, and other brain areas

i. With mutations associated with the pathophysiologyii. Found that without TDP43 in the nucleus, RNA is not processed

properly and cells die, except increasing it also kills cells

h. In any case: now we can try treating with antisense oligonucleotides to these repeat expansions, so they can’t do their toxic thing. Shown to rescue defects in mouse models and iPS cells. Also useful against SOD1.

THE NEUROMUSCULAR JUNCTION

I. Remember movement happens when upper motor neurons stimulate lower motor neurons stimulate muscle cells at the NMJ, transmitting an electrical impulse that depolarizes the muscle membrane and results in contraction. a. Each muscle fiber has only one NMJ, which is small relative to the fiberb. Remember structure: presynaptic axon terminal has vesicles containing ACh,

postsynaptic membrane has invaginations with nicotinic AChRs at the tips and voltage-gated sodium channels in the depths. The synaptic cleft is filled with basal lamina.

c. Electrical impulse to chemical neurotransmitter to depolarizationi. Resting presynaptic membrane polarized with positive charge outside

ii. AP depolarizes membrane by opening voltage-gated Na channelsiii. Presynaptic voltage-gated Ca channels open and allow Ca influxiv. Ca influx triggers fusion of ACh vesicles with the membranev. ACh diffuses across cleft, binds postsynaptic AChR

vi. AChR opens and allows sodium influxvii. (synaptic AChesterase embedded in basal lamina inactivates ACh)

viii. Depolarization of postsynaptic membrane opens voltage-gated Na channels there

ix. Postsynaptic depolarization triggers a muscle action potential, itself triggering muscle contraction

d. Presynaptic function depends on biosynthesis of ACh: choline acetyltransferase combining choline and acetyl-CoA.

i. Decreased uterine motility during pregnancy, infant born with poor tone, bilateral ptosis, poor suck, difficulty ventilating. Found to have mutated ChAT with lower affinity for acetyl-CoA, so child can’t maintain normal levels of ACh in vesicles.

ii. Normally okay but under stress (fever, exertion), may not have enough ACh to compensate for increased muscular demand. Condition improves with age.

iii. 54 yo man has trouble going up steps, can’t squat initially but can after a few tries, revealed SCC of the lung. Autoantibodies against presynaptic voltage-gated Ca channel inhibiting its opening: Lambert-Eaton myasthenic syndrome

iv. Reduced calcium limits vesicle fusion, but repeated stimulation can build up enough to generate action (stronger with time): a paraneoplastic syndrome, tumor makes something that looks like this

e. Vesicle fusion is mediated by synaptobrevin on the vesicle membrane and SNAP25 and syntaxin on the presynaptic membrane, calcium influx causes these SNARE proteins to bind and fuse vesicle and membrane.

i. Aided by synaptotagmin, vesicle calcium sensor.

ii. Woman eats home-canned vegetables, develops nausea and vomiting, ptosis, dysphagia, and paralysis, requiring mechanical ventilation for a month. Botulism: bacterial toxin has heavy chain allowing entry into axon terminal and light chain metalloprotease that cleaves SNARE proteins. Long-lasting weakness until NMJ elements are turned over.

iii. Different types of botulinum toxin cleave the 3 SNARE proteinsf. The nicotinic AChR has 5 subunits, two of which bind ACh. When both of

these bind, subunits rotate and replace bulky hydrophobic side chains inside channel with smaller hydrophilic sidechains, permitting sodium ion passage.

g. Safety margin: about 400,000 ACh vesicles/nerve terminal, up to 300 released at a time to give an excitatory post-synaptic potential of 50 mV where 10 mV is the threshold for voltage-gated sodium channels to open. Repeated stimuli deplete vesicles in the active zone and decrease the safety margin

i. 62 yo man has intermittent eyelid drooping driving or watching TV, weak voice after speaking, fatigable ptosis on exam. His safety margin is inadequate: myasthenia gravis, autoantibodies against postsynaptic nAChR blocking binding. Thus fewer AChRs available and repeated activity getting below safety margin and fatigability.

h. Succinylcholine keeps AChR open and prevents repolarization, depletion of calcium in presynaptic terminal giving flaccid paralysis, an anesthetic.

i. AChase is extremely efficient, signaling can only succeed because the receptor density is higher than enzyme density.

i. Can treat with inhibitors like pyridostigmine to increase availability of ACh in the synaptic cleft for Lambert-Eaton or myasthenia gravis

PARALYTICS AND LOCAL ANESTHETICS

I. Neuromuscular junction blocking drugs may be depolarizing (nicotinic ACh agonists resulting in sustained depolarization) or non-depolarizing (competitive antagonists keeping the receptor closed)a. Reversed by redistribution, gradual metabolism, excretion, or specific

reversal agentsb. A charged ammonium moiety keeps them from crossing the blood-brain

barrier, giving no CNS effects at all: paralysis only, no sedation or analgesiac. Used to facilitate tracheal intubation, since the first shot is the best for this; to

relax muscles for optimal surgery and allow lower use of CV depressants; and to promote respiratory synchrony while on ventilators.

