NSB Exam 2

Cannabinoids basis

"Used by 4% of world population". Popularity rank 4th: Alcohol > Caffeine > Nicotine > Cannabis Cannabis sativa cultivated for hemp fiber and marijuana. Flowering tops contain most ∆9-tetrahydrocannabinol (THC), the most potent alkaloid Cannabinoid receptors -CB1 (Gi, in basal ganglia, cerebral cortex, hypothalamus, dorsal horn) -CB2 (Gi, in immune system cells) Endocannabinoids: -Anandamide (also found in sea urchin roe and is degreased by FAAH which can be blocked by acetaminophen) -Arachidonoylglycerol

Degree of myelination as a determinant of nerve conduction velocity

"heavily myelinated" axons speed velocity of AP = up to 40 turns of myelin No K2P channels beneath compact myelin--no passive leak (channels localize to nodes and paranodal axolemma Myelin increases rm and length constant Increases conduction velocity from approx 1 m/sec up to as much as 100 m/sec

Acute flaccid myelitis (AFM)

"modern day polio" Rare condition primarily affecting otherwise healthy children Acute, asymmetric (hours to days) onset of muscle weakness and myelitis Specifically targets anterior horn cells in one or more segments (by MRI) following a viral URI Suspended-lesion type pattern Sensation remains intact, limited to gray matter. Enterovirus most commonly implicated. 2014 outbreak of D68 enterovirus respiratory illnesses assoc'd with cases clustered in Colorado and California. D71 implicate in Australia and Southeast Asia

Radiculopathies

"pinched nerve" Nerve root damage causing both sensory and motor symptoms

Spinocerebellar pathways

"unconscious proprioception" Serve the extremities Copy proprioceptive information to cerebellum during movement Allows cerebellum to send real-time corrective signals to motor cortex

Inhibitory postsynaptic potential (IPSP)

(hyperpolarizing, downward blip); a GABA or glycine receptor opens to allow Cl- influx or K+ efflux (GABA)

Excitatory postsynaptic potential (EPSP)

(the effect is depolarization, an upward blip); e.g. a glutamate receptor opens to allow Na+ influx

Friedreich's ataxia presents with gait ataxia: wide-based + steppage due to _____

- die-back of 1°sensory proprioceptor axons - reduced size of DRG, Clark's n., dorsal roots - demyelination and depletion of dorsal columns - depletion of cerebellar targets of spinocerebellars - corticospinal tract degeneration in cord - CN 7,9,12 neuronal loss - dysarthria

Cauda Equina Syndrome

-Injury at the L1 level and below resulting in a LMN lesion -Flaccid Aparalysis w/no spinal reflex activity

What is preserved in advanced neurosyphillis (syphilitic myelopathy) (tabes dorsalis)

ALS modalities Motor function

Ganglion

AN aggregated of like-functioning neurons in the PNS

Metachromatic Leukodystrophy

AR disorder with accumulation of fats called sulfatides Deficiency of lysosomal enzyme arylsulfatase and accumulation of cerebroside sulfate Infantile form (50%), juvenile (30%) and adult (20%) form In the first two forms, motor symptoms, seizures, paralysis and unresponsiveness progress over 10 years The adult form presents with psychiatric or cognitive symptoms

Spinal Muscular Atrophy (SMA)

AR genetic disorder with deletions in the survival motor neuron 1 genes (SMN1) affecting the spinal cord, nerve and muscle Type 1 SMA (also called Werdnig-Hoffman or infantile-onset) is the most severe Muscles closer to the body midline (proximal) are more affected than distal muscles Note: histologically will see neuronophagia (microglia attacking neurons)

Anterior cord syndrome lesion

ASA perfusion territory at and below lesion level: lateral/anterior funiculi; ventral horns

Atonia by propofol

Action on the spinal cord and in the pontine and medullary reticular nuclei that control the antigravity muscles leads to atonia Near the end of surgery, small doses of propofol can be used to provide rapid muscle relaxation of short duration and propofol is preferable to muscle relaxants that have a slower onset and longer duration of action.

Tricyclic antidepressants (TCAs) for Neuropathic Pain

Activate raphespinal tract by blocking 5-HT reuptake Activate descending analgesic pathway from locus ceruleus by blocking NE reuptake Improve comorbid conditions of depression and anxiety TCAs block SERT+NET+M+a1+H1 -AMITRIPTYLINE -IMIPRAMINE SSNRIs block SERT+NET -DULOXETINE -VENLAFAXINE Most effective neuropathic pain drugs are TCAs. SSRIs (FLUOXETINE) are less effective.

Multiple Sclerosis histopathology

Active plaques -hypercellular with parenchymal and perivascular lymphocytes and macrophages (fried egg appearance) and scattered reactive astrocytes -Preservation of axons Inactive plaques -hypocellular and gliotic with loss of oligodendrocytes and variable loss of axons Shadow plaques -areas of remyelination, often within larger zones of demyelination

CNS "regeneration" is conceptualized in 2 ways:

Actual replenishment of a cell population -new neurons arise from precursors cells -oligodendrocytes - arise from satellite oligo's and oligo' progenitor cells Regrowth of damaged axons within the CNS -negligible - so neurons often die as the result of axon disintegration and loss of trophic factor receptors on the lost part -absence of the laminin substrate encountered in development

Clinically isolated syndrome

Acute demyelinating episode affecting more than 1 site in CNS; initial presentation for MS in 80% of patients High incidence of going on to satisfy McDonald Criteria when MRI abnormalities are present Optic neuritis: 56% with 1 MRI lesion develop MS in 5 years; 22% with normal MRI develop MS in 5 years; >1 lesion 80% risk Transverse myelitis (usually incomplete, usually posterior cord): 60-90% risk for MS with demyelinating lesion(s) on MRI; 20% risk for MS with normal MRI Brainstem or cerebellar syndrome (such as INO): 60-90% risk of MS with demyelination MRI lesion, 20% risk with nl MRI Acceptable to initiate treatment if high index of suspicion and informed consent discussion with patient

Clinical features of Thiamine (B1) deficiency

Acute or chronic peripheral neuropathy -Variable progression, large axons, motor 50%, sensory 50% and autonomic -Occasional CN's involvement (hoarseness, facial weakness) Cerebellar degeneration Chronic or acute encephalopathy (Wernicke's or Korsakoff's) Cardiac manifestation Associated causative disorders; alcoholism, malnutrition, malabsorption, dialysis Diagnosis: reduced transketolase activity and urine thiamine Rx: Thiamine replacement.

Inflammatory Demyelinating Polyradiculoneuropathy examples

Acute/subacute (Guillain-Barre syndrome - AIDP) Chronic and indolent course (CIDP) AIDP and CIDP Variants

Components of a reflex

Afferent neuron + efferent neuron ± interneuron = "reflex arc" All elements must be intact for normoreflexic response Disruption to any of the three neurons causes hyporeflexia or areflexia Corollary: Neuropathies, radiculopathies or degenerative disease targeting sensory fibers can also produce hyporeflexia

Opioids for other use

Agonists -loperamide -diphenoxylate Partial agonists; agonist/antagonist combination -buprenorphine -butorphanol -nalbuphine -pentazocine Other agonist -tramadol -tapentadol Central antitussives -dextromethorphan -codine

3 primary components of consciousness

Alertness (Wakefulness, Arousal) (NE, 5-HT, H1) (frontal association cortex, parietal association cortex) State of receptivity to the external environment mediated via Reticular activating system (reticular formation, TMN, VTA, thalamic intralaminar nucleus) -Basic attribute that characterizes consciousness ~Sensory systems are actively gathering information ~Motor systems ready to react ~"Dimmer" switch of consciousness Attention (ACh) (anterior cingulate, medial frontal cortex) -Filtering and selection of sensory information -Required for memory & learning -Involves purpose and planning Awareness (posterior cingulate, retrosplenial cortex) Ability to process and store information in order to interact with internal or external environment Involves recall of experience, signal integration, anticipation, prediction

Muscle contraction is driven directly by _______ and maintained indirectly by ______

Alpha motor neurons Gamma motor neurons UMN co-activation of γ LMNs enables spindles to contract in parallel with extrafusal fiber contraction driven by a-MNs Without gamma's, spindles would go flaccid in an instant as extrafusals contract Flaccid spindles would cease Ia/II proprioceptive activity, causing loss of the very sensory stimulus needed to sustain muscle in a reflexive contractile state

Charcot-Marie-Tooth Disease

Also called hereditary motor and sensory neuropathy Affects the peripheral nerves Most common inherited neurological disorder (1 in 2500) Affects both motor and sensory Develops in adolescences and adulthood Foot drop is common finding Duplication of genes involved in myelin production, Peripheral Myelin Protein-22 mutated Not considered a fatal disease

Clonus

Alternating contractions and relaxations of muscles seen in an extreme form of hyperreflexia associated with upper motor neuron lesions Equivalent to partial tetanus Muscles are not given time to relax Can be evoked by reflex testing, usually the ankle jerk Measured in terms of beats

Subdivisions of motor neuron disease (MND)

Amyotrophic Lateral Sclerosis, ALS (Lou Gehrig's Disease) Progressive Bulbar Palsy Spinal Muscular Atrophy -Werdnig-Hoffmann Disease

PMP22 (transmembrane)

An integral membrane protein of compact SC myelin Less abundant than Po but important because gene mutations are causal to the most prevalent heritable peripheral neuropathy - Type 1A (and Type 1E) Charcot-Marie-Toothe disease

Po glycoprotein

An integral membrane protein of compact SC myelin a member of the Ig superfamily (good at adhesion) predominates at about 50% of total PNS myelin protein extracellular domain mediates homotypic (self) adhesion between adjacent turns of PNS myelin the major component of the PNS intraperiod line

Thalamus

An integrator containing nuclei for sensory, motor, and behavioral functions Note: VPL is the source of 3rd order somatosensory neurons

Deficits seen in conus medullaris syndrome

Anal sphincter paralysis Perianal (saddle) sensory loss Elevated ankle jerk (not seen with cauda equina syndrome) Bowel, bladder, sexual dysfunction greater than with cauda equina syndrome Symmetric findings Note: Direct hit on conus maximizes dysautonomia compared to cauda equina syndrome, which cannot produce UMN signs

Biological effects of lower motor neuron syndrome

Anterograde Wallerian degeneration -an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury (i.e. farther from the neuron's cell body) degenerates NMJ changes with muscle denervation -compensatory redistribution of ACh receptors away from the endplate -spontaneous release of ACh from disconnected presynaptic terminals Severe atrophy (>70%) of denervated muscle -reflects loss of feed-forward trophic support by LMNs

Nocebo effect

Anticipation of pain heightens perception of otherwise minor stimulus Amygdala -> PAG -> reduces activity of descending analgesics -> decreases pain threshold

Lower motor neuron syndrome

Any lesion or disease that functionally disconnects LMNs from their muscles of innervation Can occur at: any part of the LMN! (cell body, ventral root, peripheral nerve, NMJ)

Lateral funiculus

Area where motor fibers are descending which coordinate voluntary motor activity within the corticospinal tract

Lower motor neurons

Arise form C3-S2 nerve roots in ventral horn, mostly at cervical and lumbar enlargements Arise from 9 cranial nerves having general somatic motor (GSE) or brachial motor (SVE) projections α-MNs and γ-MNs, co-activated by UMNs The combination of α-MNs and γ-MNs that constitute the "final common pathway" (only communication between muscle and nervous system)

Neuropathic pain

Arises as a direct consequence of a lesion or disease the affects the somatosensory system A chronic, intensely painful experience that is difficult to treat with conventional analgesic medications Note: lesions of the peripheral or central nociceptive pathways typically result in a loss or impairment of pain sensation, however, damage to these pathways can also produce pain Etiology: Peripheral Nerve Injury Pathogenesis: Hyperalgesia - via overexpression of α2∂ subunit of N-type VGCC and Na+-channels Allodynia via Ab afferent sprouting (tactile) Sympathetically maintained

Autonomic function testing

Assess small myelinated & unmyelinated autonomic fibers -Sympathetic skin response -R-R interval variation, Valsalva ratio -QSART, other sweat testing

Glia limitans

Astrocyte processes line pial surface of the entire CNS, as well as microvessels Serves as "recognition barrier" for CNS

Lambert-Eaton (myasthenic) Syndrome

Autoimmune syndrome targeted at the voltage gated calcium channels of the (presynaptic) neuromuscular junction Symptoms often starts with extremities Can be a paraneoplastic syndrome associated with small cell lung cancer

Friedreich's ataxia

Autosomal recessive inheritance Mutation on chromosome 9 Trinucleotide repeat disorder (GAA) Mutates mitochondrial protein, frataxin ↑Mitochondrial oxyradials and Fe+2 - 50 GAA= normal - 200-1000 GA in Friedrich's Ataxia affects multiple systems including heart early onset (8-15 yrs) progressive with loss of ambulation within 15 yrs of onset; lifespan to middle age

Amyotrophic lateral sclerosis (ALS)

Average age 40 to 60 years old Most common neuromuscular disease worldwide Random distribution with no clear risk factors, all races and ethnic backgrounds are affected Most die 3 to 5 years after onset of symptoms, due to respiratory failure Early on symptoms are frequently overlooked including; twitching, cramping, weakness or stiffness of muscles, and slurred speech

Action potentials arise at the ____

Axon hillock if depolarization coming form the dendrite/cell body reaches threshold (its a booster mechanism) Note: synapses closer to the axon hillock have more of an effect than those further away

Neurogenic myopathy

Axonal degeneration leads to angular atrophic muscle fibers Reinnervation leads to muscle fiber type grouping If nerve damage continues then fiber type grouping atrophy

Peripheral fiber types of DCML

Aß (mechanoreceptors) Ia,II (muscle spindles) Ib (GTOs) Note: All high velocity & heavily myelinated

Physiologic ways to attenuate nociceptive afferents

Aß mechanoreceptor input activates inhibitory interneurons to secrete Enkephalin which inhibits the secondary neurons "Gate theory". This is the mechanism behind Stimulation induced analgesia -Transcutaneous nerve simulation (TNS) which activates low-threshold mechanoreceptors -Acupuncture in which needed rotation activates low-threshold mechanoreceptors Note: either input decreases C-fiber activation of secondary neuron Descending brainstem pathway which can dampen nociceptive input to the dorsal horn

Which nociceptor fiber mediates mediates first pain

Aδ

Sequence of onset of anesthetic action by fiber types

B fibers are the quickest, then it follows the idea of thinner (C fibers) and myelinated

New, active multiple sclerosis plaques are characterized by _______

BBB breakdown Note: the BBB appears to repair itself in chronic plaques and shadow plaques. They replace myelin with reactive astrocytes which do not make a good BBB

Norepinephrine (NE)

BIOSYNTHESIS -synthesized by oxidation of DA via dopamine-ß hydroxylase RECEPTORS (metabotropic) -α1, ß2 -ß1, ß2 TERMINATION -presynaptic NE transporter (NET) ~ inhibited by amphetamine ~ mutated NET gene causes orthostatic intolerance -degraded by COMT and MAO LOCALIZATION -CNS - locus ceruleus -PNS - postganglionic sympathetics

Histamine

BIOSYNTHESIS -synthesized from histidine histidine decarboxylase (rate-limiting) RECEPTORS and CNS EFFECTS -metabotropic -H1 type in CNS; excitatory -regulate vestibular function -regulate cortical arousal ANTIHISTAMINES = receptor antagonists -depress vestibular function, e.g. dramamine for motion sickness -cause sedation, e.g. diphenhydramine -CNS effects are minimized by newer antagonists that don't cross the BBB, e.g. cetirizine REMOVAL -Enzymatic

Serotonin (5-HT)

BIOSYNTHESIS -synthesized from tryptophan -tryptophan 5-hydroxylase (rate-limiting) produces 5-hydroxytryptophan intermediate 5-HT RECEPTORS (15 subtypes) -most (5-HT1, 5-HT2, 5-HT4 and 5-HT5) are metabotropic -only one (5-HT3) uses a ligand-gated ion channel REMOVAL MECHANISM -presynatpic uptake via SERT: specific serotonin transporter ~inhibited by SSRIs (e.g. Prozac) ~degraded by MAO

Dopamine (DA)

BIOSYNTHESIS synthesized from tyrosine in presynaptic terminal cytoplasm 1. tyrosine hydroxylase (rate-limiting) produces DOPA intermediate 2. DOPA decarboxylation yields DA RECEPTORS (metabotropic) -D1 receptors activate (increase cAMP) -D2 receptors inhibit adenyl cyclase (decrease cAMP) TERMINATION -presynaptic uptake via DA transporter (DAT) (DAT inhibited by cocaine and amphetamine) -DA degraded by monoamine oxidase (intracellular) & catechol O-methyl transferase (extracellular)

Cross sectional study

Based on a one-time contact with study participants (be it a formal encounter for physical measurements, blood draws, etc.; or via responses to a survey; or both) classify study participants by their levels of exposure and outcome Cross sectional studies document the prevalence of a condition or health event Major issue is their cross-sectional nature; they only provide a snapshot in time

Most local anesthetics are weak ____

Bases, and can enter cells at higher pH Most L.A.'s are weak bases (pKa = 7.5 - 9.0) Lidocaine with pKa= 7.8 in the interstitium with pH = 7.4 will have 29% molecules as uncharged and able to enter a cell. Intracellularly, at pH = 6.9, 89% will be charged and bind to the sodium channel. In infected tissues with extracellular pH of 6, 98% will be charged and unable to enter a cell

Muscular dystrophies

Begin in childhood and are characterized clinically by progressive muscle weakness and wasting Histologically, muscle fibers are slowly replaced by fibrosis and adipose tissue -proliferation of endomysial connective tissue -round muscle fibers of various sizes with degeneration and regeneration fo muscle fibers

CNS myelination across the lifespan

Begins actively in the 3rd trimester with most not being complete until about 3-4yr postnatally Generally follows caudal-to-rostral direction Asynchronous, even within a single tract Satellite oligodendrocytes and oligodendrocyte progenitor cells held in reserve and are poised to remyelinate Around 20yrs, association cortices e.g. dorsolateral prefrontal cortex are the last to myelinated. This area is associated with wisdom and choices, executive functions, and related to impulse control, and perhaps adolescent-onset psychiatric disorders

Deficits seen in subacute combined degeneration

Bilateral DCML modality loss Sensory ataxia; (+) Romberg/steppage gait Paresthesias Pain/temp sensation spared Less often Bilateral spastic paresis OR bilateral hypotonia if peripheral neuropathy masks UMN signs

Advanced neurosyphillis (syphilitic myelopathy) (tabes dorsalis) lesion

Bilateral death of 1°sensory afferents for DCML modalities Secondary dorsal column demyelination

Motor neuron disease variants (e.g. ALS) lesion

Bilateral death of corticospinal and/or corticobulbar neurons and secondary demyelination Bilateral death of LMNs (spinal and/or cranial); often caudal-to-rostral progression; corticobulbar form starts high Some cord LMN pools may at first be skipped or affected unilaterally

Deficits seen with advanced neurosyphillis (syphilitic myelopathy) (tabes dorsalis)

Bilateral loss of DCML modalities Sensory ataxia -> (+) Romberg sign, steppage gait Paresthesias, Lhermitte's sign often Hyporeflexic due to sensory afferent loss Cognitive deficits and cranial nerve abnormalities

Dorsal (medullary) raphe nuclei

Bilaterally symmetric nuclei that bracket the midline Obscured by the medial lemniscus Its projections descend as serotonergic raphespinal fibers

How do neurotrophins signal genomic effects?

Bind Trk receptor at growth cone Ligand-Trk complex is endocytosed "Signaling endosome" attaches to dynein motor This endosome is shuttled to cell body by retrograde axonal transport where they can then activate downstream targets such as promoters

Built in features to foster internal validity

Built-in features to foster internal validity: -Randomization protects from selection bias -Randomization balances the groups with regards to known (or unknown) confounders -Double blinding protects from observation bias Still of concern: -Loss to follow up -Non-compliance with experimental assignment Note: it requires analysis by intent-to-treat to preserve the balance afforded by randomization

Peripheral nerve

Bundle of axons degreased by connective tissue in the peripheral nervous system. Can be purely motor, sensory, autonomic, or a mixture of these afferent and efferent axons

Inferior to the epineurium exist _____

Bundles of axons Note: these are bundled by function (e.g. all motor, all sensory, or all autonomic). These bundles can divide further along the distal nerve course by destination (motor) or origin (sensory). Note: Between the bundles are blood vessels, the vaso vasorum, and adipose tissue.

Which nociceptor fiber mediates second pain

C

Cord levels ______ have the largest ventral horns (neuronal soma) for serving the arm and leg

C8-L4

Non-label Use of other Anticonvulsants for neuropathic pain

CARBAMAZEPINE for trigeminal neuralgia (1st Line for focal onset epilepsy). MOA: Prolongation of Na+-channel refractory period TOPIRAMATE (causes weight loss) MOA: GABA agonist & other mechanisms. May cause neuropathy ZONISAMIDE (sedative effect) inhibits T-type Ca2+ channel. SE: renal calculi

Carcot-Marie-Toothe disease (CMT)

CMT is the most common hereditary motor and sensory neuropathy Prevalence across all forms is 1:2500 in US CMT has multiple forms with most commonly seen are CMT1A and CMT1X -CMT1a =66% of cases; produces 3 copies of the PMP-22 gene which distorts peripheral myelin -CMT1X causes a mutation of connexin-32, which produces faulty gap junctions in SLI's

Onion bulb myelin is unique to ____

CMT1A Note: this is thin compact myelin surrounded by several proliferative Schwann cells appearing to have aborted attempts at myelination

Tyrosine hydroxlase marks:

CNS catecholaminergic neurons Image shows de-pigmented locus coeruleus immunostained for TH

Side effects and other effects of ketamine

CNS: Unlike other parenteral anesthetics, KETAMINE increases cerebral blood flow and intracranial pressure SE: Emergence delirium : hallucinations, vivid dreams, illusions complicate postop management (Rx - Benzodiazepines) CVS: Unlike other anesthetics, KETAMINE increases blood pressure, heart rate, and cardiac output. Respiratory: KETAMINE is a potent bronchodilator

Where are oligoclonal immunoglobulin bands found in multiple sclerosis

CSF but not in the serum

Crush injury to the spinal cord promotes _____ action

CSP glia limitans disrupted - axons transected distal axon segment dies breech of limitans triggers cellular reaction leptomenigeal fibroblasts invade cord at site - express surface CSP astrocytes of limitans become "reactive", add to scar, and also express surface CSP (not laminin) CSP collapses growth cone of proximal axon stump so regeneration fails

Neuropeptides released by nociceptors

Calcitonin gene-related peptide which leads to leaky capillaries (note: can induce vasodilation and edema which is important in migraine) Substance P which leads to mast cell degranulation

Nernst equation

Calculates the equilibrium potential for K+

Origin of neuropathic pain

Can arise from nerve injury, inflammation, and neuroma, etc

Central cord syndrome

Can arise within the watershed area of the central gray or congenital cavitation of the cord Most common incomplete cord syndrome Frequently found in elderly with underlying spondylosis or younger people with severe extension injury Upper extremity deficit is greater than lower extremity deficit, because the lower extremity corticospinal tracts are located lateral in the cord Ex: syringomyelia, cord compression (trauma, metastatic disease)

Hemicord (Brown-Sequard) lesion

Can be caused by: -stab injuries (rare) - often tumor (e.g. metastatic, or meningioma effacing cord) -other trauma The lesion itself is unilateral, affecting all three long tracts to some degree

Multiple sclerosis plaques

Can be present in the brain, optic nerve , and spinal cord They are areas of discrete demyelination with relative axonal sparing Most often within the periventricular white matter; also brainstem and cord -also microscopically present cortically, affecting intra-cortical myelinated fibers Plaques present over a continuum: -Acute active (demonstrate contrast enhancement on MRI) -Chronic active (healing) -Chronic inactive (variable remyelination, remain visible on MRI)

Anatomic sites of general anesthetics: Brain

Can cause unconsciousness Can also cause amnesia -Anesthetics ablate the formation of new memories while leaving prior memories intact -The α5 GABAA receptor inhibits synaptic plasticity (long term potentiation for short term memory) in CA1 pyramidal cells of hippocampus -ETOMIDATE, as a GABAA agonist, causes amnesia Note: ETOMIDATE, ISOFLURANE, or SEVOFLURANE-induced anterograde amnesia is absent in α5 GABAA receptor knockout mice

MRI showing transverse myelitis

Can produce central cord lesions 1/3 cases recover 1/3 have residual deficits 1/3 are permanently debilitated

Cardiotoxicity of local anesthetics

Cardiac arrest with obstetric epidural bupivacaine Peripheral vasodilatation → hypotension Inhibition of Ca2+ channels → decreased myocardial contractility. Na+-channel block → ↑ refractory period, ↓ firing threshold, ↓ dromotropy → -Bradycardia with a long P-R interval -Wide QRS complex -Dysrhythmias (blocks, re-entry, VTACH, VFIB)

Entrapment neuropathies

Carpal tunnel syn is by far the most common Hands & wrist numbness, tingling, parasthesia, and rarely hand weakness Electrodiagnostic study confirms the diagnosis Causes; occupation, diabetic, pregnancy, hypothyroidism, Rh A. & often is not apparent, but look for identified causes when suspected Surgical decompression is curative, splinting of the wrist, and hydrocortisone injection are useful temporizing measure

Anterior funiculus

Carries pain and temperature fibers more laterally within the spinothalamic tract

Multiple sclerosis etiology

Cause remains unknown! Most widely accepted explanation is some initial trigger early in life leads over time to autoimmune mechanisms causing demyelination Fundamental unanswered question: Is the CNS inflammation in MS initiated by an autoimmune repose peripherally, or in response to some intrinsic degenerative process within the CNS it self (current debates include molecular mimicry and bystander activation)

Upper motor neuron signs

Caused by a lesion anywhere along the corticospinal tract above the level of the deficit Exam would show: - increased deep tendon reflexes (hyperreflexia) - presence of superficial reflexes (Hoffmann's sign; Babinski sign (extensor plantar response) ) - hypertonia - atrophy (mild (<30% muscle mass loss) "disuse") - weakness, loss of dexterity, pronator drift - spastic paresis

Deafferentiation pain

Caused by damage to primary sensory neuron (e.g. viral infection, chemotherapy, diabetes, trauma, demyelination, root compression and inflammation, avulsion of the dorsal nerve root, limb amputation)

Neuropathic pain syndrome: thalamic pain syndrome

Caused by lacunar infarct of thalamus-one side Leads to contralateral allodynia

Neuropathic pain syndrome: Trigeminal and glossopharyngeal neuralgias

Caused by vascular compression of nerve roots

Effects of surgical incision

Causes nociception which can causes: -motor reflexes (requires myorelaxation- cisatracurium, succinylcholine) -awareness, perception of pain, and movement (requires anesthesia- thiopental, isoflurane, N2O) -autonomic reflexes (requires autonomic stabilization-atropine)

Cauda equina syndrome

Causes: disc herniation, trauma, neoplasm, abcess, spinal stenosis Affects >one nerve root (L2-S5) Larger lesions affect more nerve roots, producing more extensive symptoms and signs. Signs are typically asymmetric if there is a postero-lateral direction of the herniation Autonomic fibers (S2-4) descend closest to the midline, so the more central the herniation or trauma, the more likely ANS Sx will present. An abscess can affect all roots!!

Plexopathy

Causes; trauma, post infectious, nerve tumors, diabetic, hereditary, neoplastic, birth injury, and idiopathic Symptoms; prominent motor deficit, sensory deficit, pain, muscle atrophy and decreased reflexes Diagnosis; clinical and neurological exam, NCS/EMG and imaging (MRI) Treatment; identify causes , physical and occupational therapy, braces and limb support Prognosis; variable, depends on the cause and severity, pure demyelination versus axonal type.

Multiple mononeuropathies (mononeuritis multiplex)

Causes; vasculitis, , CTD, diabetes, immune mediated (MMN), infectious (leprosy, hepatitis, Lyme D), burns ... 80% over age 50 years, male>female Symptoms; pain (50%), sensory disturbances, weakness, systemic symptoms Deficit distribution follows multiple nerves pattern and can be accumulative and confluent Diagnosis; Clinical history and examination, Lab (↑ ESR), serum autoantibodies, NCS/EMG and nerve biopsy Treatment; cause specific, corticosteroids, immune-suppressive, supportive Prognosis; Good with early diagnosis and treatment, worse with no remission in 1 year and in severe cases. Death rate 6 - 10%

Histaminergic neurons

Cell bodies localize exclusively to the tuberomammillary nucleus of the hypothalamus

Sympathetic ganglion features

Cell bodies of autonomic ganglia, either sympathetic or parasympathetic, are multipolar and located directly "in-line" along the direction of information flow, unlike primary sensory pseudounipolar neurons. Synapses between pre- and post-ganglionic neurons occur in autonomic ganglia, unlike sensory ganglia, allowing integration of information. Have eccentrically positioned nucleus containing a prominent nucleous Axons and dendrites, emanate from the perimeter of postganglionic neuronal soma, unlike DRG/CN sensory ganglion neurons, which appear smooth; nerve fibers are interspersed between neuronal somata unlike in sensory ganglia Satellite cells surround neuronal soma but are much fewer than in DRG/CN sensory ganglia

Clonidine

Central alpha 2 agonist Adjunct to spinal anesthesia (decreased nociception) Adjunct to general anesthesia (sedation and anxiolysis) As antihypertensive (blocks central sympathetic outflow) For Rx of Opioid withdrawal For DDx of HTN etiology: (suppression of plasma NE after clonidine in essential HTN; no NE suppression in pheochromocytoma)

Dexmedetomidine

Central α2 agonist Adjunct to spinal anesthesia (decreased nociception) Adjunct to general anesthesia (sedation and anxiolysis)

Signaling in a neuron works by:

Changing its membrane potential to make the inside more positive (depolarization) or more negative (hyperpolarization) compared to the outside. Opened ion channels make this happen In the axon, depolarization to a threshold value triggers an action potential (AP) that doesn't decay over distance before it reaches the axon terminal to trigger discharge of neurotransmitter molecules

Types of diffusible guidance molecules

Chemorepulsive -semiphorins Chemotropic -netrins -neurotrophic factors

Extracellular matrix: Glycosaminoglycan class (proteoglycans)

Chondroitin sulfate (CSP), heparan sulfate, tenascin CSP and tenascin act as barriers to axon growth and regeneration when made by CNS scar tissue

Myasthenia Gravis

Chronic autoimmune (postsynaptic) neuromuscular disease (antibodies against the ACh receptors) Weakness and rapid fatigue of any of the muscles under voluntary control Most common in woman younger than 40 and men older than 60 Symptoms -Ptosis, drooping of eyelid -Diplopia, double vision -Impaired speech -Difficulty chewing and swallowing

Multiple Sclerosis Types

Classic (Charcot type) -relapsing remitting, primary progressive, secondary progressive Acute (Marburg type) -rapidly progressive, monophasic, short survival Neuromyelitis optica (Devic's disease) -optic neuritis and transverse myelitis Concentric sclerosis (Baló's disease) -monophasic, rapidly progressive, distinctive histopathology

Central Pontine Myelinolysis (CPM)

Classically associated with rapid correction of hyponatremia, osmotic demyelination 10% of patients will also have extrapontine mylinolysis Can be seen in other conditions with normal sodium level, e.g. AIDS, Alcohol Rapid onset of confusion, weakness, gaze palsies, dysarthria, dysphagia, hypotension Results in loss of myelin with preservation of axons and neurons often fatal, but reported cases of full recovery. May also present with Locked-in syndrome, patient is aware but cannot communicate or move

Relapsing-remitting MS (RRMS)

Clearly defined attacks of neurologic dysfunction followed by partial or complete recovery periods 85% of MS patients begin this way Relapses treated with steroids acutely Prophylactic regimens of specific immunosupressants aimed to reduce frequency and severity of exacerbations

Lateral vestibulospinal tract

Clinically more important Originate from the lateral vestibulospinal nucleus Ipsilateral projections only Target ipsilateral LMN pools to antigravity muscles in proximal limbs Keeps us upright Unilateral lesion -> fall to same side, no Romberg sign

Golgi Tendon Organ arrangement

Collagen fibrils positioned in series with extrafusal muscle fibers Ib afferents interwoven between collagen fibrils Tension in contracting muscle fibers relayed to GTO Distorts Ib terminals

Tract/fasiculus/bundle

Collection of axons traveling together in the CNS Note: the optic nerve is a contradiction to this as it is within the CNS

Central pattern generators

Collections of local circuit neurons forming segmental or multi-segmental autonomous interneuronal circuits in central cord gray They produce self sustained rhythmic motor patterns They are independent of sensory input They are independent of supraspinal input Function: they control synergistic timing of muscle contraction/relaxation and adjustment required for complex limb function needed for ambulation

Deficits seen in Motor neuron disease variants (e.g. ALS)

Combo of LMN signs (fasciculations, atrophy, hyporeflexia/weakness) + UMN signs upper limb onset (dexterity affected) lower limb onset (clumsy gait, foot drop) bulbar form: dysarthria initially, then dysphagia Note: EMG shows reduced amplitude of compound motor APs (CMAP), reflecting LMN loss to a muscle

Epidemiology of B12 deficiency

Common in US, especially among the elderly (incidence of 10% - 25% in population over 80 years of age).

Nerve sheath tumors

Common tumors of the peripheral myelin and connective tissue around the nerve Schwannoma and neurofibroma

Peroneal (fibular) neuropathy

Compression of the nerve at the fibular neck or hip injury causing foot drop Symptoms include weakness in dorsiflexion of the foot

Radial neuropathy

Compression/damage to the radial nerve along its course Examples: wrist drop, Saturday night palsy, etc

_______ accounts for the rising and declining phases of the AP (depolarization and repolarization).

Conductances through a succession opened voltage-gated channels

Endomysium

Connective tissue around each muscle fiber Inflammation in this tissue is pathologic!

Perineurium

Connective tissues that surrounds the various axon bundles and contains an inner ring of fibroblasts connected by tight junctions. . This creates a diffusion barrier preventing blood-borne solutes from accessing nerve fibers within the bundle.

General anesthetics interfere with what general steps of pain perception

Conscious perception

Posterior (dorsal) funiculus

Contains 2 dorsal columns consisting of 2 bundles of fibers that are ascending and representing dermatomes The medial ones are the gracile fasciculus and are separated from the cuneate fasciculus via the posterior intermediate sulcus

α-subunit of NaV 1.8 and 1.9 of Aẟ and C fibers

Contains binding sites for local anesthetics between residues F1764 to Y1771, the distance between which is 11A. Most effective local anesthetics are of similar lengths Note: this subunit is a 260 kDa protein with 4 domains

Multiple sclerosis treatment

Continually expanding list of choices for first and second line treatment (start with injectable medications -> oral -> IV medications) All agents tested in similarly designed clinical studies, but comparison of outcomes and head to head studies severely limited Not yet possible to predict which treatment is best suited to a given patient

Example of a hemicord lesion at T4

Contralateral loss of pin-prick sensation beginning 1-2 segments below lesion Pain and temp info coming in from left side at T4 not yet represented in lesion Pain and temp info arriving from right side at T4 can be abolished with horn loss

Transduction of sensory stimuli

Conversion of mechanical stimulus to neural activity

Local potentials

Created in a dendrite/cell body by influx of ions through an opened receptors bearing ion channel, or experimentally with a current passing electrode

Limitations of PNS regeneration

Crush outcome better than transection - for transection can ligate epineurium of distal and proximal axon segments together Re-innervation may not be not be functional - improves when the distance from lesion to target is shorter Regeneration of axon max's at rate of ~1 mm/day - reflects rate of slow component of anterograde axonal transport of tubulin monomers to growing end

Ulnar neuropathy

Cubital tunnel syndrome is ulnar nerve compression, entrapment, at the elbow (funny bone) Symptoms include numbness, tingling and/or pain in the ring and little fingers Compression of the ulnar nerve can occur in the ulnar groove at the elbow or at the wrist on Guyen's canel

Expectations of multiple sclerosis treatment

Currently available treatments proven to modify progression of disease -NOT proven to reverse established disease Relapses still may occur and are usually managed with IV steroids, but recovery is not always complete Based on frequency of relapses, severity, or side effects, treatment may be altered over time

A 45-year-old male complains of severe right arm pain. He gives a history of having slipped on the ice and severely contusing his right shoulder approximately 6 months ago. Soon thereafter, he developed sharp, knifelike pain in the right arm and forearm that lasted for a few months. There was some arm swelling and warmth. He was evaluated in an urgent care setting. There were no radio- graphic abnormalities and he was not treated. Since the injury, the pain and swelling have persisted. Physical examination reveals a right arm that is moister and hairier than the left arm. There is no specific weakness or sensory change. However, the right arm is clearly more edematous than the left, and the skin appears shiny and cool. The patient's pain most likely is due to: A. Acromioclavicular separation B. Brachial plexus injury C. Cervical radiculopathy D. Complex regional pain syndrome E. Subclavian vein thrombosis

D Complex regional pain syndrome (CRPS) types I and II are the terms that have replaced reflex sympathetic dystrophy or causalgia because of the absence of a proven causative role for the autonomic nervous system. CRPS type I is a regional pain syndrome that usually develops after tissue trauma. Examples of associated trauma include myocardial infarction, minor shoulder or limb injury, and stroke. Allodynia, hyperpathia, and spontaneous pain occur. The symptoms are unrelated to the severity of the initial trauma and are not confined to the distribution of a single peripheral nerve. CRPS type II is a regional pain syndrome that develops after injury to a specific peripheral nerve, usually a major nerve trunk. Spontaneous pain initially develops within the territory of the affected nerve but eventually may spread outside the nerve distribution. Pain is the primary clinical feature of CRPS. Vasomotor dysfunction, sudomotor abnormalities, or focal edema may occur alone or in combination but must be present for diagnosis. Localized sweating and changes in blood flow may produce temperature differences between affected and unaffected limbs.

Power scale (DTR rating)

0 absent (arreflexia) +1 trace (hyporreflexia) +2 normal +3 brisk (hyperreflexia) +4 clonus +5 (if used, tetanus)

Neurofibromatosis II

1 in 40,000 people, about 50% do not have a family history, NF2 is tumor suppressor gene Most common cause of bilateral vestibular schwannoma

Cholinergic neurons cell bodies are concentrated in:

1) midbrain - project to thalamus and cortex to mediate consciousness 2) inferior frontal lobe (basal forebrain) - project to cortex and hippocampus - activate memory mechanisms; degenerate in AD 3) Brainstem motor nuclei and cord ventral horn CNS expresses both nAchR subtypes and mAchR subtypes. nAchRs are most important for this course.

multiple sclerosis MRI of the spine tends to be ______ cord segments long

1-1.5

Somatosensory pathways

1. Dorsal column-medial lemniscus (DCML) -tactile sensation from dermatomes -conscious proprioception (position sense) from muscle spindles, Golgi tendon organs, joint capsules 2. Anterolateral system (ALS) -pain and thermal sensation, crude touch, -also itch and tickle

Events at a chemical synapse

1. Transmitter is synthesized and then stored in vesicles 2. An action potential invades the presynaptic terminal 3. Depolarization of presynaptic terminal causes opening of voltage-gated Ca2+ channel 4. Influx of Ca2+ through channels 5. Ca2+ causes vesicles to fuse with presynaptic membrane 6. Transmitter is released into synaptic cleft via exocytosis 7. Transmitter binds to receptor molecules in postsynaptic membrane 8. Opening or closing of postsynaptic channels 9. Postsynaptic current causes excitatory or inhibitory postsynaptic potential that Changs the excitability of the postsynaptic cell 10. Retrieval of vesicular membrane from plasma membrane

Mechanisms for neurotransmitter removal from cleft

1. postsynaptic receptor binding 2. presynaptic reuptake -DAT (dopamine transporter) -NET (norepi transporter) -SERT (5-HT transporter) 3. perisynaptic glial uptake -EAAT (excitatory. a.a. transporter) -also inhibitory a.a. transporter 4. enzymatc degradation in cleft -AchE (acetylcholinesterase) -COMT (catechol-O-methyl transferase) 5. Ligand-receptor endocytosis (peptides) -Substance P- neurokinin 6. diffusion/proteolysis (peptides)

Primary Progressive MS (PPMS)

10% of MS patients - associated with early mortality Steady worsening of neurologic function from the beginning Can have plateaus and minor improvements No distinct relapses and remissions

Primary Progressive multiple sclerosis

10-15% of patients experience a progressive course from onset, with gradual deterioration of function Typically presents as a progressive myelopathy; less commonly as brainstem or cerebellar syndrome Mean age at onset 40 (in RRMS mean age at onset 30) Occurs 1:1 in males and females Fewer lesions, less likely to enhance

Chemotherapy induced polyneuropathy (CIPN)

10-20% cancer patients Symptom severity relates to cumulative chemo' dose Nnset varies by drug Symptom resolution not well studied - often very slow after meds discontinued

How many thoracic nerves are there

12 pairs (T1-T12) Note: there are 12 thoracic vertebra

Cold thermoreceptors respond to ____

17-30 C (peak 20 C)

fMRI imaging of blood flow before, during and after voluntary right thumb movement

1= blood flow increase in left anterior SMA prior to movement 2= flow increase moves in left PMA and posterior SMA 3= flow increases in 1°motor cx at movement onset 4= flow increase in somatosensory cx reflects proprioception as movement occurs Concurrent changes in cerebellum (right medial hemisphere) 1,2= activated lateral hemispheric area for planning and motor programs 3,4= cerebellar output for rt upper extremity control

Glutamate is used by:

1° sensory afferents, special sensory afferents >95% cerebral and cerebellar cortical neurons learning and memory circuits Upper motor neurons

How many states do voltage-gated K+ channels have?