II. Depolarizing neuromuscular blockers are succinylcholine (ACh mimic): the fastest-acting blocker we have and hydrolyzed by pseudocholinesterase very quickly (like 10 mins)a. Creates optimal intubating conditions quickly, good for trauma, difficult

airways, rapid sequence induction b. Side effects: fasciculations for the first 10 sec, myalgias common in younger

pts, cardiac depressant effect from cross-reaction with muscarinic receptors (don’t use in babies with already high parasympathetic tone), salivation,

trismus (masseter spasm giving jaw rigidity, a sign of malignant hyperthermia)

i. Phase II block: repeated doses can cause a block of prolonged paralysis, have to dose once and correctly

c. Also causes hyperkalemia, tolerable in most pts but not if they’re already hyperkalemic; can get hyperkalemia or malignant hyperthermia if they have extrajunctional AChRs from burns, muscle trauma, immobility, or central cord neurologic disease like Duchennes MD

i. Contraindicated in these situations! d. 4% of population carries atypical pseudocholinesterase gene so that they get

a 6-8 hr paralysis and must be ventilated until succinylcholine wears offIII. Non-depolarizing neuromuscular blocking drugs are aminosteroids

(rocuronium, vecuronium) and benzylisoquinolinium derivatives (cisatracurium), competitive antagonists of ACha. Rocuronium is short duration, vecuronium is intermediateb. Vecuronium and rocuronium eliminated by liver, cisatracurium by Hoffmann

elimination (organic chemistry, does not require liver or kidney function)c. Can monitor how paralyzed someone is by checking mechanically evoked

twitch responses from peripheral nerve stimulation at several sites: ulnar nerve to adductor pollicis, facial nerve to corrugators supercilii

d. Can wear off over time, but if the case finishes before that give reversal agents: anti-cholinesterase drugs like neostigmine or edrophonium to be fast-acting

i. Give an anti-cholinergic like glycopyrrolate first to block muscarinic side effects, can use atropine in infants because acts faster although crosses BBB

IV. Local anesthetics can be used for anything where you don’t want people to feel what’s going on but you need them awake, think epidurals, peripheral nerve blocks, Lidocaine at the dentista. Function by blocking voltage-gated Na+ channels in the nerve fibers that they

diffuse through tissue to reachb. Amount of block depends on concentration and volume of anesthetic, and

amount needed to block reflects potency of anesthetic, the physicochemical environment, and properties of the nerve being targeted

c. Sensory transmission is the first to be impacted: blocks light touch, sharp pain, motor function, proprioception, and temperature in that order

d. Exist in equilibrium between neutral and cationic forms in solution, where the high protein binding form lowers movement across the placenta

e. Local anesthetics include aminoesters (chloroprocaine, hydrolyzed by plasma esterases) and aminoamides (bupivacaine, lidocaine, mepivacaine, ropivacaine, metabolized in liver)

f. The high-risk side effect is systemic absorption: risk greatest with intercostal nerve block and least with femoral/sciatic blocks since these nerves are so large. Can diminish by aspirating before placement and co-applying with epinephrine to vasoconstrict nearby vessels.

g. Toxicity to CNS (low doses give depression like coma, respiratory/CV arrest, high doses give excitation like seizures, lightheadedness a good canary) CV (arrhythmias, cardiac arrest, requires higher doses than CNS tox), and from injection directly into a nerve

MYELINATION

I. Myelin is a multilamellar specialized extension of the myelinating cell plasmalemma containing specific proteins and glycolipids, generated by Schwann cells in the PNS and oligodendrocytes in the CNS. a. Schwann cells are of neural crest origin, vs. oligodendrocytes of neural tubeb. Schwann cells may be myelinating (wrapping around axon segments) or

nonmyelinating (engulfing the axons but not actually myelinating them) – either way they isolate axons via their basal lamina

c. Schwann cells do not re-enter the cell cycle in health, although they can proliferate to repair damage. Normally 1:1 axon:Schwann cell, but for unmyelinated nerve fibers many axons per Schwann cell and renewed by constant low-level proliferation.

d. Function of myelin is to increase AP speed: saltatory conductioni. Nodes of Ranvier have high density of sodium channels and no myelin,

paranode is where the myelin attaches, then juxtaparanode with prominent potassium channels, internode

II. PNS development: Large axons attract Schwann cells to myelinate them, which in turn produces axonal enlargement. Smaller axons form Remak bundles, which a Schwann cell grabs to hold together. a. Schwann cells stay immature until they find a large axon to myelinate, highly

regulated development from neural crest cellsb. Most myelination takes place postnatally wrapping from the middle out,

giving increased cognitive and motor/sensory function throughout development

c. Case study: Guillain-Barre syndrome is characterized by slowed conduction velocity and temporal dispersion on EMG-NCS, and signs of weakness, loss of tendon reflexes, and high CSF protein without cells. Remember assctd with Campylobacter infection and diarrheal illness, a rapidly progressive autoimmune attack on myelinated PNS, a neurologic emergency.

i. Incomplete pattern of vesicles forming and macrophages stripping; temporal dispersion characteristic of acquired problem

ii. Treat with immunosuppressive medication, admission and airway support

d. Case study: Charcot-Marie-Tooth disease is usually a genetic defect in PMP22 (myelinating Schwann cell surface protein) may see hammer toes and pes cavis or claw hand, absent DTRs, severe distal muscle atrophy, slowed conduction velocity without temporal dispersion or conduction block on EMG-NCS

i. See onion bulbs on histology: Schwann cell keeps accumulating myelin layers because it knows they’re not good, eventually axon within dies. Hypertrophy of the nerve with all the extra membrane