2 open and closed Its voltage sensor responds to a Vm of about +25 mV by opening the pore

Optic neuritis

20-40 yrs old, (white) women over men Inflammation of one or both of the optic nerves Often the first indication of multiple sclerosis Symptoms include pain, visual field loss, flashing lights and color loss Neuromyelitis optica is similar to MS but is focused on the optic nerves

How many states do voltage-gated Na+ channels have?

3 open, inactivated, and closed Its voltage sensor responds to threshold potential by opening the pore

Local anesthesia requires ______ blockade

3 adjacent node

Glutamate receptor types

3 ionotropic types named after experimental agonists that activate them -Kainate, AMPA, n-methy-D-aspartate (NMDA) types are non-selective for Na+ and K+ -All excitatory -NMDA types gated Ca+2 metabotropic receptors- G protein-coupled to activate phospholipase C pathway

Hereditary neuropathies

30% or more of undiagnosed neuropathies Estimated prevalence of 1 in 2,500, the most prevalent inherited neurological diseases Hereditary neuropathies are divided into 2 main types; - Predominantly motor sensory (CMT) - Predominantly sensory autonomic (HSAN) Each category has a number of subtypes, each subtype might have several distinct genetic defects

Warmth thermoreceptors respond to ____

30-45 C (peak 40 C)

Spinal nerve roots

31 pairs cervical -C1-7 exit above like-numbered vertebra -C8 exits between vC7-T1; no vC8 thoracolumbar -T1-L5 exit below like-numbered vertebra sacral -S1-4 exit below like-numbered vertebra and exit through sacral foramina -postgang. parasymp. exit at S2-S4 -S5 exits below sacrum coccygeal -CG1 exits below 1st coccygeal segment Note: Tip of CNS (conus) extends to vL1 and perhaps L2 in the adult

Broadman areas

3b & 1 neurons: tactile stimuli 3a neurons: proprioceptive stimuli area 2 neurons: tactile and proprioceptive stimuli

Spinothalamic pathway cortical termination

3rd order thalamocortical fibers project to layer IV of the postcentral gyrus It projects to sensory homunculus specialized for precise dermatomal localization of stimulus and converting stimulus intensity and duration

A single oligodendrocyte supplies a myelin internode for as many as _______ different axons

40

Meissner afferents

40% hand mechanosensory afferents 4x > sensitivity to skin deformation than Merkel's Receptor field > Merkel's so less spatial resolution (3 mm acuity) Involved in Motion detection; grip control Rapidly adapt

How many lumbar nerves are there?

5 pairs (L1-L5) Note: there are 5 lumbar vertebra

How many sacral nerves are there?

5 pairs (S1-S5) Note: there are 5 sacral vertebra

Features of Lower Motor Neuron somata

50-70 µm soma - a large soma is needed to house sufficient organelles to maintain a long axon and its presynaptic terminals rER aggregate into basophilic Nissl bodies (aka Nissl substance) There is a prominent nucleus and nucleolus Targeted by the neurodegenerative Motor Neuron Disease, e.g Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease), as are upper motor neurons

Periventricular Leukomalacia (PVL)

55,000 births annually in US, 90% survival WM focal necrosis next to lateral ventricles followed by cavitation and collapse Diffuse reactive gliosis in surrounding WM PVL targets primarily pre-myelinating oligodendrocyte progentors - are sensitive to hypoxic-ischemic injury in childbirth Occurs mainly with premature births at 24-32gwks - before myelination and MBP+ oligodendrocytes form Long-term consequences of diffuse, delayed myelination: 10% cases lead to cerebral palsy 50% cases lead to cognitive and behavioral deficits

How many cervical nerves are there?

8 pairs (C1-C8) Note: there are only 7 cervical vertebra! Therefore C1 exits above the C1 vertebra and C8 exits below the C7 vertebra

We have _______ lower motor neurons

<1 million (<0.001% of the CNS neuron pool)

Motor unit

=LMN + all muscle fibers that it's collaterals innervate This is the minimum functional unit of contraction

Endoneurial compartment

A bundle of nerve fibers bounded by a ring of perineurium

dexmedetomidine

A central α2 agonist blocking the release of NE from the LC

Meralgia Paresthetica (skinny jeans syndrome)

A condition characterized by tingling, numbness and burning pain in the outer thigh Cause is compression of the sensory nerve, lateral femoral cutaneous nerve under the inguinal ligament Causes include: Tight clothing including belts, obesity, pregnancy, scar tissue due to surgery, seat belt injury from a car accident, heavy tool belts and gear

Nemaline Rod Myopathy

A congenital myopathy that is slowly progressive generalized muscle weakness and hypotonia at or shortly after birth ("floppy baby syndrome") Due to rod-shaped intracytoplasmic inclusions within the myocyte. These are polymerized sarcomere proteins

Epineurium

A dense connective tissue sheath that surrounds the entire nerve that replaces the meninges of the CNS Note: if a nerve is severed, the epinerium can be ligated together to promote regeneration of the axon

DCML pathway

A dorsal root ganglion accesses the spinal cord through a rootlet and then through the dorsal root entry zone (just medial to the dorsal root) It then ascends through a dorsal column; either the Gracilis (lower extremity) or cuneatus tract (upper extremity) It then synapses in the caudal part of the medulla on a second order neuron (either the N. gracilis or N. cuneatus depending on the dorsal column tract it is traveling along) It then travels along internal arcuate fibers (sensory decussation) which cross to the other side! It ascends along the medial lemniscus up to the thalamus where it will synapse with a 3rd order neuron (Ventroposterolateral nucleus aka VPL) From there, it ascends along the posterior limb of the internal capsule up to the 4th layer of the primary somatosensory cortex

General anesthesia

A drug-induced reversible depression of the CNS resulting in the loss of response to and perception of all external stimuli. Anesthesia is a collection of "component" changes in behavior or perception: -Amnesia (at 0.25 MAC for inhalational) -Unconsciousness (at 0.4 MAC) -Akinesia - immobility (at 1 MAC) -Analgesia - Analgesic required for most -Attenuation of autonomic responses to noxious stimulation (stability of cardiovascular, respiratory & thermoregulatory systems)

Dopaminergic neruons

DA neurons project diffusely in CNS Cell bodies in 3 places: -Two nuclei in midbrain -One nucleus in hypothalamus

Pelizaeus-Merzbacher Disease (PMD)

A hereditary hypomyelinating disorder It is a X-linked leukodystrophy; mutation, deletion, or duplication of myelin proteolipid protein (PLP1) gene locus Presents with spastic quadriplegia; ataxia Developmental delay Not inflammatory, unlike MS Length-dependent axon degeneration

Fibromyalgia

A long-term disorder causing chronic body-wide pain, depression, anxiety, sleep disturbances, and headache Higher prevalence in females Proposed mechanisms is due to a down regulation of descending analgesic systems causing a decreased pain threshold Treatment: Duloxetine (e.g. Cymbalta) - 5HT/NE uptake inhibitor (SNRI) -first FDA approved antidepressant for treatment of fibromyalgia associated neuropathic pain and depression

Neuromuscular junction

A motor axon collateralizes (branches) to innervate several myocytes, each receiving one presynaptic terminal (motor endplate) AchR localizes to apices of junctional folds. Sarcomeres are easily seen.

Tay Sachs

A neuronal storage disease AR genetic lipid metabolism disorder that causes destruction of neurons in the brain and spinal cord A misfolded mutant enzyme hexosaminidase A, located in lysosomes, cannot metabolize GM2 gangliosides The accumulated gangliosides remain within the lysosomes also known as a lysosomal storage disease Fatal by age 3-5, late-onset type does not always shorten life expectancy

Phantom limb

A neuropathic pain syndrome (damage/dysfunction of pain afferents or CNS pain pathways) Seen with amputation or congenital absence Due to a compensatory overactivity of secondary and tertiary neurons still somatotopically dedicated to differentiated limbs Can fool the visual systems to reduce pain

Myelin basic protein

A peripheral membrane protein of compact SC myelin located on cytoplasmic face of membrane main contributor of PNS major dense line

Myelin membrane consists of ____

A relatively simple composition of glycolipids and structural proteins, which differ between SC/PNS myelin and OC/CNS myelin. Myelin proteins are autoimmune targets of multiple sclerosis, the most prevalent demyelinating disease of the CNS. In the PNS, faulty expression of a myelin structural protein is causal to the most common heritable peripheral neuropathy - Charcot-Marie Toothe disease Note: Due to its high lipid content, myelin is selectively labeled by lipophilic histologic stains, including sudan black at the cellular level, luxol fast blue and Weigert stains at tissue levels, and osmium tetroxide for TEM.

Gower sign

A sign that indicates generalized muscle weakness in children Will have a positive sign in DMD

Two-point discrimination

A test of sensory acuity which reflects receptor field size (ability to detect two points as distinct) Measured as minimal inter-stimulus distance required to perceive two distinct stimuli Depends on receptor field size and receptor density Greatest sensitivity in hands, parts of the face, toes due to small field size and highest receptor density

Ligand-receptor endocytosis of Substance P-bound neurokinin

A) Substance P receptors (neurokinin) expressed in the membrane surface of a neuronal cell body and dendrites B) Negligible internal expression of the receptor within the dendrite. C) Substance P addition triggers ligand-mediated endocytosis of SP-neurokinin complex. This conveys the signal to the neuronal genome and also terminates the effect of minute amounts of Substance P in the synaptic cleft. D) Internal staining for the receptor in the dendrite compared to B

Features of postganglionic parasympathetic ganglia

The cell bodies of postganglionic parasympathetic neurons reside near or within the wall of the innervated organ. They are classically observed in the walls of the alimentary canal, where they contribute to the enteric nervous system. They are most apparent in the submucosa and muscula externa.

Action potentials require voltage-gated Na+, K+ and Ca+2 ion channels with homologous features

The channel is formed by a single long polypeptide with 4 domains (I-IV), each exhibiting a 6 transmembrane repeats. The charged voltage sensor = S4 domain (blue). serves to open and close the channel depending on membrane voltage. The pink part of the polypeptide is the ion selectivity filter contributed by each of the 4 domains. It lines the channel pore when the four subunits assemble to form the pore and determine which ion passes through the channel. Voltage-gated K+ and Ca+2 channels have the same general construct but differ in the AA sequences of their voltage sensor and selectivity filter.

The electrical properties of the pseudounipolar neuron are unique in that _______

The entire span of the afferent process carrying info toward the cell body and away from it into the CNS behaves as an axon. Action potentials travel the entire distance but bypass the displaced cell body.

Pioneer axons

The first to lay down in a developing tract and prefer to elongate against pathways made of cell adhesion molecules

motor unit

The functional unit of the neuromuscular system consisting of: -A lower motor neuron -Multiple muscle fibers

Posterior Reversible Encephalopathy Syndrome (PRES)

The inability of the posterior circulation to autoregulate in response to acute changes in blood pressure causing non-infarct edema, commonly in the parieto-occipital regions -Acute hypertensive encephalopathy or reversible posterior leukoencephalopathy Symptoms include headaches, seizures, visual disturbance and encephalopathy

Depressant and anxiolytic drugs bind to and potentiate _______

The inhibitory effects of activated GABA receptors Ionotropic GABA receptors are pentameric They bind barbiturate drugs, e.g. phenobarbital, at their pore domain to increase the duration of Cl- channel opening, thereby enhancing GABAergic effects They bind benzodiazepines at α and ß subunits of GABAA receptors to increase frequency of Cl- channel opening and enhance GABAergic transmission They bind ethanol, which augments GABA receptor function in many ways

Resting membrane potential (Vr)

The inside of the neuron is negatively charged relative to the outside due to the preponderance of Na+ ions outside the cell that cannot cross the membrane at rest. Even though the concentration of K+ ions inside the cell is greater than outside, the total number of cations (Na+ and K+) outside the cell outnumbers cations inside the cell. Chloride anion also predominates outside the cell but its effect on resting membrane potential is counteracted by organic anions that accumulate inside the cell. So, a recording electrode that penetrates the cell will read a fraction of a volt, around -70 to -90mV due to this charge imbalance.

pyramidal cells of Betz

The largest upper motor neurons

Conus medullaris syndrome

The lowest CNS injury Generally occurs adjacent to vertebral bodies L1 and L2 Causes: -burst fracture -neoplasia, trauma, central disc herniation (vT12-L1, L1-L2)

Use-dependent block

The more you use the channel in the presence of the same concentration of an inhibitor, the greater the degree of blockade

Organization of the cauda equina

The most medial of the descending contain the preganglionic parasympathetic fibers More lateral are those nerve roots involved in strength, reflexes, and sensory disturbances of the lower extremities

Central Pontine Myelinolysis (CPM) histology

The myelin is absent centrally but the axons remain Note: stains would show axons present, but the myelin is missing! (not as blue with LFB stain, bubble appearance of H&E, etc)

Multiple sclerosis at the optic nerve gross findings

The optic nerves/chiasm/tract will show lesions!

Leptomeninges

The pia mater and arachnoid together which extend to cover the dorsal and ventral nerve roots and are replaced by connective tissue distal to the dorsal root ganglia

Generation of an action potential: All or none

The rising and declining phases of the AP result from the successive opening and closing of v-gated Na+ channels and v-gated K+ channels, respectively, at any given point along the axon. Both ions travel down their concentration gradients across the axon. Na+ influxes; K+ effluxes. The AP propagates toward the terminal because Na+ influx at one point along the axon is sufficient to bring the adjacent point to threshold. The AP travels only one way toward the terminal because the previously opened v-gated Na+ channels, beginning at the axon hillock, are transiently inactivated.

Points to remember about the NMJ

The round clear synaptic vesicles each contain ~10,000 molecules of acetylcholine (Ach) and easily identify the presynaptic terminal. The postynaptic cell (myocyte) has junctional folds. Nicotinic cholinergic receptors are expressed only at the apices of the folds. Finally, the synaptic cleft contains electron dense material corresponding to acetylcholinesterse (AchE), which hydrolyzes Ach and is the site of action of AchE inhibitor drugs, e.g. neostigmine. Notice the large dense-core vesicles that contain neuromodulatory peptides Most EMs of the NMJ do not look as clean as the preceding slides. Here you can identify the presynaptic terminal and postsynaptic myocyte. The myocyte is packed with sarcomeres and mitochondria in cross section. In this image AchE is stained very lightly.

Chronic pain and central sensitization

The stimulus intensity on nociceptors no longer correlates with the perception of pain Mechanism behind chronic wind-up: - long term potentiation enhances EPSPs in secondary dorsal horn neurons - Glial cells reposed to GLU and Substance P released from primary afferents by releasing neuroactive substances that feed back into afferents to increase their GLU release >> open NMDA receptors to Ca2+ via displacement of Mg2+ >> increase GLU receptor expression and increase EPSPs

Why does hypotension come before anesthesia?

The sympathetic preganglionic B fibers (myelinated) are blocked before unmyelinated C fibers (although C are slightly thinner).

Where does the conus medullaris end?

The tip of the conus medullar is descends to the inferior limit of the L1 vertebral body

What determines action potential velocity in peripheral nerves

The varying diameter, myelin presence, and myelin thickness of the peripheral nerves

____________ are the two most ATP- demanding processes in the CNS. Na+K+ATPase alone accounts for 2/3 of the brain's basal energy demand!!

The work of Na+K+ ATPase and motor proteins for axon transport

Reflexive response to stretch requires what four different axonal connections within muscle

There are 2 sensory types -stimulated by deformed intrafusal fibers Group Ia axons - innervate nuclear bag fiber subset - fire phasically only during stretch onset Group II axons - innervate both nuclear bag and nuclear chain fiber subsets -fire tonically in proportion to stretch degree There are then 2 LMN inputs Alpha-motor neurons - stimulate extrafusal fiber contraction (twitch) Gamma-motor neurons -Stimulate intrafusal fiber contraction -Assures spindle afferent activity is maintained regardless of degree of muscle contraction -Required to sustain reflexive contraction -Way for cortex to assure that various spinal reflexes are adapted to overall aim of movement -Activity can't be clinically evaluated

Mechanism of Sympathetically Maintained Pain

There are sprouting of postganglionic sympathetic afferents into DRG for sympathetically maintained pain (stress causes pain) 1. Pathological afferent fibers release NE and express α2 2. DRG neurons express ectopic α1 receptors 3. Any sympathetic activation is then sensed as a pain signal

Injury/inflammation initiation of the complex pain response

There is a local release of H+. autocoids, etc into the damaged tissue near sensory afferent endings leading to sensitization of nociceptors Activated nociceptors release neuropeptides which mediate tissue damage processes including: -vasodilation -tissue edema/swelling -redness/heat -leukocyte recruitment/activation

Watershed areas of the spinal cord

There is a watershed area between the two perfusion territories (ASA and PSA) and longitudinally at the mid-thoracic level

Treatment of diabetic neuropathies

There is currently no therapy that reverses diabetic neuropathy Rigorous control of blood glucose proven to prevent or slow the course of diabetic NP (demonstrated by large controlled clinical trials) Treatment of painful diabetic neuropathy (Antidepressants & antiepileptic drugs have demonstrated efficacy in randomized clinical trials)

Subluxation of vertebra

There is dramatic displacing of one of the vertebra This leads to a pinched cord which promotes central cavitation which can grow!

MRI showing compression injury that effectively transects cord

There will be negligible to no recovery for segments below the lesion Generates central cord lesion

TRP channel mediate _____

Thermal transduction TRPM8, TRPV4 and TRPV3 expressed in C and Aδ sensory afferents (and in keratinocytes) contribute to sense of physiologic temperature range Different thermal receptors exhibit graded response to temperature subranges Note: -Warm: TRPV4, TRPV3 -Cool: TRPM8

Corticobulbar neurons

These are the cortical UMNs to brainstem motor nuclei 2 origins: cortical eye fields and primary motor cortex Involved in indirect (CN 3,4,6) innervation via the reticular formation or direct (CN 5,7,11,12) innervation of cranial nerve motor nuclei

Nodes of Ranvier histology

These areas lack compact myelin and are where all the voltage gated ion channels are located Note: the area between these nodes are the myelin internodes

Course of the cortical spinal axons

These cell bodies for these neurons within the primary motor cortex project axons which leave the cortical gray into the subcortical white matter through the corona radiata. They then enter through the poster limb of the internal capsule and then leave through the cerebral peduncles They enter the pons where the descending fibers mostly cross at the pyramidal decussation where the continue their decent throughout he lateral corticospinal tract Some fibers that remain ipsilateral will descend through the anterior corticospinal tract

Oligodendrocyte radiation sensitivity

These cells are very sensitive to radiation Can lead to transient demyelination and depletion of the progenitor pool Therefore there is a small margin of error for anti-tumor dosing

Opioids for neuropathic pain

These do not affect neuropathic pain alone TRAMADOL hydrochloride - opioid-like -Weak µ-opioid receptor agonism -Enhances the endogenous analgesic descending serotonergic and adrenergic systems -Effective, first-line medication before a traditional opioid Opioid+ NSAID combinations -NSAIDs decreases hyperalgesia by ↓ PGE2 Opioids -PAG has µ receptors (serotonergic pathway) -Locus ceruleus stimulated by opioids → ↑NE in dorsal horn → DHN inhibition → ↓ pain

Postsynaptic potentials

These local potentials occur in the postsynaptic neuron or myocyte and reflect ion channel opening in response to NT binding of postsynaptic receptors. Their formation is detected by a recording electrode impaled in the postsynaptic neuron or myocyte. -EPSP -IPSP -EPP

Dendritic spines

They add enormous and dynamic surface area to at the dendrite to accommodate as many as 10^5 synapses per neuron Spines appear and disappear along the same stretch of dendrite imagined in vivo during the course of a learning experience

All axons in peripheral nerves are invested in one of two ways by SCs

They are either myelinated by concentric wrappings of SC myelin membrane, or simply ensheathed within invaginations of non-myelinating SCs, e.g., postganglionic autonomics.

Are upper motor neurons excitatory or inhibitory?

They are excitatory and thus glutamatergic Note: only a few synapse directly on LMNs

What are the effects of peripheral and central sensitization?

They can make normally innocuous stimuli perceived as painful (allodynia), and pain perception of noxious stimuli perceived as more intense than usual (hyperalgesia)

Commonalities of lower motor neurons

They collateralize Each collateral terminates as a single NMJ on the motor endplate of a muscle fibers (myocyte)

Upper motor neuron function

They command, coordinate, and modulate LMNs and associated local circuits to organize and execute movements

How do neurons compensate for the poor conduction of cell membranes?

They have an elaborate mechanism for generating and propagating electrical signals based on current flow back and forth across their plasma membranes through channels that open for current passage (conductance) This mechanism enables neurons, like myocytes, to function as "excitable cells"

Which fibers are blocked first with local anesthesia?

Thinner and myelinated fibers Thinner fibers (of same type) are blocked first. Myelinated fibers are blocked first (vs. unmyelinated of same diameter)

What is the strength of the recommendation?

This conveys how confident the panel making recommendations is on the applicability of the recommendation in clinical practice. The Academy of Neurology classified the strength of their recommendations as follows: Level A: Strongest level, denoted as "must." -These recommendations are based on high confidence in the evidence, and the therapy has high benefit and low risk. -This recommendation must be followed Level B: Denoted as "should" -These recommendations imply less stringent requirement than Level A, but are still based on the evidence. The therapy is considered to have moderate benefit relative to harm -This recommendation should be followed most of the time. Level C: Denoted as "may" -Is the lowest recommendation level, denotes small benefit relative to harm. -Allows the highest discretion by practitioner to follow or not Level U: Denoted as "unproven" -Implies data are inadequate to support or refute the use of a therapy. No recommendation is formulated.

Histology of neuromuscular junction

This gold chloride stain identifies collaterals of a single axon, each forming a stained presynatpic terminal apposing an unstained motor endplate on a different myofibril.

Neuropathic pain syndrome: diabetic neuropathy

This is a microvascular disease and when there is ischemia of peripheral nerves leading to symmetric polyneuropathy where there is a loss of sensation with a glove and sock distribution Note: #1 cause (deafferentiation)

What "class of evidence" is the recommendation based upon?

This is directly related to the type of epidemiological studies that were evaluated to formulate the recommendation. aIn the case of therapeutic recommendations, as per the OCEBM table, the best evidence comes from systematic reviews or meta-analysis of RCT. The second level of evidence comes from individual randomized trials or (exceptionally) observational study with a dramatic effect The Academy of Neurology classified the evidence used in the formulation of their guidelines as follows: -Class I: A RCT of the intervention of interest with masked or objective outcome assessment, in a representative population. Additionally, masked allocation of treatment, no more than 2 endpoints specified, clear definition of inclusion and exclusion criteria, no more than 20% loss to follow up, non-compliance low. -Class II: A RCT of the intervention of interest with masked or objective outcome assessment, in a representative population, but lacking one of the additional criteria specified for Class I -Class III: All other controlled trials, provided they include a description of major confounding differences between treatment groups, and outcome assessment is masked. -Class IV: Studies that (1) did not include patients with the disease, (2) did not include comparison group, (3) had undefined intervention or outcome measures, or (4) had no measures of effectiveness or statistical precision presented or calculable.

Classes of Mechanoreceptors

Those that convey tactile information and those that convey proprioception Tactile: -Meissner's corpuscle (touch-change and vibration <100 Hz) - Merkel's disk (fine touch) - Pacinian corpuscle (vibration 100-400 Hz) - Ruffini's corpuscle (magnitude and direction of stretch) Proprioception - Muscle spindles (limb position sense) - Golgi tendon organ (limb position sense) - Joint receptors

What cancer is often associated with Myasthenia gravis

Thymoma 40-50% of patents will present with this

Goal of any available and emerging therapies for multiple sclerosis

To prevent new plaques and reducing the severity of the plaques that do form The secondary goal is neuroprotection from the ongoing inflammatory processes of chronic active/smoldering plaques Note: must have correct diagnosis to start any treatment!

Modes of local anesthetic administration

Topical Infiltration (dont have to know the exact location of the nerve) Nerve block(must know the exact location of the nerve) Spinal (in the CSF) Epidural

Complete spinal cord injury

Total absence of sensation and motor function caudal to the level of injury Ex: trauma, transverse myelitis

Sequential effects of tetanus poisoning

Toxin first reaches CNS through the shortest LMNs - explains early masseter rigidity and facial effects due to LMN disinhibition - axial musculature affected before appendicular Normal sensory stimuli trigger motor neuron hyperactivity -somatic sensory stimulation produces exaggerated reflex -special sensory stimulation, e.g. auditory (all attributed to loss of normal inhibitory neuronal dampening of LMN activity) Death ensues from respiratory failure

Transverse lesion types

Transection Cavitation Transverse myelitis Metastatic neoplasia Large MS lesion Anylosing spondylitis

Dorsal column-medial lemniscus (DCML) pathway

Transmits information from cutaneous mechanoreceptors and proprioceptors to 1° somatosensory cortex Conveys specific sensory modalities (4) a. discriminative touch (fine touch) (Merkel endings, Meissner corpuscles) b. vibration/pressure (Pacinian corpuscles) c. joint position and movement (primarily GTOs and muscle spindles) ("position sense" = kinesthesia) Preserves stimulus location, intensity, nature Consciousness awareness

Autoimmune inflammatory demyelinating lesions

Transverse myelitis -bilateral lesion - many segments affected - symmetric lesion Multiple sclerosis - random focal lesions - usually unilateral, unless both DC's - usually 1, maybe 2 segments - generally triangular lesions

Transmission pathway of nociceptor signal

Travels along DRG neuron and synapses to an interneuron in the dorsal horn This interneuron synapses on a second neuron which crosses over and gives rise to the spinothalamic tract This projects to the thalamus which in turn projects to the primary somatosensory cortex (sensory-discriminative features of pain) and the limbic system (affective-motivational aspects of pain). Note perception of pain occurs in the frontal cortex

Principles of Rx of Neuropathic Pain in Clinical Medicine

Treat underlying disease (e.g., control of hyperglycemia). Remove neurotoxic substance (e.g., lead exposure). Use NSAIDs/ NSAID + opioid combinations for acute symptomatic relief. Use adjuvant analgesics (e.g., TCAs and Anticonvulsants) Use topicals (lidocaine patches, capsaicin). Use somatic and sympathetic nerve blocks in some patients Use occupational and physical therapy Use non-pharmacologic pain relief techniques (e.g., contrast baths, hypnosis, mirror therapy in phantom limb pain).

T/F? The oligodendrocyte cell body is connected but distant from the myelin sheath it produces?

True

Allergy to local anesthetics

True hypersensitivity reactions to local anesthetic agents—as distinct from systemic toxicity caused by excessive plasma concentration—are quite uncommon. Esters are more likely to induce an allergic reaction because they are derivatives of para-aminobenzoic acid (PABA), a known allergen. Sulfonamide preps: -TMP-SMX -SULFASALAZINE -DAPSONE -sulfonylurea receptor blockers (GLIPIZIDE) -ester local anesthetics (PROCAINE) -FUROSEMIDE -HCTZ -CELECOXIB -SUMATRIPTAN

Hirschprung's disease is a multigenic neurocristopathy

Two susceptibility genes identified - both encode receptors -ret protooncogene receptor tyrosine kinase (activated by glia-derived neurotrophic factor (GDNF)) -endothelin B receptor (EDNRB) - g-protein-linked (activated by endothelins) GDNF/endothelin signaling normally drives proliferation and differentiation of enteric plexus neurons Ret and EDNRB mutations in migratory neural crest cell account for ~20% of Hirschprung's cases No evidence of ligand depletion or mutation, or mutation of the low-affinity GDNF receptor

Presentation of Multiple sclerosis

Typical presentations: -Optic neuritis -Internuclear ophthalmoplegia -Partial or complete transverse myelitis Initial event termed "clinically isolated syndrome" (CIS) Attack defined as "patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection" Once MS suspected, must prove dissemination in time and space

Sciatic neuropathy

Typically due to injury in the buttocks, trauma or needle sticks Weakness in knee flexors, ankle flexors and extensors Numbness/and or pain

Cord compression at the level of the cord affect on the descending motor system

UMN axons and LMNs are affected by cord compression LE UMN signs may precede UE signs as meningioma compresses cord May see UE signs first with expanding central lesion

Posterior cord syndrome

Uncommon syndrome due to extension injury Loss of positioning sense due to disruption of the dorsal columns Good prognosis Ex: tertiary syphillis, B12 deficiency, PSA infarction Note: bilateral lesion

Clinical characteristics of neuropathic pain

Unusual burning, tingling, or electric shock-like quality Sharp, shooting pain over peripheral distribution of nerve May occur spontaneously, without any stimulus Mild nociceptive stimulus produces disproportional pain (Hyperpathia or Hyperalgesia) (via overexpression of α2d subunit of N-type VGCC and Na+-channels) Non-nociceptive stimulus (light touch) evokes exquisite pain (Allodynia) (via sprouting of Aβ fibers on to DHN) Stress produces pain (Sympathetically maintained) (via sprouting of postganglionic sympathetic afferents on to DRG neurons) Sensory deficit present in the area of pain (however, 5% lidocaine patch effective in postherpetic neuralgia) Ameliorating effect of Sympathectomy Unresponsive to opioids

Which neurons are damaged with ALS

Upper motor neuron damage -Dysphagia, difficulty swallowing -Dysarthria, difficulty speaking or forming words -Muscle spasticity and hyperreflexia (Babinski's sign) Lower motor neuron damage -Weakness and atrophy -Cramping -Fasciculations, superficial muscle twitching

Spinothalamic tract

Used to detect location, intensity, and duration of : pain, crude touch, itch, tickle, sexual sensation where it is transmitted to the parietal lobe

Conus medullaris syndorme summary

Usual cause is severe trauma to lower back; also tethered cord Vertebral level L1-L2, corresponding to sacral cord segments, i.e. conus bilateral effects; cauda equina syndrome, which is asymmetric Impotence/sexual, bowel, bladder dysfunction common, more than cauda equina syndrome Ankle jerk elevated if S1 cord segment involved; generally less motor dysfunction than cauda equina lesion Anesthesia restricted to saddle whereas LE usually affected in cauda equina syndrome

Primary somatosensory cortex (S1)

VPL neurons project to layer IV Brodman areas 3a, 3b,1 & 2 span postcent. g. + posterior paracentral lobule each of the 4 areas contains a complete representation of the body functional properties of cortical neurons in each area are distinct neurons in the 4 regions reflect parallel input from functionally distinct sensory receptors

Size comparison of ventral roots to dorsal roots in ALS

Ventral roots are smaller than the dorsal roots This is due to a loss of motor neurons

Blood supply to the spinal cord

Vertebral a. -> Midline Anterior Spinal artery supplies the anterior 2/3 of the spinal cord PICA-> Paired Posterior Spinal artery which lie within the dorsal intermediate septum and supplies the dorsal columns and dorsal horns Segmental arteries e.g. intercostals->spinal medullary a.-> radicular artery which helps to supply the rootlets of the dorsal and ventral horns. These spinal medullary anastomose with the PSA and ASA to provide additional perfusion pressure

Desflurane

Volatile, not flammable, NOT explosive High vapor pressure requiring pressurized vaporizer Very low blood : gas partition coefficient (0.45) Low solubility in fat: requires less downward titration in long surgeries to achieve a rapid emergence. Advantageous in morbidly obese patients Not metabolized to trifluoroacetate = No immune-mediated hepatitis Induction - in less than 5 minutes; Awakening - in 5 - 10 min. Side Effects: -Most pungent and irritating to the airway - coughing, salivation, bronchospasm -Anesthesia induced with an IV agent, with desflurane for maintenance

Isoflurane

Volatile, not flammable, not explosive, pungent. Most commonly used inhalational anesthetic in the US Blood : gas partition coefficient lower than that of halothane or enflurane Induction - in less than 10 minutes Induction: 3%; Maintenance 1.5-2% Side Effects: -Hypotension due to ↓ SVR (unlike halothane, where cardiac output is reduced) -Respiratory suppression -Potentiation of neuromuscular blocking agents -Decrease in GFR -Malignant hyperthermia -"Coronary Steal" syndrome (like DIPYRIDAMOLE)

Functions of lower motor neurons

Volitional movement Automatic/semiautomatic movements: postural adjustments Many are characteristically human: speaking, writing

Levels at which lower motor neurons are controlled

Volitionally, by descending cortical "upper" motor neurons Suprasegmentally by somatosensory and special sensory cues Segmentally, by sensory-driven reflexes Segmentally, by local neural networks Segmentally by recurrent inhibition (Renshaw cells)

Neuronal programmed cell death

We develop with an overabundance of fetal neurons Programmed cell death (PCD) matches the number functional neurons to their target cells In so doing, neurons compete for target cell-derived trophic factors that suppress caspase-mediated degradative pathways Unsuccessful neurons de-suppress apoptosis and die

Peri-plaque

Where oligodendrocyte progenitors mature and attempt remyelination Where remyelination is aborted by immune-mediated killing of newly differentiated oligodendrocytes Killing mediated in part by inflammatory cytokines e.g., TNFa, FAS released from autoreactive T-cells Battle of remyelination vs demyelination

Metachromatic Leukodystrophy Imaging/Histology

White matter destruction is shown as white on T2 Cereboside sulfates interact with stains to produce a change in color of tissues Note: histology shows bloom cells that are nice and pink as well

Charcot-Marie-Tooth Disease Histology

Will see "onion bulb" where multiple Schwann cells rap the axons

Histology of inflammatory neuropathy

Will see a lot of inflammatory cells (lymphocytes and macrophages) between axons!

Tay Sachs histology

Will see ballooned neurons containing enlarged lysosomes due to the accumulation of breakdown products within the lysosomes Note: transmission microscopy would show these lysosomes that are referred to as Zebra bodies

Progressive Multifocal Leukoencephalopathy (PML) Histology

Will see large, markedly atypical astrocytes and macrophages Will also see high cellularity that can often be confused with glioma Can see ground glass appearance of oligodendrocytes

Guillain-Barre Syndrome Histology

Will see nerve with chronic inflammation that leads to myelin destruction

Endoneurium

Wisps of connective tissue consisting of collagen fibers around individual nerve fibers in nerve Note: this is not organized into discrete tissue layers like the perineurium or epineurium

MRI at the level of the brain Multiple Sclerosis findings

With T2, will see areas of white lesions

Watershed area of spinal cord

Within the central gray of the spinal cord at the interface between the ASA and PSA This makes the central gray vulnerable to contusions!

Pacinian afferents

Within the dermis and deeper More rapidly adapting than Meissner's corpuscles Extremely sensitive to vibration Lowest threshold for indentation (10 nm) Largest receptive field Least spatial acuity (10+ mm) 10-15% hand mechanoreceptors

Why is xenon the ideal anesthetic?

Xenon has no effect on: -Cardiac output or cardiac rhythm -Pulmonary function -Hepatic or renal function Xenon is not metabolized at all in the human body It is not a pollutant or an occupational hazard, and does not add to global warming or the greenhouse gas effect Xenon provides some degree of analgesia

Can disorders producing LMN signs obscure upstream UMN damage?

YES

Can multiple sclerosis plaques be dynamic or static?

YES

Do local anesthetics have to get inside the cell to bind to voltage-gated sodium channels?

YES

Does each sensory afferent fiber have a receptive field?

YES

Does myelin conserve space?

YES

Is most of our motor activity housekeeping and works below the level of consciousness?

YES

Does stretch reflex maintain set muscle length against any load?

YES Ex. Gravitational pull on forearm stretches biceps -Stretch excites biceps Ia/II afferents -Excites alpha-MNs to homonymous and synergistic muscles -Reciprocally inhibits (hyperpolarizes) LMNs to the antagonist muscle

Do some muscles lack reflex control?

YES Examples: -extraoculars -larynx intrinsics Note: contraction of these is volitional

Do cortically generated movements also receive a sensory assist?

YES Sensory-guided movement requires projections from somatosensory association cortices to prefrontal cx, premotor cx and motor cx -Visually cued movement from area 7 -Somatosensory cued movement from areas 5/7 -Pure volitional movements from prefrontal cortex via PFC and areas 5/7 project to M1 (primary motor cx; area 4) and premotor cx Premotor cx in turn projects to area 4 Premotor cx contains movement formulas and specialized neuronsfor programming movements e.g. mirror neurons

Are CNS myelin protein and glycolipids highly immunogenic?

YES The CNS is normally an immunologically privileged site. For unclear reasons, most likely an earlier viral insult, young adults develop a vigorous T-cell and humorally mediated autoimmune response to OC/CNS myelin proteins, characterizing multiple sclerosis. The main proteins of the major dense and intraperiod lines are the predominant autoantigens recognized in the disease Examples include proteolipid protein (PLP) and Myelin basic protein (MBP)

Do motor units vary in size?

YES The smallest are found in precisely controlled muscles (ex. stapedius or larynx intrinsics) The largest are found in muscles that generate the most power (ex. gastrocnemius) Note: there can even be multiple unit sizes within some muscles

Is high frequency stimulation required to release neuropeptide co-transmitters?

YES e.g. Primary pain & temp sensory neurons release GLU ± Substance P and/or CGRP if sufficiently stimulated

Can axoaxonic (presynaptic) inhibition occur at the presynaptic terminal?

YES hyperpolarization counteracts AP voltage-gated Ca 2+ channels can't open

Do segmental reflexes talk to each other to orchestrate stereotyped limb movement?

YES via local circuit neurons

Do large caliber axons and myelinated axons move signals farther and faster?

YES! Note: this matters a lot for motor and sensory axons needing to convey information a great distance between extremities and the CNS

Does compact myelin have periodicity (e.g. constant thickness per turn)

YES! Under higher magnification the periodicity of compact myelin is highlighted by alternating dark and light lines; the distance between the dark lines is ~14 nm. Dark lines are termed major dense lines Light intervening lines are termed intraperiod lines The first turn of SC around the axon (inner loop) does not compact and shows a thin rim of cytoplasm

Can a single axoaxonic IPSP generated at the hillock counteract thousands of EPSPs produced more distally along the dendrite branches

YES! (ex. basket neuron) Note: The closer a synapse is to the axon hillock the greater the influence of its PSP on summation.

Do axons crossing the pia also switch myelin forming cells?

YES, CNS uses oligodendrocytes whereas the PNS uses Schwann cells This changes the potential of damaged axons to grow (more potential for regrowth in the PNS)

Are dendrites typically more complex than axons?