III. CNS myelination develops postnatally through puberty and beyond, giving the increase in brain size a. Myelination by oligodendrocytes, each of which sends processes around

multiple axonsb. CNS myelination can be disrupted by malnutrition, prenatal exposure to

alcohol, and thyroid diseasec. Note oligodendrocytes also support axons in other important ways:

astrocytes convert glucose to lactate and give that to axons directly or through oligodendrocytes via MCT1, then axons use that for metabolism

i. Killing this transporter kills the neurons, MCT1 is importantd. Case study: multiple sclerosis is an autoimmune demyelinating disease of the

CNS, characterized by neurologic symptoms jumping around the body (presenting then clearing up, distinct over several months) with central and peripheral findings, inflammatory markers in CSF and GAD-enhancing and FLAIR+ lesions in CNS on MRI

i. Treat with immunomodulatory therapye. Other CNS demyelination can come from vitamin B12 deficiency, central

pontine myelinolysis (mostly iatrogenic, too-rapid alterations in brain osmolarity injures oligodendrocytes), tabes dorsalis (neurosyphilis)

f. CNS has compact myelin with PLP (proteolipid protein) and noncompact myelin with myelin oligodendrocyte glycoprotein. PNS has compact myelin with mostly Po glycoprotein and 5% Pmp22 and noncompact myelin with myelin associated glycoprotein. Both CNS and PNS compact myelin have myelin basic protein.

CASE CONFERENCE: SPINE DISEASE

I. The spine is flexible and protective – C1 and C2 joints are most flexible, the thoracic spine is the least flexible, and the sacrum and coccyx are fixed. a. Remember a vertebra has a body and spinal processes, which articulate with

the next vertebrae at discs and facet joints. The spinal cord becomes cauda equina around L1-2. Spinal nerves exit at vertebral foramina; these and the central canal are prone to mechanical compromise.

b. Spine is stabilized by the osseo-ligamentous structures, active muscular support, and automatic CNS control.

c. Spondylosis is degeneration of the spine secondary to range of motion, usually affecting the lumbar spine first. As intervertebral discs lose water, they shrink and stress the spine and begin to bulge into the central canal.

d. Spinal stenosis (narrowing) occurs as elements begin to get stressed and hypertrophy, or may be congenital. Myelopathy is compression of the spinal cord, neurogenic claudication is central stenosis affecting the cauda equina, and radiculopathy is lateral recess or foraminal stenosis affecting a nerve root.

II. Remember that we can never deny someone’s experience of pain. The gold standard for pain is patient report of pain. a. ¾ adults will have back pain, the most common cause of disability and

second most common reason for visiting a PCP. 90% of that is nonspecific due to strained muscles and ligaments.

i. However, you have to be careful not to miss anything life-threatening, like a dissecting aortic aneurysm being referred to the spine.

ii. Can be mechanical, inflammatory, metabolic, or extra-spinal. b. Inflammatory may be infection (more common in immunocompromised pts),

neoplasm, ankylosing spondylitis. Pain increases with inactivity and see early morning stiffness; typically slow onset, pain at night is concerning for cancer.

c. Mechanical may be spondylosis (related to aging), disc prolapse, spondylolisthesis (one vertebra slipping forward onto the one below). Activity will make mechanical pain worse, rest will make it better.

d. Oral, pharyngeal, pleural, retroperitoneal, aortic, and pelvic structures can all refer pain to the spine.

e. Cervical myelopathy: get neck pain with urinary urgency progressing to incontinence, difficulty coordinating fine motor movements (weakness, stiffness, clumsiness) as well as trouble walking. Will see hyperreflexia and Hoffman’s and Babinski’s signs.

f. Pseudoclaudication: normal vascular system with cramping pain and weakness in calves upon walking, aching in back and heavy symptoms down legs, relieved by leaning forward. Attributed to spinal stenosis. Always evaluate for cauda equina syndrome: triad of saddle anesthesia, loss of bowel/bladder function, and lower extremity weakness. A surgical emergency to decompress or it will become permanent!

i. A progressive neurologic deficit or unrelenting pain should go to a neurosurgeon; bowel/bladder issues or cauda equina should go to emergency.

III. Can image the spine with x-rays (great for bony anatomy), CT myelogram (good for neural structures, risk of higher radiation and contrast dye), MRI is good a. Remember if you look at the spine, there’s a good chance you’ll find

something “wrong”, and then have to decide if that’s really causing any symptoms.

b. 80% of pts with acute low back pain will be back to normal in 6 weeks to 3 mos no matter what they do. Can give assurance and education that they’ll likely get better, medication to improve pain, and PT to improve motion.

c. Operative treatment includes stabilization of the bony spine and decompression of the neurological elements. We can’t always predict who will benefit from surgery, but we do it when there’s a progressive neurological deficit. Pain can be an indication for surgery if you decide with the pt that the pain warrants surgery.

OVERVIEW OF MOVEMENT DISORDERS

I. Movement disorders are diseases of the brain: either too little (akinesia) or too much movement (tremor, dystonia). Start analysis with where it is. a. Tremors are involuntary oscillating movements, rhythmic with variable

amplitude and fixed frequency. May occur at rest (against gravity) or in action (when the muscle is contracting); action tremors can be postural (maintaining tonic movement) or kinetic (while moving); kinetic tremors can be simple (moving) or intention (moving against a target).

i. Essential tremors are common, onset around 20 or 60 yrs, postural tremor affecting both hands and the head.

ii. Parkinson’s disease with tremor has unilateral tremor of arm and leg onset 55-65 yrs, see a rest tremor and re-emergent postural tremor (without action tremor between), and progressive

b. Dystonia is an abnormal posture due to co-contraction of antagonistic muscles, maybe with twisting corrective movements, not rhythmic.