YES, it receives the great majority of synaptic inputs for a neuron on account of its enormous surface area

Does increasing the conductance of any ion (ion channel opening) change the Vm?

Yes! When an ionotropic receptor (a receptor that contains a pore for ion flux) is opened by a ligand or a particular voltage sensor, increased permeability for the gated ion shifts Vm toward the equilibrium potential for that ion

Is Wallerian degeneration in the PNS follows by axonal regrowth?

Yes, although reinnervation isn't always faithfully directed to the original target

Can we detect loss of analgesia during general anesthesia?

Yes, if the general anesthesia is inadequate, there will be an increase in HR and BP

Is multiple sclerosis an autoimmune disease?

Yes, it is an inflammatory autoimmune disease affecting the central nervous system, that results from disruptions in immune tolerance

Do gap junctions exist in the nervous system?

Yes, to mediate electrical synapses (left) but are not principal sites of disease, neurotransmission or drug action Note: Chemical synaptic transmission (right) is the prime mode of signalling by neurons acting on other neurons, myocytes and glandular cells

Does pain information from one side of the body ascend on the opposite side of the cord?

Yes, unlike DCML! Your 1st order afferents such as C fibers (slow pain) and A-delta fibers (fast) synapse in the dorsal horn gray matter. The 2nd order projection neurons then decussate in the cord, 1-2 cord segments above the dorsal root entry level

A 36-yr-old female diagnosed with multiple sclerosis complains of clumsiness when walking and trouble with upright balance. Sensory examination is remarkable for loss vibration and position sense on the left lower extremity. Fine touch to all but the little toe is absent. She walks with a sensory gait and has a Romberg sign. A lesion along the DC-ML pathway could localize to the (more than one is possible): A. Right paracentral lobule B. Right superior parietal lobule C. Left fasciculus gracilis D. Right fasciculus cuneatus E. Left internal capsule, post. limb

You have to know the pathway and crossover level to answer the question correctly!! LLE>Left gracilis tract/nucleus>right ML>right IC>Right paracentral lobule

Lower motor neuron activity is controlled by _______

a balance of excitatory and inhibitory synaptic inputs LMNs prevented from spontaneous firing by tonically active inhibitory local interneurons under descending control by various UMNs LMNs become overactive when tonic inhibition is reduced by UMN lesions or toxins affecting interneurons, e.g. tetanus toxin

Myelin

a living, biochemically specialized extension of the plasma membrane produced by Schwann cells (SCs) in the PNS and oligodendrocytes (OCs) in the CNS. The high lipid:protein ratio of myelin is the inverse of other eukaryotic cell membranes and required for myelin to function in its insulatory role that increases the velocity of action potentials along the axon

The reticular formation is a general structure that includes:

a pool of non-motor neurons as well as motor neurons

How do α1 and α2 agonist help local anesthetics?

a1-agonism prolongs anesthetic action by: - decreased Absorption from vasoconstriction (less systemic toxicity) - increased Local concentration a2-agonism in DHN produces antinociception -Spinal administration of a2 agonists produces anesthesia. -Systemic administration causes hyperalgesia ( blocks descending antinociception from locus coeruleus) Agents: -Epinephrine (a1a2b1b2b3 agonist) -Clonidine (central a2 agonist) -Dexmedetomidine (central a2 agonist)

syringomyelia

abnormal longitudinal cavities in the spinal cord cause paresthesias and muscle weakness Its classification depends on the connection with the fourth ventricle. For our purposes, we will consider these to be extra-canalicular Note: it can affect the anterior white commissure thereby preventing pain and temperature sensation from the dermatomes contributed to those crossing axons within this commissure Exam often shows a CAPE sensory deficit (if very large, may show sacral sparing)

Proposed multiple sclerosis pathophysiology

activated autoreactive T cells cross the BBB into the CNS where they cause inflammation, demyelination, and neurodegeneration

In skin, noxious heat may also elicit signaling of nociceptors via signaling by ______

activated keratinocytes

Axon pathfinding requires collaboration between _____

adhesion molecules (cell-cell e.g. N-CAM or cell-substrate e.g. integrin, proteoglycan) and soluble growth factors (e.g. NGF)

Scorpion toxin

alpha-toxin: binds and slows the inactivation domain of vNa. beta-toxin: binds to the voltage sensor of vNA to keep it in an activated stage, thereby reducing threshold needed to trigger an AP. In general, scorpion toxins augment or prolong the AP

Central Pattern Generator for ambulation manages _____

alternating flexion and extensions of lower limbs during locomotion

Sensitivity to pin-prick tests for ____

analgesia/hypalgesia/ hypoalgesia in dermatomes; more precise than fine touch

Anterior white commissure

area where axons cross from one side of spinal cord to the other

Spinoreticular pathway mediates:

arousal, emotion, motivation to the frontal lobe and limbic system

Gracilis fasciculus in sacral sections

ascending tract that carries sensory information from mid thoracic and lower extremities to brain (spans entire spinal cord) In sections, it is located near the medial portion of the dorsal horn. They are somatotopically mapped with the lower cord levels mapping to the more medial portions!

Gracilis fasciculus in lumbar sections

ascending tract that carries sensory information from mid thoracic and lower extremities to brain (spans entire spinal cord) In sections, it is located near the medial portion of the dorsal horn. However, the more medial is dedicated to the sacral fibers and just lateral to that is the lumbar fibers They are somatotopically mapped with the lower cord levels mapping to the more medial portions!

Gracilis fasciculus in thoracic sections

ascending tract that carries sensory information from mid thoracic and lower extremities to brain (spans entire spinal cord) In the medial portion medial to the dorsal horns, However, the more medial is dedicated to the sacral fibers and just lateral to that is the lumbar fibers, and lateral to those are the lower thoracic fibers (T12-T6) with the lower levels mapping more medially

Every CNS synapse is surrounded by _____

astrocyte endfeet These function to: (1) removal of AA NTs from the synaptic cleft (2) catabolism of GLU and GABA to GLN > resupplied to neurons > converted back to GLU or GABA (3) GLU-receptor mediated release of local vasodilatory signals

End plate potential (EPP)

at the NMJ causing local depolarization, an upward blip) of a skeletal myocyte via opeining of a nicotinic AChR receptor to allow Na+ influx; this is a type of EPSP is named for the myocyte

Golgi tendon organs (Ib)-mediated reflexes complement stretch reflexes to ______

automate postural and movement changes They work towards maintaining constant force of muscle contraction (tension) for ordinary motor activites GTO/Ib activity can stimulate or inhibit homonymous muscle depending on stimulus magnitude

A centrally directed injury in cauda equina syndrome can mimimic _____

autonomic symptoms and signs of conus medullaris syndrome; except there will be no UMN signs detectable with CES!!

With somatosensation, signaling direction is _____

away from the location of perceived stimulus and towards the brain Note: lesions anywhere along this pathway can alter sensation at site of stimulus

Reticulospinal tracts control _____

axial and proximal musculature Innervate LMN pools and intersegmental central gray that respond reflexively to somatosensory and special sensory stimuli, e.g. postural adjustments; start reflex, and voluntary postural changes via corticoreticular input Pontine -Pontine RF -> medially directed reticulospinals -Supply medial LMN groups throughout cord -Control axial adjustments Medullary -Medullary RF -> laterally directed counterparts -Control proximal limb adjustments Also innervate gamma LMNs

Ventral corticospinal tract projects to ______

axial muscles

Tetanospasmin moves transynaptically, upstream from LMNs into ______

axon terminals of CNS inhibitory neurons It then blocks the release of GABA and glycine by inhibitory neurons synapsing on LMNs Disinhibited LMNs due to unopposed excitatory inputs leads to hyperreflexia, muscle spasms, and tetanus

Demyelination occurs secondary to ______

axonal degeneration Therefore; ischemia, stroke, and motor neuron disease can lead to demyelinating disorder

Upper motor neuron activity is modulated by the ______

basal ganglia

Cocaine inhibits reuptake of ________

catecholamines (NE locally, dopamine centrally)

A large disc herniation at the level of the cauda equine can cause ______

cauda equina syndromeC

Cord contusion can cause ______

cavitation and Wallerian degeneration of long tracts 1. e.g.T4 compression -> anoxic death of GM neurons at T4 (min-hrs) 2. Apoptosis spreads 1-2 segments ± lesion level (days-weeks) 3. Lesion expands to WM; Wallerian degeneration of long tract neurons Effects: -long tracts severed by the cavitation -distal cord still alive; perfused by spinal medullary arteries -segmental reflexes are intact above and hyperactive below

Peptide neurotransmitters are synthesized in the _____

cell body These are prepackaged in vesicles and travel to the presynaptic terminal via fast phase anterograde transport Note: these vesicles also contain enzymes that generate the final form of the neurotransmitter

Syringomyelia

central cord syndrome with abnormal longitudinal cavities in the spinal cord cause sensory loss and muscle weakness Bilateral lesions, can be tiny yet symptomatic

Spinomesencephalic tract mediates:

central modulation of pain via activation of descending analgesic pathways

What OTC antihistamine has the least potential to cross the BBB and cause sedation (better than loratidine)

cetirizine

What is the only local anesthetics that produces vasoconstriction and reduces bleeding?

cocaine

VLPO (ventrolateral preoptic nucleus)

collection of neurons in the hypothalamus, most important area involved in sleep!

endoneurium

connective tissue around each axon/myelin Inflammation in this tissue is pathologic

_________ modulate rubrospinal activity

corticospinals

And with regards to the validity of diagnostic tests, such as the measurement of Oligoclonal IgG bands in both plasma and CSF to diagnose MS, it is usually explored in a________

cross-sectional study format. In one snapshot, the sensitivity and specificity of a test are evaluated by applying it to persons with the disease and persons free of the disease.

Neuropathic pain is caused by ____

damage or dysfunction to portions of the pain pathway itself

Midbrain DA neurons contain ____

dark neuromelanin pigment, hence the their name, substatia nigra

The large majority of synapses are on a neuron's ________

dendrites and these are excitatory

High sensory acuity reflects _________

dense sensory innervation of afferents with small receptor fields Note: it is a function of arborization of axon collaterals Note: smallest fields in most densely innervated skin: fingertips, lips, toes

Hypesthesia

diminished tactile sensibility

Lateral corticospinal tract projects to ______

distal extremity muscles

Inhaled general anesthetics (propofol, halothane, isoflurane) _________PSDCNs

down-regulate They do so by working indirectly by enhancing activity of surrounding GABAergic/glycinergic interneurons These then decrease PSDCN firing via their activation of GABA receptors, leading to a loss of visceral sensation

Nerve conduction study

eRprocedure to measure the speed at which an electrical impulse travels along a nerve

Lesions to the _________ limb can diminish or abolish spinal reflexes

efferent OR afferent

Hoffmann's sign

elicited by flipping either the volar or dorsal surfaces of the middle finger and observing the reflex contraction of the thumb and index finger It is the UE counterpart of the Babinski sign

epineurium

encloses the entire nerve

Chemical synaptic transmission entails ______

energy transduction

Neuronal ___________ blocked by general anesthetics

excitability and excitatory

denticulate ligaments

extensions of pia mater that secure cord to dura mater

Except for the first turn and last turn of myelin, the SC compacts its concentric wrappings by ______

extruding most of the cytoplasm. This forms compact myelin, which gives myelin its insulating property to speed the velocity of action potential propagation along the underlying axon and shows the characteristic profile in sections stained for lipid with osmium tetroxide.

Clinical signs of tetanus

face and neck spasticity and rigidity trismus - tonic contraction of muscles of mastication elevated jaw-jerk reflex spasticity - back, abdomen, face hyperreflexia - elevated DTRs bilateral hypertonicity extreme sustained muscular spasms

3 classes of lower motor neurons differ by _____

force capability and fatiguability of their motor units Include: -slow twitch (slowly fatigable) with red fibers due to high content of myoglobin and use aerobic metabolism - intermediate (fast fatigue-resistant with pink fibers due to presence of myoglobin but not as much as slow twitch -fast twitch (fast fatigable) with white fibers due to a low content of myoglobin and uses anaerobic metabolism

corticobulbar axons descend through the _______

genu of the internal capsule

Oxford Centre for Evidence Based Medicine (Oxford CEBM)

hierarchy to the type of study that can best answer clinical questions

CB1 expression is high in the _____

hippocampus, neocortex, hypothalamus, basal ganglia and cerebellum

Intrauterine hypoxia can lead to ____

hypomyelinating disorder Causes death oligodendrocyte progenitors in premies (periventricular leukomalacia) Note: this is one of the causes of cerebral palsy!

Most corticospinals signal to lower motor neurons _______

indirectly through polysynaptic control via intervening segmental interneurons Note: segmental interneuron banks tonically inhibit LMNs and unintended movement breakthrough

What are the most dangerous drugs in clinical use?

inhalation anesthetics

Synapses on the cell body (axosomatic) or axon (axoaxonic) are ____

inhibitory and powerful because they are close to the initial segment of the axon where summation occurs

The majority of patients with multiple sclerosis follow an ______ course

initial relapsing remitting course (mainly acute plaques with some chronic active)

Overall basal ganglia function

initiate, cease and scale a motor behavior as planned (extends to verbiage and gestures) control the "idle" or baseline of motor activity mediate premotor control of cortical UMNs Note: is synonymous with the older term (extra-pyramidal system)

Cord transection can arise from:

injury large central cavitation transverse myelitis

Mechanical nociceptors respond to _____

intense force

Mechano/thermal nociceptors respond to _____

intense force and noxious temperatures (<17 or >45 C)

Thalamocortical neurons carrying spinoreticular input ascend through the _______

internal capsule (anterior limb)

Reticulothalamic fibers project to ____

intralaminar thalamic nucleic (e.g. centromedian nuclei (CM) )

Treatment for Complex Regional Pain Syndrome (CRPS)

intrathecal administration of Clonidine (α2 agonist) (note: systemic administration, it can act on the locus coeruleus and won't pass the BBB which can lead to increased pain because the descending pathway of LC is blocked) Phentolamine (α1 blocker) Sympathectomy

Pronator drift

involuntary turning or lowering of forearm when outstretched Caused by a contralateral UMN lesion to cortex or capsule

Reflex

involuntary, stereotyped motor response to a sensory input

Released NTs bind and activate _____

ionotropic and metabotropic postsynaptic receptors "Fast" NTs (Ach, Glu, Asp, GABA, GLY) diffuse across the cleft and bind ionotropic receptors, i.e. when activated open an intrinsic ion channel allowing flux of certain ions (6,7) occurs.

Perfusion territories of the paired posterior spinal arteries

ipsilateral DC + dorsal horn ipsilateral DC nuclei

During development, astrocytes express _______ in their surface ECM and provide a favorable adhesive substrate for axon growth.

laminin

Throughout life, Schwann cell expression of ______ plays a crucial role in promoting regeneration of damaged PNS axons

laminin

Extracellular matrix glycoproteins- Fibrous protein class: laminin, fibronectin

laminin is a favorable substratum for neurite extension contains arg-gly-asp (RGD) sequence critical for receptor binding Laminin binds to a specific integrin receptor on the growth cone surface to signal genomic effects (up-regulation of cytoskeleton expression and assembly)

Axon diameter as a determinant of nerve conduction velocity

large fibers offer less resistance (ri) to charge diffusion through cytoplasm; - adjacent regions brought to threshold faster

Biogenic amine properties

like amino acid NTs and Ach, they're synthesized in the presynaptic terminal loaded into dense-core vesicles via a vesicular amine transporter (VMAT) receptors almost exclusively slower metabotropic type and excitatory in effect removal occurs by (1) neuronal reuptake via specific transporters into presynaptic terminal(DAT, NET and SERT) (2) enzymatic degradation - monoamine oxidase (MAO) - catechol-O-methyl transferase (COMT) defective function implicated in psychiatric illnesses pathways targeted by drugs of abuse - cocaine is a reuptake inhibitor - amphetamines force release of DA/NE from terminals, block reuptake and inhibit monoamine oxidase reduced in untreated PKU

While evidence from a RCT underlies the information about treatments for MS, the question of prognosis can only be answered through ______

long term follow up, that is, cohort studies.

Which axons are differentially affected with Chemotherapy induced polyneuropathy (CIPN)

longest axons differentially affected - sensory axons 1st, then LMNs -paresthesias, allodynia (via similar affects on pain afferents -reduced or absent Achilles tendon reflex -eventual weakness

In addition to demyelination and death of myelin-producing oligodendrocytes, MS progression is now attributed to _______

loss of axons

Poliovirus is neurotropic for ______

lower motor neurons It binds to poliovirus receptor (PVR)= CD155 glycoprotein, an Ig super-family member expressed at LMN axon terminals The Virus-PVR complex endocytosed and retrogradely transported via dynein to LMN soma in ventral horn leading to neurolysis It preferentially infects/lyses distal pools of lower extremity LMNs leading to paresis/paralysis It eventually infects LMNs at C3-C5 causing respiratory paralysis However, it typically spares UMNs and sensory tracts

Location of the ambulation central pattern generator

lumbar enlargement

Rate of action potential firing is roughly proportional to ___

magnitude of the depolarization, assuming it's suprathreshold However, sensory afferents are distinguished by temporal dynamics of response to sensory stimulation Slowly adapting receptors with Sustained discharge in presence of ongoing stimulus is good for detecting spatial aspects i.e. size and shape of texture Rapidly adapting receptors soon become quiescent despite sustained stimulation and is good for detecting dynamic changes in Stimulus e.g. movement

Transduction in a mechanosensory receptor afferent begins with _____

mechanical deformation of the encapsulated nerve ending Ex: membrane stretch opened receptor pore -> Na+ influxes -> Generator potential (=local potential) if sufficient will trigger action potential; however sub threshold stimuli is measurable but will not be perceived since no action potential was generated

Thalamocortical projections from centromedian nuclei project to structures ________

mediating pain-associated responses: -amygdala (fear) - hypothalamus (fight-or-flight) - anterior cingulate cortex and anterior ínsula (misery index, mood) - frontal lobe (language cortex, prefrontal cortex) (cursing, avoidance, judgement)

Apraxias are detected on ______

mental status exam ideomotor - loose ability to do familiar tasks or work tools (show me how) ideational - cant conceive of how to do something familiarv(tell me how) constructional - can't replicate what the examiner demonstrates gait- can't put one foot in front of the other

B12 is a cofactor for ____

methionine synthase (responsible for methylation reactions for myelin sheath) - lack of B12 can lead to hyperhomocystinemia/uria which leads to dementias and vascular disease Methylmalonyl-CoA mutase (responsible for pushing methylmalonyl CoA to Succinyl CoA) -lack of B12 can lead to elevated methylmalonic acid (MMA) which leads to abnormal fatty acids and destabilized myelin

________ alleviates intractable pain in bowel cancer patients

midline myelotomy

Muscle stretch, e.g. transiently evoked by a reflex hammer, mechanically distorts ______

muscle spindle (Ia) afferents, not GTO (Ib) afferents At rest there is a slow tonic firing rate of of Ia spindle afferents. With stretch: -Muscle stretch increases firing rate of Ia spindle afferents -As the degree of stretch increases, Ia firing rate increases -GTO afferents (Ib) respond poorly to passive stretch (respond instead to tension)

Fiber types are termed by ________

myelin extent Most myelinated -LMNs, GTOs (Ib), and Muscle spindles (1a) Next most myelinated (αß fibers) - Meissner corpuscle, Merkel disks, and Pacinian corpuscles Next (αδ fibers) - Sharp pain, cold, crude touch, preganglionic autonomic nervous system Least myelinated (C fibers) - Slow pain, heat, itch, and postganglionics

Each myelinating SC forms a single expanse of myelin, termed a _____

myelin internode, which encircles a stretch of axon concentrically as many as 100 times while remaining alive and attached to the SC. One SC forms one myelin internode around one axon. A myelin internode typically spans a few hundred microns of axon length. So a PNS axon approaching 1 meter in length requires upward of 105 internodes made by as many SCs for complete myelination of its axon.

The innermost wrap of SC is a long way from its cell body. How do they keep the myelin sheath alive and replenished with macromolecules?

narrow channels where the SC membrane does not collapse on itself serve to traffic cytoplasm between the nucleus/perinuclear cytoplasm and the inner most turn of myelin surrounding the axon. These cytoplasmic channels include the most distal (innermost) SC turn, termed the "inner loop," the outermost turn in which the nucleus resides (outer loop), as well as interconnecting channels running perpendicular between the inner and outer loops, as shown by the black arrows. Channels along the internodal edge that border the Node of Ranvier are termed paranodal loops because they border the Node of Ranvier. The interior channels that course between the outer and inner loops are termed Schmidt-Lanterman incisures (SLI). Longitudinal sectioning of myelinated axon (left side of image) reveals the SLI appear as progressively more displaced separations.

For K+ (-90 mV), its open channel pushes Vm to a more __________

negative value, toward -90mV, a hyperpolarizing, i.e., inhibitory effect. Hyperpolarizing a neuron inhibits that neuron from signaling its target cells.

Hirschsprung disease is an example of receptor mutation effecting _____

neural crest progeny migratory vagal and sacral neural crest normally develop postganglionic cholinergic neurons in gut wall of alimentary canal Vagal crest -> foregut and midgut Sacral crest -> hindgut

Schwann cells develop from _____

neural crest, as do all other neural cell types whose cell bodies are located in the PNS

Endocannabinoids

neuromodulatory lipids that interact with cannabinoid (CB) receptors, the molecular target of the xenobiotic, tetrahydrocannabinol derived from arachidonic acid, synthesized on demand, not stored in vesicles anandamide, 2-arachidonylglcerol naturally occurring in CNS diffuses through plasma membrane as retrograde signal acting on presynaptic neuron CB1 receptors: appetite, pain-sensation, mood, memory

Net charge in the cell and out is ____

neutral

Nicotinic cholinergic receptor configuration

non-selective cation channels with 3-nm diameter pore five tetrapass subunits - NMJ typically 2α:ß:ε:𝛿 - Neuronal is 3α:2ß each subunit has a pore-lining domain Ach binding site on each α subunit - occupation triggers conformation shift to open cation pore - prototypical of other NT-gated ion channels

Renshaw cells

normally allow LMN to self-limit activity glycinergic ventral horn interneurons excited by LMN collaterals suppress LMN activity site of tetanus toxin action

Polymodal nociceptors respond to ______

noxious temperatures and chemicals

Preganglionic neurons arise from _____

nuclei for cranial nerves 3,7,9,10 and cord segments S2-S4.

Membrane potential reflects ___

only a change in the distribution of opposing charges stacked up close on either side of the cell membrane

NMDA receptors

only receptor that conducts Ca2+ in addition to Na+/K+ pore normally plugged with Mg2+ pore passes Ca2+ only when postsynaptic cell is depolarized by activity of neighboring AMPA Glu receptors, pushing Mg2+ out of pore

Brainstem central pattern generators are evident for _______

other stereotypical motor functions and control (e.g. grasping, chewing, respiration, heart rate)

The Schwann cell body is contained within the ______

outermost wrapping of any PNS myelin internode

Any lesion above the sensory decussation along the ascending pathway lateral or blocks _______

perception deficit on the opposite side (contralateral)

Any lesion below the sensory decussation along the ascending pathway lateral or blocks _______

perception deficit on the same side (ipsilateral)

The length and time constants are dependent on _____

physical properties of axons Most importantly the relative resistance (r) to current flow. This is provided chiefly by resistance at two site: -At the plasma membrane (rm): Myelinated axons greatly restrict current leakage across the axolemma (has no K2P channels); the more turns of myelin the less leakage. Resistance across the axolemma (rm) of an axon skyrockets if that axon is myelinated. -Intracellular axoplasm (ri): The larger the diameter of an axon the less obstructions there are for a bolus of influxed ions to diffuse along it. There is more room to flow around cytoskeletal components, vesicles, etc. The larger the axon diameter the smaller is the ri

Frontal corteical projections to PAG regulates _______

placebo and nocebo effects that determine descending system function

Regeneration potential of axons damaged in the CNS is _____

poor

Corticospinal axons descend through the _____

poster limb of the internal capsule

Severe upper motor neuron lesion can produce _____ signs

posturing Associated with impending or ongoing central herniation and the descending pressure cone, or direct brainstem lesions affecting UMN pathways, e.g. pontine stroke in basis pontis Can also be produced by a higher capsular infarct affecting one side Reflect loss of UMN subsets depending on the lesion level Can be unilateral or bilateral

Intention and planning of motor movements is carried out by ______

premotor and supplemental motor areas (collectively termed area 6) Encodes programmed selection of movements appropriate for the behavior - learned motor tasks PMA and SMA neurons are somatotopically dedicated to M1 PMA and SMA neurons fire msec before UMNs in primary motor cortex actually execute movement PMA neurons especially concerned with visually guided movements SMA concerned with movement sequence and simultaneous use of both UEs and LEs Broca's area (pars opercularis) part of area 6

Small molecule neurotransmitters are synthesized only in the _____

presynaptic terminal, not in the cell body However, the rate limiting enzyme needed in the presynaptic terminal is made in the cell body and travel by slow phase anterograde transport

Multiple sclerosis is thought to be due to an imbalance between _____

pro-inflammatory and anti-inflammatory helper T cells

Local circuit interneurons ascend/descend in ________

propiospinal tract Note: their cell bodies are within the central gray

Spine disease at or below L2 produces _______

radiculopathy only, NOT myelopathy

Opioid and cannabinoid infusion into PAG (or dorsal horn or limbic centers stimulates endogenous analgesic pathways) ____________

raise pain threshold The do so via stimulation of the descending analgesic pathways

Deficits seen in anterior cord syndrome

rapid onset paralysis of the lower extremities, no strength bilateral segmental and infrasegmental LMN Sx acute spinal shock subsides-> flaccid paralysis persists because ventral horn also hypoperfused caudal to the lesion variable urinary and fecal incontinence bilateral loss of pain/temp below the lesion sparing of DCML modalities

Receptive field size and architecture depends on _____

receptor morphology and receptor depth in skin collateralization

Ionotropic receptors

receptors that are coupled to ion channels and affect the neuron by causing those channels to open Ex: those neurons involved in voluntary movement and sensation

Spinal anesthesia

regional anesthesia produced by injecting medication into the subarachnoid space or within the epidural space

Normal myelin is compacted and allows for _____

saltatory conduction Note: in MS, these plaques of demyelination leads to a short circuit such that further propagation fo the action potential is blocked

Primary proprioceptive afferents collateralize forming ______

segmental reflex arcs

Vestibulospinal tract activity is regulated by ______

sensory apparatus of the inner ear via CN8 and cerebellum (unconscious control)

medial winging of scapula

serratus anterior paralysis (long thoracic nerve palsy)

During delivery, Erb's palsy can be caused by ____

shoulder dystocia (they baby's neck is stretched and damaged during birth)

anesthetics that quickly achieve higher blood concentration general have a ____ onset of action

slower

Sensory threshold

smallest intensity detected

The spinal cord resides within the ______

spinal canal

Tracts within the anterolateral system

spinothalamic (used for localizing pain and its intensity) spinoreticular (responsible for the emotional component of protracted pain) spinomesencephalic (activates descending analgesic fibers)

Normal cognitive decline in aging is attributed to ____

subtle myelin changes that slow cognition

When looking for evidence regarding a clinical question you need to answer, the highest level will be given by_______

systematic reviews (which in this context include meta-analysis). Next level will be well designed and executed individual studies.

The term, "nerve fiber" should be reserved for_______

the PNS and = a single axon + its SC partner, either myelinating or ensheathing.

The specific modality conveyed by any pain- or temperature-sensitive afferent neuron is conferred by ____

the channels and receptors it expresses at its peripheral, free nerve endings

For each of the randomized controlled clinical trial, the cohort, the case-control and the cross-sectional study, the end result is ______

the classification of study participants with regards to the exposure and outcome under investigation.

Periaqueductal gray (PAG)

the gray matter around the cerebral aqueduct Site where the spinomesencephalic tract terminates and regulates activity of small PAG interneurons producing endogenous opioid peptides: enkephalins, endorphins,dynorphins, endogenous cannabinoids. These leads to activation of descending pain-inhibitory pathways

Process of ensheathment

the initial engulfment of an axon within a furrow of the SC plasma membrane. The two sides of the longitudinally aligned SC furrow meet to form a slit, termed the outer mesaxon. For non-myelinated axons, they remain ensheathed within these SC furrows, which develop no further.

Proteolipid protein (PLP) of CNS myelin

the major integral membrane protein of the OC and its myelin I membrane Its extracellular domains space apart adjacent turns of myelin and thus account for the intraperiod line

Myelin basic protein (MBP) of CNS myelin

the major peripheral membrane protein on its cytoplasmic face ~30% of myelin protein osmophilic - determines the major dense (MD) line

Modality of sensory stimuli

the stimulus form, e.g. vibration vs discriminative touch (= fine touch)

Multiple sclerosis is a CNS demyelination that is separated in _____

time and space Separation in space = exam deficits referable to >1 CNS lesion or >1 MRI lesion Separation in time = >1 clinical event by history or presence of both enhancing and non-enhancing plaques simultaneously on MRI

Proprioceptors produce a _____ response

tonic GPs maintained for stimulus duration -Train of APs produced as long as threshold stimulus persists -Stimulus intensity encoded in frequency of APs

Opened Na+ channels drive Vm_______

towards the equilibrium potential for Na+ (+55 mV) which is depolarizing i.e. excitatory, making the neuron more likely to propagate a signal.

lateral winging of scapula

trapezius paralysis (spinal accessory nerve palsy or dorsal scapular nerve palsy)

Rate limiting enzyme for DA, NE, and EPI synthesis

tyrosine hydroxylase (TH)

Radiculopathic pain

unique in a neurologic exam and is described as "shooting" pain referred to the normally innervated dermatome of the compressed spinal nerve

Limbic inputs can ______ descending analgesic systems

up-regulate The amygdala projects to the PAG and centrally activates descending analgesic system in a flight or fight response

Suprasegmental levels of sensorimotor integration affect

upper motor neuron system

Cervical disc herniations

vC4-5 (7%), vC5-C6 (18%), vC6-C7 (46%) Affected nerve root corresponds to lower numbered vertebra Herniation direction is lateral toward nerve root Rarely central, due to posterior longitudinal ligament

Lumbar disc herniations

vL3-L4 (3-10%), vL4-L5 (40-45%), vL5-S1 (45-50%) Herniations below vL2 affect only spinal nerve roots, NOT CNS and produce no UMN signs Note: more common than cervical herniations

ADEM is now most frequently associated with ______

varicella-chickenpox but also rubella, mumps, influenza and mono

Lower motor neurons functionally organize in the ______

ventral horn Retrograde tracer (horse radish peroxidase) labels LMN cell bodies in ventral horn according to muscle (inject tracer near muscle and see where it retrogradely travels) They are somatotopically organized in longitudinal and lateral planes (those distal muscles are more lateral and those more proximal muscles are more medial) LMN pools for each muscle are arranged in columns across multiple segments

The somata (plural of soma) of lower motor neurons (LMNs), whose axons cross the pial surface to become PNS nerve fibers, are located in the _____

ventral horn of the spinal cord or cranial nerve motor nuclei of the CNS.

The higher the cord level the more ________ it contains

vertical fibers

Myelin paranodes segregate _____

voltage gated Na+ and voltage gated K+ channels The Na+ channels are found right in the middle of the nodes The K+ are found paranodal The tight junctions between the paranodal loops and the axon segregate the two channel types

When are N-of-1 trials indicated?

whenever there is substantial uncertainty regarding the comparative effectiveness of treatments being considered for an individual patient. They require substantial patient collaboration and involvement but ultimately lead to truly individualized optimal therapy decisions.

Location of sensory stimuli

where the stimuli occurs

Secondary Progressive multiple sclerosis

~70% of RRMS patients go on to a secondary progressive course after 10-15 years (wide range of time frames) Diagnosed when patient demonstrates disease progression independent of discrete relapses for at least 6 months Typically gradual deterioration with regard to gait, balance, spasticity, or bladder function May also include cognitive decline Relapses may or may not continue to occur; minor improvements or plateaus can be seen

Opioid receptor types and function

µ (mu) -Endorphins > enkephalins > dynorphins 𝛿 (delta) - Enkephalins > endorphins & dynorphins k (kappa) - Dynorphins >> endorphins & enkphalins NOR (novel opioid) -Nociceptin/ Orphanin FQ Note: opioid drugs act mostly via the µ receptor

Opioid receptor function and distribution

↓Pain: Nociceptor, Dorsal horn, PAG, Thalamus ↓Respiration, ↓Coughing, ↑Vomiting, ↑Miosis: Ventral brainstem ↓LH, ↓FSH, ↑Prolactin, ↑ADH: Hypothalamus ↑Mood and behavior: Limbic structures ↓Peristalsis: Enteric nervous system

Nociceptive and antinociceptive neurotransmission in the dorsal horn

DRG nociceptor neuron terminal fibril synapses on the nociceptive interneuron which then synapses on the spinothalamic neuron The raphespinal axon synapses on the antinociceptive interneuron and then projects on the DRG nociceptor neuron terminal fibril inhibiting its release of substance P Note: ceruleospinal axon can also release NE which activates α2 receptors on the nociceptive interneuron

Therapeutic use of cannabinoids

DRONABINOL - Synthetic Δ9-THC analog -Chemotherapy-induced nausea and vomiting refractory to other agents. -Improves appetite. -Useful in cancer cachexia and HIV-induced wasting syndrome. NABILONE - Δ9-THC analog -Adjunct therapy of neuropathic pain RIMONABANT - inverse agonist of CB1 receptor -For smoking cessation -Rx of obesity (BMI >30 kg/m2).

ALS imaging and gross

Damage in the primary motor strip that generally appears symmetrical There is symmetrical loss of fibers within eh pyramids, and thus corticospinal tracts Note: symmetrical!!

2 physiologic roles of myelin

Decreases CNS energy (ATP) demand Increases the length constant

Neuropathic pain: Descending endogenous analgesic system

Defective neurotransmission reduces efficacy of endogenous analgesic system e.g. fibromyalgia symptoms may co-present with depression

Krabbe Disease

Deficiency of galactocerebrosidase beta galactosidase Accumulation of galactocerebroside Autosomal recessive Life expectancy of 2 years Symptoms include floppy to rigid tone, difficulty feeding, failure to thrive, vision loss and seizures Note: MRI T2 would show areas of white matter appearing light where it should be dark Note: Histology shows globoid cells

5 criteria for defining a neurotransmitter

Demonstrable synthesis in the presynaptic neuron Packaging into vesicles prior to release into the cleft Exocytosis Diffusion across the cleft to bind specific receptors A mechanism of termination, e.g, uptake, diffusion, enzymatic degradation

Neuropathic pain syndrome: multiple sclerosis

Demyelinated axons increase v-gated Na+ channel density increased probability of epiphatic crosstalk from demyelinated afferents (DC modalities) to pain afferents in dorsal root or horn

Neurotoxin Shellfish Poisoning

Develop from consumption of fish that have consumed brevetoxins Presentation: GI - nausea and vomiting Neurologic - paresthesias, vertigo, ataxia Respiratory - coughing, dyspnia, bronchospasm

Subacute spinal cord compression

Develops over days to weeks Usually due to metastatic extramedullary tumor, a subdural or an epidural abscess or hematoma, or a cervical herniated disk.

Chronic spinal cord compression

Develops over months to years Osteophytes protrude into cervical, thoracic, or lumbar spinal canal; or spondylosis, when the spinal narrows in spinal stenosis Less commonly due to AVM's and slow-growing extramedullary tumors.

Acute spinal cord compression

Develops within minutes to hours Often due to trauma (e.g, vertebral crush fracture with displaced fragments, acute disk herniation, vertebral subluxation or dislocation).

A 55 Y/O M presented with; 1 year progressive feet burning pain, tingling, numbness and hyperesthesia. He has no weakness, urinary or bowel dysfunction, however he complained of sexual impotence. He has DM II for 7 years & HTN. Examination; symmetrically reduced sensation to all modalities to above ankles, decreased ankle reflex and normal strength. Lab; normal CBCD, serum chemistry showed elevated glucose level and HgbA1c. Sensory conduction study reduced sural nerve sensory action potential bilaterally and mildly slow conduction velocity. Motor conduction study normal. Needle EMG few spontaneous activity and reduced recruitment in the feet muscles.

Diabetic neuropathy

Neuropathic pain examples

Diabetic neuropathy Postherpetic neuralgia Trigeminal neuralgia Phantom limb pain

Diabetic Neuropathy types

Diabetic neuropathy is one of the most common late complications of diabetes Distal symmetrical polyneuropathy -Predominant involvement of sensory fibers Proximal diabetic neuropathy -(diabetic amyotrophy, plexopathy, polyradiculopathy) Diabetic mononeuropathy -(cranial or limb mononeuropathy, truncal radiculopathy) Focal compression neuropathies -(Carpal tunnel syndrome, ulnar neuropathy) Acute painful neuropathy -(very rare)

30-year-old female presents to your OBGYN clinic with a chief complaint of "I have crampy pain in my lower abdomen, I have been dropping my coffee cup in the morning and my right leg has been numb for about a month, I also have blurred vision in my right eye" Afebrile CSF, oligoclonal bands (IgG) not detected in serum Myelin basic protein in the CSF

Diagnosis: multiple sclerosis

Subacute combined degeneration mechanism of development

Dietary B12 deficiency; B12 malabsorption in terminal ileum; lack of intrinsic factor secreted by gastric parietal cells; pH too low in ileum; stomach pH too high

Treatment of B12 deficiency

Dietary folate can reverse the hematologic effects of B12 deficiency (megaloblastic anemia) but not the CNS effects, indicating different mechanisms are at play. B12 injection can reverse neurologic effects if treatment is early.

What determines affected lumbosacral nerve root?