i. Important whether it’s one or both sides, whether it’s primary vs secondary (resulting from an abscess or lesion), whether it started under 26 yo (typically genetic and primary)

ii. Distribution is important, focal is like eye, segmental whole head, generalized all body parts

c. Akinesia is a progressive reduction in amplitude and speed: movements are too little or too slow.

i. Can assess with finger tap, eye blink rate, reduced arm swingii. Remember Parkinson’s disease can have both bradykinesia and

tremor and rigidity

LIMBIC SYSTEM

I. The limbic system manages reward, motivation, and memory, determining what stimuli are worth pursuing. It constantly updates the value of environmental stimuli based on other data coming into the brain. a. Vaguely circuitous structure passes from the cingulate gyrus to the cerebral

cortex and also to the hippocampus, through the fornix, to the mammillary bodies and anterior thalamic nuclei.

b. Case of HM (bilateral resection of temporal lobes for seizure control) demonstrated that formation of new memories was managed in that area.

c. The hippocampus is critical for declarative memory (things we say), but not procedural memory (things we learn to do, motor-based) – HM could improve at a motor task and retain that from day to day despite not remembering doing the task.

d. Hippocampus also has some lateralized involvement in spatial memory, and some cells in the hippocampus fire at particular coordinates in a space, but it’s unclear that it’s necessary for this skill.

II. The basolateral amygdala receives input from the thalamus, auditory cortex, and visual cortex and sends output to the central gray areas of the midbrain to travel down the pons and spinal cord.

a. While the hippocampus maps what the stimuli are, the amygdala assigns value to particular stimuli given current and past associations.

b. Assigns both positive and aversive value in different circuits, conscious and unconscious processing, a key driver of behavior.

i. Lesioning the amygdala in monkeys gives a lack of aversive responses. In people, recognize a frightening stimulus as such but won’t engage emotional response, vs. lesioning hippocampus you can get afraid but can’t say what you’re scared of

III. The nucleus accumbens is the major dopaminergic circuit engaged in reward and behavioral motivation. Remember there’s the substantia nigra in the midbrain which projects to the striatum, and the mesolimbic pathway that projects from the ventral tegmental area to the ventral striatum and frontal cortex. a. Mesolimbic system drives motivation for movement via the nucleus

accumbens in the ventral striatum, which mediates rewarding behaviorsb. Cocaine blocks dopamine reuptake, but unclear whether that increased

dopamine tone mediates physiological reward through this same mesolimbic system.

i. Pretty good evidence that many drugs of abuse (cocaine, nicotine, marijuana) act through this system, where marijuana binds to the same receptors on GABA-ergic neurons that endocannabinoids bind to disinhibit DA release. (suppress GABA to disinhibit reward)

c. Dopaminergic neurons manage associative learning: rewards trigger DA neuron firing so that brain pays attention to the surrounding circumstances. After learning, DA neurons fire in response to the cue, not the reward. If reward does not follow the cue, DA neurons will go silent for a bit to let the brain know it’s no longer a reward-rich environment.

PERIPHERAL NEUROPATHIES

I. Peripheral neuropathies may affect motor, sensory, or autonomic nerves and constitute a major burden of disease. a. Remember most nerves are mixed sensory and motor; spinal nerves form by

joining ventral and dorsal roots, then splitting into dorsal and ventral rami and perhaps forming plexuses before splitting into individual nerves.

b. Remember peripheral nerves have individual myelinated axons bundled by endoneurium, perineurium, and epineurium into nerves. Nerves contain blood vessels, occlusion of which gives painful peripheral nerve ischemia.

c. Insults result in distal axonal degeneration and consumption by macrophages. Things that affect the myelin sheath may be systemic or localized, Schwann cells support the neuron so as they die the axons will begin to die too. Axonal regeneration is possible but time-limited before an irreversible lesion occurs.

II. Peripheral neuropathies may result from damage to the nerve itself or from systemic disease.

a. Classified by the type of fiber, the pattern, time course, pathologic feature, and etiology.

b. Start with the anatomic location of the complaint (CNS or PNS? Systemic or focal?) mostly taken from the history.

c. Next what types of fibers are involved (what functions are affected?)i. Motor fibers will see muscle weakness, atrophy, possibly

fasciculations or cramp, loss of gross and/or fine motor skills. The first interosseous muscle and calf muscles commonly atrophy.

ii. Large sensory fibers may display positive Romberg sign (sensory ataxia, proprioceptive defect), loss of tendon reflexes, poor vibration sense, numbness; for small fibers parasthesias and shock-like pain or loss of pinprick and temperature sensation, possibly numbness

1. Neuropathic pain is burning or like pins and needles, vs nociceptive pain from tissue injury is more sharp/aching

iii. Autonomic fibers may see sexual dysfunction, urinary or GI symptoms, lightheadedness on standing

d. Now localize within the PNS: is it dermatomal like one nerve root, a full plexus, a mononeuropathy (like carpal tunnel syndrome), mononeuropathy multiplex, or polyneuropathy (stocking glove distribution)

e. Then time course: acute (days) is nerve injury, vasculitic mononeuropathy; subacute (days to weeks) is polyradiculopathy, proximal diabetic neuropathy, paraneoplastic neuropathy; chronic (months to years) is diabetic polyneuropathy or others; very chronic is hereditary.

f. Then think about the primary pathological process, is it axonal or demyelinating? Generally has to be done by EMG/NCS or biopsy.