Direction of herniation Posterolateral - lesioned root = number for the lower vertebra Far lateral - lesioned root = number for the upper vertebra Central - root numbered for one level below the herniated vertebral pair

Wallerian degeneration in the CNS

Disintegration of axon segment distal to lesion + demyelinated and oligodendrocyte death axon distal segment Negligible regeneration Loss of long tract function

Apraxia

Disorders of high cognitive motor function (cortical lesions affecting motor programs) Lesions are within the premotor area (PMA), supplemental motor area (SMA), or areas 5/7 Lesions can be caused by stroke, cortical atrophy in dementia, most often affecting parietal lobe and its motor connections to SMA/PMA Patient presents with: -inability to formulate previously learned, movement sequence -intact desire and physical ability (strength, reflexes intact) Note: NOT caused by weakness, deafferentiation, abnormal tone or posture, movement disorders, e.g. tremor or chorea, intellectual deterioration or poor comprehension

Channelopathies

Disorders of ion channels that results from point mutations that produce a spectrum of neurological deficits. These are numerous for voltage-gated Ca2+ channels with examples such as: -FHM: familial hemiplegic migraine -EA2: epileptic ataxia type 2 -CSNB: congenital stationary night blindness -paralysis

Deficits seen with a Hemicord (Brown-Sequard) lesion

Dissociated sensory loss to the body - DCML modalities lost on one side of the body with ALS modalitles lost on the other Infrasegmental -Ipsilateral UMN signs below lesion level -Ipsilateral DCML signs below lesion level -Contralateral spinal analgesia up to 1-2 segments below lesion Segmental -Ipsilateral LMN signs due to loss of roots (if affected)) -Band of ipsilateral segmental anesthesia if dorsal horn and its Lissauer's tract are lesioned

Electrodiagnostic study (EDX's)

Document or exclude polyneuropathy Determine pathophysiology, and fibers type (demyelinating v. axonal, motor v. sensory; large v. small fibers) Assess disease severity Establish the presence of a coexisting disorder (focal entrapment, root lesion) Pitfalls: NCS can be normal in patients with selective small fiber involvement

Staining for dopaminergic neuron

Dopamine is not found in cell bodies of its producer neurons (substantia nigra of the brainstem), unlike the enzymes that make it Therefore, Synthetic enzymes for DA, e.g. tyrosine hydroxylase, are good markers for the producer cell bodies Staining specifically for dopamine would mark presynaptic terminals and structures targeted by these terminals

Soma of somatic afferent (primary sensory) neurons carrying information from skin, Golgi tendon organs and muscle spindles into the CNS are located in ________

Dorsal Root Ganglia (DRG) and in cranial nerve ganglia which are outside the CNS and displaced from the nerve itself

Visceral pain is carried by the ____

Dorsal column system The general visceral afferents come in and synapse on secondary post-synaptic dorsal column neurons (PDCN) which arise deep in the dorsal horn ascend within FG for abdominal and FC for thoracic

4 pathways of the spinocerebellar pathways

Dorsal spinocerebellar tr. (lower extremity) Cuneocerebellar tr.(upper extremity) Ventral spinocerebellar tr.(lower extremity) Rostral spinocerebellar tr. (upper extremity) Note: first two are involved with stretch and position information for individual muscles Note: the last two are involved in cord feedback to cerebellum about neuronal activity engaged for entire limb Note: these pathways are not clinically isolated on examination

Opioid basics

Dried milky exudate of the opium seed-capsule contains >20 alkaloids. Medically relevant: Morphine, Codeine, Papaverine Opiates = Opium-derived analgesics Opioids = Opiates + Synthetic analogs + Endogenous

X-Linked Duchenne and Becker Muscular Dystrophy

Duchenne's is the most common fatal muscular genetic disorder -Death in late teens to twenties Mutations in the dystrophin gene Dystrophin and the dystrophin-associated protein complex form an interface between the intracellular contractile apparatus (sarcomere) and the extracellular connective tissue matrix Normal at birth with progressive weakness and death due to respiratory and cardiac failure Pseudohypertrophy of the calf muscles is a constant finding due to fat infiltration into the muscle Note: Becker is a variant of Duchenne (partial penetrance (50%) of the mutated gene)

Subacute combined degeneration

Due to B12 deficiency or malabsorption Seen often in the Elderly, malnourished, chronic antacid use, N2O use, or vegan diet in subclinical cases

Posterior Cord Syndrome

Due to mass occupying lesion or ischemia of PSA territory Deficits: -segmental cord level (ipsilateral loss of DCML modalities at and below lesion level) -Infarction of cuneate or gracile nuclei (ipsilateral hemisensory deficit for DCML modalities)

Backpack injury

Due to poorly fitting backpacks Leads to shoulder, neck muscles, and spinal injuries

Prevalence of Distal Polyneuropathy by Duration of NIDDM (non-insulin dependent diabetes mellitus)

Duration of diabetes increases, so does prevalence of those with Distal Polyneuropathy 10% of patients have neuropathy at time of diagnosis 50% develop neuropathy within 25 years of diabetes 25 - 30% of neuropathies are associated with pain

Process of myelination

During myelination the axon remains stationary - it does not "grab" the leading edge of the SC and pull it while rotating. Instead, the SC does all the work, growing its myelin membrane as the leading edge which repeatedly encircles the axon by undercutting the most recently layed down turn so as to remain closest to the axon. The blue dot (left) shows the leading edge.

Non-analgesic use of opioids

Dyspnea due to Acute left ventricular failure and Acute pulmonary edema, as in MI. -I.V. morphine may produce dramatic improvement. -MOA: ↓ Anxiety (perception of dyspnea) ↓ Preload (↓ venous tone) ↓ Afterload (↓ PVR) -Morphine is contraindicated in pulmonary edema due to respiratory disease. Central Antitussive: Cough, like pain, is a protective reflex. When it does not serve useful purpose, then it should be suppressed. -Codeine - 10 or 20 mg - ineffective as analgesic - but effective as antitussive. Hydrocodone is also used. -Dextromethorphan - Dextro- isomer of codeine analog methorphan. No analgesic or addictive properties. OTC drug. Diarrhea: DIPHENOXYLATE and LOPERAMIDE Shivering: MEPERIDINE (MOA - action on subtype of α2)

Aging of the spine

Each level of the spine (24 vertebrae) functions as a three-joint complex, two facet joints and one disc joint The spine is a flexible multi segmented column requiring healthy ligaments, tendons and muscle to keep it in alignment Kyphosis a forward rounding of the back

How signals pass along an axon

Each time a voltage-gated Na+ channel opens, the influx of Na+ causes a tiny local potential (depolarization) that brings the neighboring downstream stretch of axon to threshold, which in turn triggers its voltage-gated Na+ channels to open to the same degree and length of time, thereby propagating the AP along theaxon without decrement!! The AP appears to move down the axon because of the sequential opening and closing of ions that traverse the axolemma, like a string of trapdoors running its length to the terminal.

Cervical cord compression

Elderly - cervical spondylosis Degenerative changes; atlanto-axial subluxation in advanced arthritis Reduction of spinal canal diameter and spinal cord compression. Intervertebral discs dry out resulting in loss of disc height. Osteophytic spurs develop at margins of end plates as a means to stabilize adjacent vertebrae whose hypermobility is caused by the degenerated disc

What is the goal of treatment in fibromyalgia?

Elevated [NE/5HT] in the dorsal horn

Emerging concepts of emotional pain

Emotional and physical pain are on the same continuum Neural structures activated in the limbic system by physical pain are also activated by the social pain of exclusion (ant. cingulate g. and amygdala) Pain alerts us to withdraw and avoid the stimulus for the sake of protecting the organism. Sensorimotor integration is engaged. The emotional component of pain, i.e., suffering, is intended to enable us to remember and avoid future danger. The affect can be adaptive or maladaptive. "Mirror neurons" allow our personal suffering to develop empathy in us for others, but not everyone develops this experience-based capacity. Mental illness can lower the pain threshold and exacerbate suffering.This underscores shared neurotransmitter systems and anatomic correlates of physical and emotional pain. Conversely, chronic pain is maladaptive and promotes negative behavioral consequences > mental illness.

Epimysium

Encloses the entire muscle

Cannabinoids and cannabinoid receptors

Endogenous cannabinoids: e.g. Anandamide Receptors: CB1 and CB2. Function as neuromodulators to regulate synaptic plasticity, learning, pain, emotion, anxiety, etc. Work in retrograde direction on presynaptic terminal

Hirschsprung disease (aganglionic megacolon)

Enteric plexuses fail to develop in the hindgut Lower bowel remains tonically constricted, preventing fecal bolus from descending though it

Mononeuropathies examples

Entrapment neuropathy Acute compression or traumatic Ischemic (diabetes, vasculitis) Infectious (herpes zoster, leprosy) Infiltrative (tumor, sarcoidosis, granulomas) HNPP Immune-mediated (MMN)

Amyotrophic Lateral Sclerosis (ALS)

Epidemiology: -Uniform world-wide distribution -Incidence 0.2 to 2.4 per 100,000 per year -The usual age of onset is between 40 and 70 years, rarely before age 30 years -Prevalence: 3 to 8 per 100,000 Clinical symptoms and signs: -Muscle weakness; usually associated with wasting -Continuous progression and spread to adjacent region (arms, legs or bulbar) -Remissions in symptoms or signs is rare -Bulbar onset in 20% to 30% of all ALS cases (Dysarthria, Dysphagia, pesudobulbar affect) -Respiratory failure at later stage -Muscle cramps and fasciculations are common -Combination of upper and lower motor neuron signs -Bladder & bowel function, and extra-ocular movement are spared -Spared cognitive function, sensation and coordination Pathology; -motor neuron loss, vacuolation and neurofilamentous changes (Bunina bodies and ubiquitine) -Degeneration of corticospinal and corticobulbar tracts -Secondary degeneration of motor axons -The cause remains unknown, probably premature aging of motor neurons Laboratory features -EMG: ~Widespread denervation and partial reinnervation in several body regions ~Small CMAP, low normal CV's and normal SNAP -Usually normal laboratory studies except for mildly elevated Serum CK -CSF: Usually normal -Normal brain and cervical brain MRI except for age related degenerative changes -Muscle biopsy reveals changes of chronic and acute denervation Treatment -No effective treatment available FDA approved treatment; ~Riluzole (Rilutek) may increase survival by an average 3 months. ~Edaravone (Radicava) infusion showed 5 points vs. 7.5 points placebo decline (P 0.0013) on ALSFRS from baseline to week 24 treatment. -Symptoms management; spasticity, muscle cramps and pain, depression, anxiety, sialorrhea, pseudobulbar affect... -Nutritional support -Respiratory support and monitoring -Overall survival 3 to 4 years

Interventional Strategies (Injections & Surgery) for neuropathic pain

Epidural corticosteroid injections in lumbar disc herniation and lumbar stenosis Spinal cord stimulation (stimulator in dorsal spinal cord blocks pain processing) Deep brain stimulation Intrathecal opioids (very low-dose opioid with minimal systemic side effects). Intrathecal clonidine, baclofen Sympathetic blockade Surgery (glycerol rhizotomy & microvascular decompression in trigeminal neuralgia)

Cerebellar lesion signs

Error-filled movements: -Ataxia = uncoordinated movement Cerebellar ataxia signs -Asynergia -Dysmetria -Dysdiadochokinesia -Intention tremor (only during intended movement) -Truncal swaying

Small molecule neurotransmitters

Ester -acetycholine (Ach) Amino Acid -glutamate (Glu) ~ 95% of CNS neurons! -aspartate (Asp) -gamma-aminobutyric acid (GABA) -glycine (Gly) which replaces GABA in the spinal cord Biogenic Amines ~Catecholamines -dopamine (DA) -norepinephrine (NE) -epinephrine (EPI) ~Indoleamine -serotonin (5HT) ~Imidazoleamine -histamine (HIST)

Main 2 structures of local anesthetics

Ester link - these under go De-esterification by plasma pseudocholinesterase → Short acting Amide link - these undergo Hydrolysis in hepatocytes by mixed function oxidase → Long acting

Methemoglobinemia with Prilocaine

Etiology: -Cytochrome b5 reductase or antioxidant protein 2 deficiency -Hemoglobin M -Toxicity (e.g., PRILOCAINE, LIDOCAINE, BENZOCAINE, sulfonamides, nitrates/nitrites, GTN) Pathogenesis: -O-toluidine, the liver metabolite of Prilocaine, oxidizes Hb (Fe2+) to MetHb (Fe3+). Clinical Manifestation: -Cyanosis -Cutaneous discoloration (gray) -Tachypnea -Dyspnea -Exercise intolerance -Fatigue -Dizziness and syncope -Weakness Dx: -Eight Wavelength Pulse Oximetry (gives SpCO and SpMet in addition to SpO2) Rx: -Methylene Blue ("MetB for MetHb"). Requires intact G6PD. -Vitamin C

Erythromelalgia (with Nav1.7 mutation or Polycythemia Vera)

Etiology: -Mutations in the SCN9A gene (encoding Nav1.7 expressed in sensory and sympathetic nerves) -Myeloproliferative disorders: Polycythemia Vera and Essential Thrombocytosis. -Drugs: CCBs, BROMOCRIPTINE, and PERGOLIDE Clinical Features: -Burning pain and erythema of the extremities with warm exposure. -Relieved by exposing the affected area to cool air or water or by elevation -DDx: Ischemia secondary to peripheral arterial disorders (peripheral pulses present in erythromelalgia) Rx: Aspirin or other NSAIDs

Acute nociceptive pain

Etiology: Thermal, Chemical, Mechanical Stimuli Pathogenesis: Activation of high-threshold afferents (Ad & C fibers of DRG neurons) → ↑ Firing of DHN → Acute pain

Chronic nociceptive pain

Etiology: Tissue Injury & Inflammation Pathogenesis: Hyperalgesia - via peripheral and central sensitization

Acute effects of marijuana

Euphoria, drowsiness, or sedation Anxiety Sensation of slowed time Slowed reaction time Auditory or visual distortions Conjunctival injection Tachycardia Increased appetite Angina Potentially beneficial effects: -Anti-nausea effects (used for chemotherapeutic agents) -Analgesic effects (neuropathic pain) -Muscle-relaxing, anti-convulsion effects -Reduction of intraocular pressure for glaucoma treatment

Repetitive Motor Nerve Stimulation (RMNS)

Evaluation of motor potential stability in response to motor nerve stimulation at frequency range (3Hz - 20 Hz). Utilized in patients with suspected NMJ disorder; Postsynaptic -myasthenia gravis, -organophosphate poisoning, -curare paralysis. Presynaptic -LEMS -Botulism, -Tic paralysis

Why do patients in pain fall asleep after local anesthesia?

Example: During labor, at the onset of spinal/ epidural local anesthesia, women fall in profound sleep. Spinoreticular pain signaling blocked by local anesthetics product hypnosis (there is no NTS signal to keep awake leading to an accumulation of adenosine which activates the VLPO and leads to hypnosis)

Neuropathic pain: Third order neuron

Examples: Thalamic stroke can cause thalamic pain syndrome -Lacunar infarct (unilateral) -Contralateral analgesia and paresthesiascontralateral allodynia

Neurotoxicity of local anesthetics

Excitation Phase: -Starts with change in thought processes -Followed by perioral paresthesia (numbness) -Whole body flushing feeling -Tinnitus -Tongue paresthesia -Dizziness -Blurred vision -Restlessness, agitation, nervousness, paranoia -Muscle twitching heralds the onset of tonic-clonic seizures. -Generalized seizures (Rx. Midazolam) Depression Phase: -Slurred speech, Drowsiness, Coma -Respiratory arrest -Cardiac arrest

3 classes of cell adhesion molecules

Extracellular matrix glycoproteins CAMs (cell adhesion molecules) Ephrins

Neurotrophins: A Family of Neurotrophic Growth Factors

Family of homologous 10-20 kDa peptide growth factors released by target cells of innervation in CNS and PNS -nerve growth factor (NGF) (knockout causes phenotype) -neurotrophin-3, -4, -5 (NT3, NT4, NT5) -brain-derived neurotrophic factor (BDNF)

Neurotrophins bind to ____

Family of homologous Trk (tyrosine kinase domains) receptors which are transmembrane -trkA (NGF) -trkB(BDNF, NT-4/5) -trkC(NT-3)

Webscope DRG image

Find DRG neurons and satellite cell In the adjacent dorsal root ganglion. Observe the segregated nerve fibers

Webscope Sympathetic ganglion image

Find the postganglionic sympathetic neuronal somata and satellite cells. Observe the nerve fibers interspersed between the neuron cell bodies.

DCML somatosensory modalities

Fine touch Position sense (proprioception) Vibration Pressure

Multiple sclerosis histopathology

Foamy macrophages and Creutzfeldt cells distinguish MS plaques from glioblastomas.

Serotonergic neurons

Found exclusively in the raphe nuclei of the brainstem Project diffusely throughout CNS

Features of preganglionic sympathetic neurons

Found in lateral horn and only at spinal cord segments T1-L2 Their axons will join up with those of the LMNs that leave through the ventral horn

Tetrodotoxin (TTX)

Found in puffer fish and some other ocean species in the Pacific - not in USA coastal waters. Blocks the pore region of v-gated Na+ channels at nM levels to eliminate the AP, leading to paralysis, sensory loss and rapid death. Fugu - a potentially deadly culinary delicacy

Locus ceruleus

Found in the rostral pontine tegmentum Continas neuromelanin pigment Houses the brain's only noradrenergic neurons

Transient Receptor Potential (TRP) Channels

Found on nociceptors! TRPV1: respond to noxious heat (>43 C), vanilloids, e.g. capsaicin on both Aδ and C fiber endings TRPV2: noxious heat TRPV4: noxious force TRPA1: noxious force ASIC3: H+ causing myocardial ischemic pain

Nociceptors

Free nerve endings with receptors that transduce painful stimuli They contain different ion channels activated to trigger receptor potentials in bare nerve endings

Mirror neurons

Frontal lobe neurons that fire when performing certain actions or when observing another doing so. The brain's mirroring of another's action may enable imitation, language learning, and empathy.

Thoracic injury paraplegics can respond to ______

Funcional electrical simulation (FES) Externally worn FES computer times and applies weak electrical current in a precise signaling sequence optimal for inducing motor control of lower extremities: microprocessor switch for walking, sitting, or standing Current travels bidirectionally along peroneal nerve to NMJ and to cord -> CPG activation Final common pathway (LMN->) must be intact for FES to work Note: cervical cord must be intact

Effector pathways downstream of metabotropic receptor activation are associated with _______

G-protein-coupled signal transduction mechanisms

What connects Schmidit-Lanterman incisures (SLI)

Gap junctions connect SLI across apposing turns of myelin. This allows substances to move "cross country" radially and rapidly between the cell body and innermost turn across consecutive turns of myelin without having to take a concentric path, around turn after turn of myelin through SLI, which is slow and inefficient.

What type of receptor is µ?

Gi type Therefore it inhibits adenyl cyclase

Equilibrium potential (E)

Given the high [K] inside setup by Na+K+-ATPase, K wants to flow out of the cell down its concentration gradient through K2P channels. However, as more and more cations collect outside the cell, K+ efflux is dampened and then becomes opposed by electrostatic repulsion. When these two forces are equal, K+ has reached its "equilibrium potential (E)" also known as the Nernst potential. This is the voltage for which the force of diffusion for K is exactly counterbalanced by the electro-chemical force pulling cations in the opposite direction. At E for K+ there is no net movement across the plasma membrane.

Properties of local potentials

Graded according to the strength of the stimulus. A more intense or prolonged stimulus opens more ion gates than a weaker stimulus. Thus, more Na+ enters the cell and the voltage changes more than it does with a weaker stimulus Decremental, getting weaker as they spread from the point of stimulation. The decline in strength occurs because as Na+ spreads out under the plasma membrane and depolarizes it, and K+ effluxes through K2P. As a result, the voltage shift caused by influxed Na+ diminishes rapidly with distance. This prevents a single local potential from having any long-distance effects. Reversible - if stimulation ceases, K+ diffusion out of the cell quickly returns the membrane voltage to its resting potential.

Axon growth cone

Growing end of formative axon/dendrite - explores environment for guidance cues and trophic signals Expresses receptors for diffusible and cell surface-bound macromolecules signaling attraction, repulsion, survival and differentiated gene expression Responds to steerage signals with genomic effects to: -add cytoskeletal protein monomers to elongate axon at its growing end -suppress apoptosis programs that otherwise kill neurons -convert growth cone to functional synaptic terminal

A 21 Y/O M presented with 6 years history of progressive gait difficulty, frequent tripping, atrophy of anterior leg muscles and mild hands weakness. Patient's father and maternal aunt has less severe distal legs weakness and feet deformity. Neuroexam; high arched feet hammer toes, absent DTR's in LE & reduced in UE, weakness and atrophy of anterior leg muscles, partial bilateral foot drop and reduced sensation distally. Lab studies all were normal. NCS/EMG; slow motor conduction velocity in all limbs uniformly, absent sensory potentials in the feet and, sign of symmetric chronic denervation in the feet and distal leg muscles . DNA genetic testing revealed PMP22 duplication

Hereditary neuropathy

_______ acuity areas are disproportionately represented in sensory homunculus

High Note: these generally come from Merkel's discs which have the smallest receptor fields and the greatest acuity

Xenon effects

High-affinity NMDA receptor blocker Unlike other NMDA receptor blocker -No neurotoxicity; inhibits neurotoxicity of ketamine and N2O Xenon inhibits -Cholinergic N α4ß2 receptors which contribute to spinally mediated analgesia. -Plasma membrane Ca2+ ATPase -5-HT3 → reduces anesthesia-emergent nausea and vomiting Xenon MAC = 71% (more potent than N2O) Xenon induces robust cardioprotection and neuroprotection (ischemic preconditioning)

______concentration of anesthetics required for induction than for maintenance (neural inertia)

Higher

Psychosomatic pain

Historically deemed imaginary; faking illness or psychiatric reasons Now we better understand! Ex: depression and associated aches and pains are due to a global deficit in NE or 5-HT receptor signaling which leads to: - defective descending analgesic pathways causing decreased pain threshold -defective ascending projections from the LC and raphe to frontal lobe and limbic system which manifest as psychiatric mood/anxiety disorders

Gracilis tubercle and Cuneatus tubercle

House the respective nuclei and can be seen on the dorsal aspect of the brain stem

Ventroposterolateral nucleus (VPL)

Houses the cell bodies for the 3rd order neurons mapping with the arms more medially and the lower extremities/sacral more laterally Note: injury to the VPL at this location is above the sensory decussation, so you would interrupt contralateral sensory information

Length constant (λ)

How far an influxed bolus of ions can diffuse along a neuron before the depolarization it causes will decrease to 37% of its initial effect Note: this image shows one of 1mm

Time constant

How long it takes from the moment of current influx through an opened receptor or by injection for the effect to dissipate to 37% of its original value

I.V. anesthetics

Hydrophobic molecules. Single intravenous bolus -> rapid partitioning into brain and cord -> anesthesia within a single circulation time. Rapid drop in blood levels -> redistribution of anesthetic out of CNS back into the blood. Termination of action: diffusion into perfusion-poor tissues (muscle, viscera, adipose tissue). -Example: After a single bolus of THIOPENTAL, emergence time = 10 minutes. -However, if infused over time, emergence may take >24 h Context-Sensitive Half-Life: Half-life depends on total dose, duration of administration, distribution in adipose tissue.