g. Think about other contributing factors: medical history of diabetes, HIV, or autoimmune disease, medications including vitamin B6, family hx

h. Do any further testing you want (EMG/NCS, imaging, biopsy, blood work)i. EMG tells you which nerves are involved, NCS tells you how they’re

affected with integrity of myelin etc, testing large nerves onlyii. Skin punch biopsy looks at small sensory and autonomic nerves and

whether they’re still present or diminishediii. Can biopsy sural nerve (purely sensory with minor skin distribution

on lateral malleolus of ankle) to look at vasculitis (a neurological emergency, progressive but treatable) or amyloid neuropathy

III. Mononeuropathies are typically caused by compression, anatomical impingement – frequently median neuropathy at the wrist, ulnar neuropathy at the elbow, radial palsy wrist drop, etca. Traumatic neuropathies are usually mononeuropathies or plexopathies, like

shoulder dystocia causing brachial plexus injury. Can be complete or incomplete, may be recoverable with quick surgical ligation.

b. Mononeuropathy multiplex involves at least two nerve distributions and usually an axonal neuropathy. Could be diabetic amyotrophy, sarcoid, leprosy, top of ddx should be vasculitis

i. Vasculitic neuropathy is inflammation of the blood vessels inside the nerve, leading to occlusion and acute necrosis: very treatable

c. Leprosy is an infection of nonmyelinating Schwann cells, giving profound anesthesia in small fibers and mutilative ulcerations

d. Polyneuropathy is generalized peripheral nerves, distal axonopathy with longest axons affected first (stocking-glove pattern). Most commonly resulting from diabetes but not well correlated with control of disease. Note we have no drugs that treat these damaged nerves.

e. Toxic neuropathies may result from antineoplastics, isoniazid if not supplemented with B6; deficits stabilize with drug withdrawal. Also common in alcoholics, slow onset painful distal axonal sensory-motor. May result from deficiencies of B1, B2, B3, B6, B12, E, or excess of B6.

f. Charcot Marie Tooth disease is the most common inherited neurologic disease: very slowly progressive distal weakness, think pes cavis, hammer toes, calf atrophy. CMT1 is autosomal dominant, demyelinating, common.

g. Autoimmune damage of myelin is Guillain Barre Syndrome (AIDP, acute inflammatory polyradiculoneuropathy) or chronic CIDP. AIDP may progress in less than 4 weeks to quadriplegia but will slowly recover with supportive care. CIDP lasts longer, both respond to immune modulation therapy.

i. Guillain Barre Syndrome: ascending flaccid paralysis and loss of tendon reflexes over days

ii. CIDP: asymmetric progressive weakness and sensory loss over mosh. Overall disease-modifying treatment for peripheral neuropathy is abysmal.

Identify and treat underlying medical problems and work on PT, OT to gain maximum independence and self-care ability. Even neuropathic pain is poorly controlled: anticonvulsants, tricyclic antidepressants work in about 40% of pts.

CASE CONFERENCE: ELECTROMYOGRAPHY AND NERVE CONDUCTION STUDIES

I. Nerve conduction testing examines the features of externally generated electrical impulses that travel down nerves, particularly the amplitude (height of the measured wave) and latency (time from stimulus to measurement). a. An increase in latency is characteristic of a demyelinating neuropathy, as it

takes longer for a signal to travel down a nerve. Axonal neuropathies affect amplitude, since fewer APs are being propagated.

i. Ex. Guillian Barre has long distal latency but preserved amplitude, diabetic polyneuropathy has increased latency and decreased amplitude, CMT1 has slow uniform decreased conduction velocity

ii. Can localize neuropathy by testing conduction velocity along a nerve, pinching causes focal demyelination and local slowing

iii. Look at sensory function in the arm with the radial nerve on the dorsum of the hand, sural nerve on the lateral malleolus of ankle

II. Remember each motor unit typically serves 200-600 myofibers, and each muscle may be controlled by up to 100 motor units. Each motor neuron controls only one type of muscle fiber, and the fiber typing is determined by the motor neuron and can be changed with reinnervation. The myofibers of each motor unit are distributed throughout a muscle (mosaic).

a. Electromyography: when you put an EMG needle into a muscle, it will read out a characteristic signal for each motor unit that fires.

b. May generate force by increasing the firing rate of a motor neuron or recruiting more motor neurons to fire

c. When a nerve is cut, the acutely denervated myofibrils upregulate elements that make them electrically unstable and spontaneously twitch, takes two weeks to develop. Healthy muscle has no electrical activity at rest.

d. Fibrillations: small resting electrical deflections from contraction of a single myofiber

e. After cutting a nerve, eventually nearby motor units will take over its fibers and their potentials will become larger in amplitude and longer in duration; thus motor neuropathy over time gets loss of fine control

f. In a myopathy, you’ll see a lot of motor units turning on at once because it’s harder to generate the force: early recruitment. Sometimes fibrillations.

i. If it starts to fire when you put the needle in, an irritable myopathy, think inflammatory process; steroid-induced myopathy shrinks type 2 fibers, will be weak but silent at rest.

ii. Fasciculations are firing of one motor unit, twitching the skin but not moving the joint – can be from exercise, caffeine, stress, or think ALS in the context of muscle atrophy.

NEUROMUSCULAR TBL

I. Asymmetric gradual patchy spread of upper and lower motor neuron signs, eventually above and below the neck, is classic for motor neuron disease like ALS. a. Atrophy with fasciculations, selective motor neuron lossb. Neurogenic atrophy on biopsy shows fiber type grouping from denervation

followed by reinnervation. c. UMN: hyperreflexia, Babinski, spasticity, no fasciculations, mild atrophy.

LMN: reduced/absent reflexes, flaccid, fasciculations, prominent atrophy.II. Myasthenia gravis: characteristically neuromuscular fatigue, especially in ocular

muscles, and other bulbar weakness. Limb weakness is proximal more than distal.

III. High CK levels (over 200) when consistent with an inability to localize a lesion can be confirmatory for a myopathy. a. Myopathies can be acquired or inherited, but it’s hard to diagnose and

impossible to treat inherited myopathies, so try to rule out acquired. b. Acquired myopathies can be autoimmune, endocrine, toxic, or inclusion body

myositis. i. Autoimmune: symmetric proximal limb weakness, sub-acute, often

coexisting manifestations and other autoimmune diseases. ii. Endocrine myopathy can be hypothyroid with symmetric proximal

muscle weakness

iii. Many known myotoxins but statins are the most common and problematic: mild myotoxicity gives muscle pain, severe is proximal muscle weakness. Symptoms resolve when statin is stopped.

iv. Inclusion body myositis is often asymmetric weakness in wrist flexors, distal finger flexors, quadriceps, triceps, ankle dorsiflexors, with dysphagia common. Slowly progressive. Will see primary inflammation and rimmed vacuoles on biopsy.

BASAL GANGLIA CIRCUITRY AND FUNCTION

I. The basal ganglia receive input from the cerebral cortex and return output through the thalamus to the cortex. a. These are subcortical nuclei in the telencephalon: the striatum (caudate,

putamen, nucleus accumbens), the globus pallidus, the subthalamic nucleus, and the substantia nigra.

i. Caudate nucleus is in the lateral wall of the lateral ventricle, separated from the putamen by the internal capsule

b. Striatum neurons are mostly GABAergic medium spiny projection neurons; globus pallidus has pars externa and interna (the major output nucleus of the basal ganglia), also GABAergic

c. More inferiorly, the nucleus accumbens is found in the ventral striatum, and the substantia nigra in the cerebral peduncles has pars compacta (dopaminergic) and reticulata (GABAergic, also output center)

d. Together, these regulate activity in the motor, oculomotor, associative, and limbic areas of cerebral cortex via parallel circuits of thalamic output

e. Input to the basal ganglia goes mostly to the striatum: frontal association cortex and occipital/temporal cortex to the caudate, somatosensory and motor areas to putamen, limbic areas to nucleus accumbens. Also, the centromedian nucleus of the thalamus receives sensory afferents and projects to the striatum.

f. The striatum projects to the globus pallidus pars interna, which inhibits ventral anterior and ventral lateral thalamic nuclei, which project to the cortex: overall loop regulates cortical activity. The substantia nigra pars reticulata goes via the ventral anterior thalamic nucleus to the frontal eye fields and UMNs in the superior colliculus: oculomotor circuit.

g. The subthalamic nucleus receives excitatory input from the cortex and inhibitory input from the globus pallidus pars externa, and gives excitatory input to the globus pallidus pars interna.

II. The motor loop of the basal ganglia has direct and indirect pathways with opposing effects on cortical activity. Dopamine modulates activity to balance cortical activity; dysfunction can give movement disorders. a. The direct pathway facilitates movement, giving action selection or

reinforcement. Cortex excites striatum, striatum inhibits GPi, reducing its inhibition of VA thalamus, VA thalamus excites cortex.

b. The indirect pathway inhibits movement and suppresses motor programs. Cortex excites striatum, striatum inhibits GPe, reducing its inhibition of STN,

so STN can excite GPi, GPi inhibits VA thalamus, reducing excitatory input from VA to cortex.

i. Cortical input to STN drives GPi to inhibit thalamus: hyperdirect pathway suppresses motor patterns

c. Dopaminergic neurons from the substantia nigra pars compacta have a basal discharge rate increased by cortical input and decreased by the basal ganglia: firing reflects reward value and motivation.

i. Striatal neurons in the direct pathway express D1 receptors, so that dopamine enhances the excitability (Glu response) of these neurons.

ii. Striatal neurons in the indirect pathway express D2 receptors, so that dopamine reduces the excitability (Glu response) of these neurons.

iii. Loss of these neurons causes Parkinson’s disease, with its hypokinetic motor features: akinesia, bradykinesia, rigidity, resting tremor (decreased function of direct pathway relative to indirect)

iv. So when DA neurons degenerate in PD, the subthalamic nucleus and globus pallidus pars interna tend to have excess activity – targets of lesions or more recently deep brain stimulation

d. Compare to Huntington’s Disease, which causes degeneration of striatal neurons, preferentially from the indirect pathway and presents as a hyperkinetic disorder (chorea)

PATHOGENESIS OF PARKINSONISM

I. Anything that causes Parkinsonism affects the substantia nigra pars compacta. Parkinsonism is defined as any combination of a rest tremor, bradykinesia, rigidity, loss of postural reflexes, flexed posture, and freezing (difficult to initiate walking)a. Parkinson Disease is quite common, with onset between 40-70 yrs and

average life expectancy after diagnosis of around 15 yrs. Characterized by rigidity, bradykinesia, rest tremor, postural instability, mask-like facies (devoid of expression and associative movements), and festinating gait (small shuffling steps, start slow and get faster, maybe trouble stopping)

b. Grossly, see pallor in substantia nigra. Microscopically, see Lewy bodies, neuronal cytoplasmic inclusions with a halo: composed of misfolded a-synuclein, also found in pigmented neurons of the locus ceruleus. Also see Lewy neurites, misfolded a-synuclein in the axons and dendrites.

i. Alpha-synuclein is a normal protein, thought that function is related to synaptic transport.

c. PD is mostly caused by aging (1% of population over 60), is rarely inherited but not fully sporadic, and is associated with environmental exposure (MPTP, pesticide/herbicide)

i. Multiple mutations generate familial PD; familial forms can have much earlier onset than sporadic (~30 yo)

II. Dementia with Lewy bodies is responsible for about 20% of all dementias. a. Generally sporadic, onset after age 65 and survival about 8 yrs. Difficult to

distinguish clinically from Alzheimer’s, often clinical and pathologic overlap

b. Three key clinical features are visual hallucinations, very prominent fluctuations in alertness and attention, and some Parkinsonism; also often repeated falls, syncope, and sleep disturbance

c. Pathologically, see Lewy bodies in the brainstem as in PD, as well as cortical Lewy bodies in limbic and association areas and hippocampal Lewy neurites

i. Tend to form caudally first and spread rostrally, can’t be distinguished cellularly from Parkinson’s disease

ii. Debated whether it’s a continuum of PD: tend to call it Parkinson disease dementia if the PD comes first, dementia with Lewy bodies if dementia is initial or concurrent with parkinsonism

III. Progressive supranuclear palsy causes a pretty high fraction of cases that present as PD: onset 45-75 yrs and survival 10 yrsa. Classically presents as akinetic Parkinsonism with mild/absent tremors,

issues with vertical gaze, and unresponsive to L-DOPA. However, not all pts have the eye findings and recently some pts have cognitive deficits

b. Grossly see pallor of substantia nigra and variable midbrain and cortical atrophy; microscopically see tau-positive tangles in neurons as well as changes in glial cells like tufted astrocytes and oligodendroglial inclusions.

i. Tau protein is microtubule-associated, when hyperphosphorylated it dissociates into inclusions but unclear how this causes cell death

c. Because PSP involves so many brain areas it can’t be targeted with L-DOPA therapy like the more isolated PD can be

IV. Multiple system atrophy was the first disease to demonstrate the importance of glial cells in neurodegenerative disease. Has three syndromes: MSA with predominant parkinsonism, with cerebellar features, or autonomic failure. Generally sporadic progressive disease with onset in 50s and survival 5-10 yrs.a. MSA-P: parkinsonism without tremor, minimal response to L-DOPA. MSA-C

has cerebellar gait and limb ataxia, myoclonus, cerebellar tremor. Autonomic failure has orthostatic hypotension, urinary incontinence or retention.

b. MSA-P see both pallor of substantia nigra and generalized midbrain atrophy; MSA-C see pons and cerebellum atrophy. MSA-A involves lateral gray column and anterior horn of spinal cord.

c. Again so many areas that L-DOPA doesn’t work. Characteristic a-synuclein inclusions in oligodendroglia.

CASE CONFERENCE: DEEP BRAIN STIMULATION

I. Carbidopa/levodopa delay the time to increased disability from Parkinson’s by five years, but don’t actually slow the progression of the disease. a. Furthermore, as the number of dopaminergic neurons decreases, the

therapeutic range for the drugs gets narrower, so that pts begin to oscillate between chorea and symptomatic tremors/rigidity. Can supplement with amantadine to fight the dyskinesia and longer-acting DOPAs, but all still allow this cycling.

b. The discovery that the GPi was tonically inhibiting the thalamus so that it couldn’t activate the cortex for normal motor function and the discovery that electrical stimulation of the STN at 100 Hz silenced it combined into DBS.

c. The goal of DBS is to fill in the gaps between doses of L-DOPA. It gives reduced tremor, bradykinesia, and rigidity and improved activities of daily living.

d. Will typically only address things that medication also fixes, since it’s acting on the same pathway as DOPAs. So, look for pts with medication-responsive symptoms but who can’t take oral levodopa due to impulse control disorders, dyskinesia, or decreased efficacy.

i. Test PD symptoms off and on medication to develop realistic expectations

ii. Also do neuropsychological testing, because some pts who get DBS get cognitive decline, and those who are already cognitively impaired are more likely to suffer from this.

e. Surgery has two steps, placing the brain leads and implanting the pulse generator

i. Brain leads can be an awake surgery with the head stabilized and local anesthetic, allows real-time testing of physiologically optimal symptom control but scary af

ii. Alternately can put under general anesthesia and use MRI to guide electrode placement

f. Generally: DBS helps tremor, stiffness, shuffling, dystonia; will not help mood disorders, cognitive impairment, or balance (likely to be a problem the longer the pt has had PD), and complications of possible biofilm

CEREBELLUM ANATOMY AND FUNCTION

I. The cerebellum has 4x as many neurons as the cerebral cortex and functions to modify motor commands that are initiated elsewhere, important for balance, posture, coordination, AND cognition! a. Anatomy: has right and left hemispheres separated by the vermis with

anterior, posterior, and flocculonodular lobes. b. Contains deep nuclei, which take in information and do most of the output:

fastigial nucleus medially, then interposed nuclei, dentate nucleus. i. Fastigial receives input from vermis, processes vestibular,

somatosensory, auditory, visual information, and projects to vestibular nuclei and reticular formation. Along with flocculonodular lobe, does vestibular reflexes and balance.

ii. Interposed nuclei receive input from paravermis, spinal, somatosensory, auditory, visual information, and project to red nucleus. Along with vermis and paravermis, does motor coordination.

iii. Dentate nucleus receives input from lateral cerebellar hemispheres, motor and cognitive information, and projects to red nucleus and thalamus (complex sequencing and coordination)

c. Connect to the rest of the brain via the superior, middle, and inferior cerebellar peduncles.

i. Inferior brings input from medulla and vestibular nuclei, middle brings pons input (primary input), superior brings output from cerebellar nuclei

d. Cerebellar cortex has outer molecular layer with dendrites of Purkinje cells and parallel fibers (axons of granule cells), Purkinje cell layer with their somas, and granular layer with granule cells.

e. Purkinje cells have extensive 2D dendritic trees, connected by parallel fibers running orthogonally to other Purkinje cells. The effect of their output depends on what they’re signaling to, rather than intrinsic features. Receive excitatory input from climbing fibers from the inferior olive, send inhibitory projections to cerebellar nuclei, which manage all cerebellar output.

i. Parallel fibers do frequent basal simple spikes; complex spikes from climbing fibers are rarer and stronger, event information, suppressing simple spike information.

f. Mossy fibers from the pons excite granule cells, which send their axons to the molecular layer as parallel fibers that connect Purkinje cells.

II. The cerebellum acts in some ways as a feedforward controller, which allows fast action without mid-action modification. Feedback after the fact allows for trial-and-error learning by repetition. a. Mossy fibers transmit the desired motor output, climbing fibers convey the

error signal and can override mossy fibers. Thus: learningb. Cerebellum fine-tunes motor coordination, so when it’s damaged, pts can’t

produced smooth, well-timed movements. Get disjointed movement with incorrect trajectories and deficits with motor learning and adaptation.

c. Cerebellar ataxia is cerebellar neuronal degeneration due to endogenous factors. Inability to do tandem walk, as can’t do fine-tuning of muscles compensating for balance. Ataxia on knee to shin and finger to nose bilaterally.

d. Note also that cerebellum and cerebral cortex regions oscillate together and are thought to be functionally coupled: thought to also do fine timing of high-level thought coordination (planning, language)

i. Difficulties word finding, impaired verbal working memory, executive function, and some emotion

ii. For word finding and plan execution, seems they’re not catching errors they make, also generate inefficient plans

iii. Also a degree of agitation and aggression scaling with motor deficits, not other emotion categories: inability to regulate emotions?

CASE CONFERENCE HUNTINGTON’S DISEASE

I. Huntington’s Disease has a mean onset around 45 yo, progressing to death in 15-25 years. About 1/10,000 in the US have the disease at any time. a. Clinical features: progressive triad of movement, cognitive, and emotional

disorders. Movement is chorea, quick jerky random involuntary movements

and loss of ability to coordinate that looks like parkinsonism. Cognitive starts with executive dysfunction (trouble sequencing, accessing information) that turns into global dementia. Emotional features include affect disorders and personality changes and are the most variable part of the disease.

b. Pathologically: disorder of the basal ganglia, especially caudate and putamen, as medium spiny neurons are lost first. Eventually shrinkage of cortex.

c. HD results from a one-gene defect: a repeat polyQ expansion of the Huntingtin gene; protein product expressed widely in the body but dramatic effects only in certain regions of the brain

i. No disease under 35 repeats; longer expansions give earlier onset because less stable

ii. Anticipation occurs in paternal transmission, maternal is stableiii. Though other genes that manage DNA repair can modify risk via age

of onset, unclear mechanism d. Loss of the neurons that project out of the striatum; significant striatal

atrophy occurs for years before functional changes and diagnosis. e. Natural history: chorea tends to plateau, but motor impairment and cognitive

problems become more and more debilitating. II. Htt protein is large with poorly understood function. Pathologically, the polyQ

expansion causes a conformational shift from an alpha helical to a beta sheet structure. These form characteristic intranuclear inclusion bodies. a. Unknown why different populations of neurons are susceptible to different

aggregates and inclusions, or even whether inclusions are the toxic partb. Thought perhaps the fragments can interfere with transcription and nuclear

pore transport before even forming the inclusions, but unknown – so therapeutically trying to prevent original conformational transition.

c. Also seems to be prion-like spread of disease throughout the brain. Here, we hypothesize that disease starts in the striatum. Disruption of the many circuits mediated by the basal ganglia gives the motor, cognitive, and emotional changes.

III. HD is not a disease of dopaminergic neurons and has both hyperkinetic and hypokinetic features, but early in the disease chorea may respond to dopamine blockersa. Such as tetrabenazine: a vesicular monoamine transporter inhibitor, so the

CNS dopaminergic neuron vesicles get depleted and can’t release more, but also depletes NE and 5HT: major side effect is depression

b. Recently approved austedo (deuterated tetrabenazine) will supposedly give the same effect with less toxicity, since it’s degraded less quickly so can be dosed less aggressively

c. Haloperidol (D2 blockers) can be effective for chorea and doesn’t cause depression but eventually gives tardive dyskinesia, as it sensitizes cells to dopamine release

d. Can try to treat depression, irritability pharmacologically, behavioral and social issues with appropriate interventions, but can’t do anything to even slow the disease.

e. Currently working on antisense oligos and enhanced protein degradation to target the disease itself, oligos have to be administered by lumbar puncture or viral vector directly to the brain, but seem promising

f. Will ideally develop a safe treatment that can be administered long before symptoms start to show to prevent any decline at all