Central sensitization promotes ______

Hyperalgesia Note: it occurs in dorsal horn and higher CNS levels (thalamus) Mechanism: - Nociceptor afferents release GLU in dorsal horn causing EPSPs in secondary neurons -High level of C-fiber activity causes summation of slow EPSPs in secondary neuron = wind-up - Wind-up acutely sensitizes dorsal neurons to fire more aggressively -Wound up secondary neurons respond to previous sub threshold stimuli by firing more APs perceived as a greater intensity of pain -The perceived intensity increases with each successive stimulus presentation, due to progressive wind-up

Characteristics of Pathogenetic Elements of Neuropathic Pain

Hyperalgesia: Increased response to a normally painful stimulus -Peripheral sensitization-Chronic nociceptive: - Central sensitization-Chronic nociceptive & Neuropathic Allodynia: Pain due to a stimulus that does not normally provoke pain Sympathetically maintained: Stress (sympathetic activation) causes pain

Peripheral sensitization promotes ____

Hyperalgsia (degree of painful stimuli is elevated) and allodynia (stimuli that is not normally painful is all of a sudden is) Mechanism: -primary sensitization of nociceptors in the injured area causes secondary sensitization of bystander nociceptors in surrounding tissue - This leads to normally painful stimuli perceived as worse than usual (hyperalgsia); subthreshold stimuli can now activate nociceptors and be perceived as painful (allodynia)

Kallmann Syndrome

Hypogonadism and infertility: agenesis of GnRH-producing neurons Hyposmia or anosmia: olfactory system agenesis 16 gene defects identified covering all modes of inheritance Type inherited as X-linked recessive: -Mutates Kal1 gene encoding ECM protein, anosmin-1 -Blocks migration of bipotential neuron precursors from olfactory placode -Neither olfactory bulbs nor hypothalamic GnRH-producing neurons can form

General adverse effects of general anesthesia

Hypotension - due to vasodilation, myocardial depression, blunting of baroreception, and decrease in sympathetic tone Respiratory depression - elimination of ventilatory drive, loss of gag reflex, cough reflex, myorelaxation by curare agents -Respiratory depression necessitates endotracheal intubation Hypothermia (temp < 36C) - low ambient temperature, cold IV fluids, lowering of set point, vasodilation, decrease in metabolic rate. -Hypothermia may lead to infection, cardiac and thrombotic complications. -Rx: warm fluids, heat exchangers, water filled garments with microprocessor control of temperature. Nausea and vomiting: Rx: 5-HT3 antagonist ONDANSETRON Emergence: Excitement, tachycardia, restlessness, crying, moaning Malignant hyperthermia (RyR mutation) with volatiles, succinylcholine. Rx: DANTROLENE

Ketamine

IV anesthetic MOA: NMDA receptor blockade -Useful for certain pediatric procedures -Good for patients at risk for hypotension or bronchospasm Emergence delirium precludes routine use Profound analgesia (unlike other I.V. anesthetics) Can cause Dissociative anesthesia -Unresponsiveness to commands, Amnesia, Eyes open -Move their limbs involuntarily, Spontaneous respiration Administered I.V. but also effective by I.M., PO, and PR routes

Etomidate

IV anesthetic that doesn't cause hypotension MOA: Agonist for GABAA receptors CLINICAL USE -For induction of patients at risk for hypotension. -High incidence of pain on injection (Rx-Lidocaine). -Myoclonic movements Rx: Benzodiazepines or opioids CVS: Maintains cardiovascular stability in coronary artery disease, cardiomyopathy, cerebral vascular disease, and/or hypovolemia

Afferents for intrafusal fibers and stretch receptors

Ia II Ia spindle afferents encircle intrafusal muscle fibers and report changes in muscle length and speed of extrafusal fiber contraction II spindle afferents encircle intrafusal fibers and produce sustained responses to constant muscle lengths

Afferents for Golgi tendon organs

Ib Ib afferents supply GTOs and relay information about changes in muscle tension

Anatomic sites for general anesthetics: Spinal cord

Immobilization in response to a surgical incision (the end point used in determining MAC) results from inhalational anesthetic action in the spinal cord. -MAC unaffected by decerebration or cervical cord transection. -ISOFLURANE to brain only → MAC 3% -ISOFLURANE to body only (excluding brain) → MAC 1% PROPOFOL inhibits ventral horn neurons via a GABAergic mechanism ISOFLURANE inhibits ventral and dorsal horn neurons AtVisceral pain inhibition by action on dorsal column medial lemniscus (DCML) system → primary visceral cortex (insular gyri)

Guillain-Barre Syndrome

Immune system attack of peripheral myelin Often precedes an infection (2 in 100,000) -Respiratory and GI Timeline -Symptoms worsen for several weeks -Symptoms plateau for 1 month -Recovery 1 year 1 in 10 have long-term complications Symptoms -Weakness and tingling or loss of sensation starting in the feet and legs then spreading to the upper body and arms -Slow heart rate and difficulty controlling bladder, respiratory depression, 3-5% of patients can die

Carnitine deficiency and cardiotoxicity of local anesthetics

In carnitine deficiency, fatty acids accumulate in cardiomyocytes. Bupivacaine accumulation is increased to cause cardiotoxicity. Treat with lipid infusion

Dawson's fingers

In multiple sclerosis, perivascular demyelination creating the appearance of finger projections oriented transversely on an axial scan.

Where is the termination territories of the spinocerebellar pathways serving extremities?

In the paravermis

Adrenoleukodystrophy

Inability to catabolize very-long-chain fatty acids within peroxisomes Adrenal insufficiency Childhood to adult types Most aggressive is the X-linked form Symptoms include vision loss, difficulty hearing and talking, difficulty swallowing and walking, fatigue, seizures and dementia

Alcoholic neuropathies

Incidence 9% of all alcoholics Often painful mixed sensory motor neuropathy, legs > arms Attributed to thiamine and other vitamins and nutrients deficiency, and toxic effect of alcohol Low serum or erythrocyte transketolase activity Degeneration of terminal axons, gracile fasciculi, distal vagus and recurrent laryngeal nerve in advanced cases Signs of CNS impairment might be encountered

Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)Guillain-Barré Syndrome (GBS)

Incidence: 2 to 6/100,000/year, ages 8 M. to 8 years Antecedent infection, vaccination or trauma in >50% Acute/subacute progressive onset (few days to 2 W) Clinical features: -Progressive weakness: proximal & distal; symmetric (quadriplegia in 30%; bed bound another 30%) -Paresthesias is often the initial presentation -Respiratory failure (~33%) require intubations) -Cranial nerves involvement (CN VII palsy in ~50%) -Low back and radicular pain in ~ 70% -Autonomic dysfunction in ~ 50 % -Depressed or absent Tendon Reflexes Pathology & Pathogenesis: -Segmental demyelination and cellular infiltrate -Axonal degeneration may occur is severe cases -Cell mediated immunologic reaction directed at PN's -No virus or microbial agent can be isolate Diagnosis: -Nerve conduction studies: Demyelination ± Axonal loss -CSF: elevated protein (albumino-cytological dissociation) -Serum and hematology studies Only abnormal with associated infection or other disorder Treatment: -Immunomodulation ~Plasma Exchange or IV IgG definitely indicated (provide equal benefit) ~Not Corticosteroids -Ventilatory support and monitoring -Treatment of autonomic dysfunction -Physical therapy, and SC heparin to reduce thromboembolic events -Satisfactory recovery in 80%, permanent residua in 15% and permanent disability in 5% of cases.

Gq-coupled receptors on nociceptors

Include: -bradykinin -histamine -prostaglandins -serotonin

ADEM treatment

Includes reducing inflammation

Treatment for specific examples of neuropathic pain

Includes: -diabetic neuropathy -post herpetic neuralgia -trigeminal neuralgia -central pain -phantom limb pain

Proprioception

Incorporates the sense of limb position, movement, and force or effort of movement Involves activation of mechanoreceptor subset in skeletal muscles, tendons and joints Cutaneous mechanoreceptors collaborate to provide information about skin stretch during movement

Basic processes in multiple sclerosis plaque formation

Inflammation, myelin breakdown, astrogliosis, oligodendrocyte injury, axonal loss, and remyelination

31-year-old man, previously healthy, who had mild upper respiratory tract infection 7 days earlier, developed new onset feet numbness that extended to the ankles and knees over 2 days. Additionally he developed lower limbs weakness, poor balance and hands weakness over the next couple days. He complained of mild shortness of breath Exam: weak hands and legs, absent reflexes, and vibratory and proprioceptive loss in feet/hands Labs: Normal CBC, LFTs, urinalysis Negative ANA, RF titer Negative porphyria testing Negative heavy metals screen CSF analysis: protein 88, WBC 3 (lymphocytes) Normal glucose, cell count, gram stain, and bacteriology studies Nerve conduction study showed increased distal latency, slow conduction velocity and proximal CMAP dispersion.

Inflammatory Demyelinating Polyradiculoneuropathy

Dermatomyositis

Inflammatory disorder of the skin (rash) followed by a myositis, seen in adults and children Perifascicular atrophy (very small fibers near the fascicle) High association with a new cancer in adults (paraneoplastic syndrome) (should screen for possible cancers)

Afferent pathways for pain (and temperature)

Information from pain/ temperature sensory afferents innervating trunk & limbs routed to brain via the anterolateral system (ALS) Similar afferents in head & face track via trigeminal pathways Projections routed to appropriate parietal somatosensory areas for perception and localization

Charcot-Marie-Tooth Disease (CMT)

Inherited chronic progressive polyneuropathy Affects myelinated motor and sensory axons. Symptoms are predominantly motor. Associated musculoskeletal deformities are common The majority are autosomal dominant, 13% X-linked and few are recessive CMT1 is characterized by slow nerve conduction and histological evidence of demyelination CMT2 is characterized by later age of onset, and axonal loss Genetic testing has enabled specific diagnosis in a number of CMT subtypes

Dendrotoxins (mambas, wasps), Apamin (bees)

Inhibit voltage-gated K+ channels Prolong AP decay

Diagnostic criteria for multiple sclerosis

Initially developed so that inclusion of subjects into clinical trials would be more uniform First McDonald criteria adopted in 2001; refined 2005, again 2010 and 2017 Dissemination in Space: evidence of involvement of at least two CNS sites -Objective evidence may include exam findings, abnormal visual evoked potentials, or demyelinating lesions on MRI Dissemination in Time: evidence of at least two attacks -Can be satisfied by history alone -If only one attack, may apply MRI criteria

Deficits seen in a transverse injury

Initially: spinal shock -Flaccid paralysis and sensory loss below lesion -Loss of DTRs, impaired sympathetic outflow -Causes hypotension and poikilothermia depending on lesion level -Absent sphincter tone and reflexes Weeks-months after injury -Bilateral loss of sensation segmentally and below -motor/sensory levels can improve -Bilateral spasticity infrasegmentally -Bilateral LMN signs remain segmentally -Incontinence and spastic bladder Note: the bulbocavernosus and anal wink reflexes are the 1st to return if any do; if not it is a complete spinal cord injury!

Intravenous regional anesthesia

Injected I.V. distal to pressure cuff to arrest blood flow; effective until cuff is depressurized. Used in limb surgery. Drugs: LIDOCAINE, PRILOCAINE. Adverse effects: Systemic toxicity when cuff released before 20 min.

Infiltration local anesthetics

Injected in tissue around incision for minor operations. Drugs: ARTICAINE (dental) LIDOCAINE, PROCAINE, BUPIVACAINE EPINEPHRINE often added for vasoconstriction to keep the local anesthetic where you want it and also to prevent bleeding, but do not use for fingers, toes, ears, nose, or penis (end-artery supplied). Gangrene might ensue. Antidote of epinephrine: PHENTOLAMINE (α1α2-blocker) For retrobulbar - Hyaluronidase (a hydrolyzer of connective tissue polysaccharides), added to enhance the retrobulbar spread. Systemic toxicity in high concentration and large areas of application.

Spinal local anesthetic

Injected into CSF, in subarachnoid space to act on spinal cord and spinal roots. Used for surgery of abdomen, pelvis, leg, in obstetrics. Drugs: TETRACAINE, BUPIVACAINE, LEVOBUPIVACAINE. Adverse effects: -Bradycardia, hypotension- due to sympathetic block - Respiratory depression - due to phrenic nerve or respiratory center block Minimize cranial spread by: -Elevating head -Add 10% dextrose to make it heavier than CSF Urinary retention - due to pelvic parasympathetic block

Epidural (peridural, extradural) local anesthetics

Injected into epidural space to act on DRG and roots. Used for surgery of abdomen, pelvis, leg, in obstetrics ("painless" childbirth). Drugs: LIDOCAINE, LEVOBUPIVACAINE Adverse effects: -Similar to spinal, but less likely because cranial spread is limited -Urinary retention - pelvic parasympathetic block

Regional nerve block local anesthetic

Injected near peripheral nerves. Used for surgical and dental analgesia. Pudendal block for episiotomy. Drugs: Most. LIDOCAINE is widely used Adverse effects: -Onset of anesthesia - slower. - Needs accuracy of injection.

Klumpkes Palsy

Injury to the Lower plexus (C8-T1) There is paralysis of muscles of the forearm and hand

Erb-Duchenne Palsy

Injury to the upper brachial plexus (C5-C6) Presents with weakness and loss of motion in the arm Waiter's tip- arm hands by the side and is rotated medially; the forearm is extended and pronated

Local circuit neurons

Interconnect cord segments and segmental reflexes vertically They cross midline Coordinately regulate LMN output from multiple segments to control posture and total limb activity

Hemicord lesion at the level of the cord affect on the descending motor system

Ipsilateral UMN Sx below lesion level Ipsilateral LMN signs at lesion Level No motor impairment above lesion

Brown-Sequard syndrome

Ipsilateral motor weakness and contralateral sensory deficit due to hemisection of the spinal cord May result from rotational injury such as fracture-dislocation or from penetrating trauma such as a stab wound Ex: Extramedullary tumor Note: hemicord lesion

Anterior cord syndorme

Ischemic condition caused by ASA hypoperfusion May be due to artery of Adamkiewicz compromise due to aortic clamping above renal a.- acute Can also be due to cervical spondylosis with aging which narrows the spinal canal Can also be caused by systemic vascular disease May also be caused by a central directed disc herniation (has to be severe)

Central Cord syndrome

Ischemic damage to watershed area between perfusion territories of ASA and PSA Watershed affects central gray Causes: -Intramedullary neoplasias -Most commonly traumatic compression at any level -Developmental lesions (associated with Chiari malformations as syringomyelias) -lesion consequent to hyperextension injury (UE deficits > LE deficits in the age-related syndrome)

What 2 ways does Ca2+ influx stimulate exocytosis of small molecule neurotransmitters

It activates Ca+2-calmodulin-dependent protein (CAM) kinase, which phosphorylates the linker protein, synapsin. This detaches snyapsin-bound vesicles from the cytoskeleton to enable their diffusion to and docking at the presynaptic terminal face. Voltage-gated Ca+2 channels are restricted to the presynaptic terminal face and proximal to active zones. Within the active zone, SNARE proteins on the cytoplasmic face of the presynaptic terminal membrane (SNAP-25, syntaxin) loosely bind their counterparts inserted into the synaptic vesicle wall (synaptotagmin, synaptobrevin), thereby docking a vesicle for fusion/exocytosis. These proteins account for the presynaptic density visualized by TEM in tissue sections stained with osmium tetroxide. Vesicle fusion is triggered by influxed Ca+2, which binds synaptotagmin, the Ca+2 sensor of the SNARE protein complex, to tighten the complex in a conformationthat promotes membrane fusion and exocytosis of NT into the cleft.

Cerebellum as another moment modulator and sensorimotor integrator

It is a sensory structure derived from alar plate that works as a movement error detector It receives advanced, descending copy of intended movement command from area 6 It also receives real-time movement feedback via spinocerebellar and vestibulocerebellar proprioceptors It compares the two inputs and sends corrective signals to the primary motor cortex via a thalamic relay generating a smooth, error free movement

The relative permeability of a resting neuron is almost exclusively restricted to ______

K+

For a neuron at rest, only ______ permeability determines the "resting" membrane potential (Vr)

K+ The neurilemma contains K+ leak (K2P) channels K2P channels are always open Note: resting membrane is essentially impermeable to Na+ Cl-. Ca2+

For a neuron at rest, Na+/K+-ATPase maintains the separation of Na+ and K+ ions as:

K+ - intracellular: 140 mM - extracellular: 5 mM Na+ - intracellular: 5-15 mM - extracellular: 145 mM

Nernst potential for K+, Na+ and Cl-

K+: -90 mV Na+: +55 mV Cl-: -65 mV

Brevetoxins

Karenia brevis is the species of dinoflagellate algae that surfaces along coastal Florida (red tide) where the sea breeze aerosolizes the brevetoxins it produces. Brevetoxins bind the α-subunit of voltage-gated sodium channels to reduce the threshold required for the AP to form and prolong mean Na+ channel open time, thereby effectively delaying inactivation of the AP. The effect is symptomatic but not lethal. Note: these can also be ingested via consuming fish that have in turn consumed these brevetoxins

Use-dependent block clinical relevance

L.A. binding accessibility is highest in the open state L.A. binding affinity is highest in the inactivated state Cells with long action potential (Purkinje) are more vulnerable to inactivation state binding Ischemic tissue has more cells in the inactivated state Cardiomyocytes exhibit use-dependent block more than neurons do

Lidocaine & Capsaicin Patches (for neuropathic pain?)

LIDOCAINE 5% patch for back pain CAPSAICIN 8% patch for postherpetic neuralgia. -A single 1-hour application of the capsaicin patch can result in attenuation of pain for up to 12 weeks -Desensitization of TRPV1 receptors

Perfusion territories of the single anterior spinal artery

LSCT, ALS and ventral horns bilaterally Descending ANS bilaterally

Diagnostic work-up for peripheral neuropathies

Laboratory -CBCD, comprehensive metabolic panel, HbA1c] 2 hour GTT, TSH, T4, B12, Fasting lipid panel ANA, ESR, Rheumatoid factor, SS-A /SS-B antibodies SPEP, UPEP + immunoelectrophoresis and If indicated HIV antibody, heavy metals screen Electrodiagnostic Study Autonomic Functions tests Nerve biopsy only in selected patients

Disorders that affect the presynaptic terminal

Lambert-Eaton myasthenia syndrome attacks presynaptic Ca2+ channels Congenital myasthenic syndromes result in impaired vesicle recycling Cognitive disorders impair transsynaptic signaling Latrotoxin (black widow) triggers vesicle fusion causing all NTs to be dumped in the CNS Botulinum and tetanus toxins affect SNARE proteins involved in vesicle fusion

Artery of Adamkiewicz

Largest anterior medullary segmental artery Unpaired, left side in ~75% of patients, though this is variable IT provides a critical boost to the ASA perfusion of caudal 1/3 of cord, including lumbar enlargement It typically feeds the ASA at ~vT10 Its territory is vulnerable to ischemia during surgical repair of aortic aneurysm

_______ reflects last phase of CNS development

Late myelination of frontal-limbic structures

Cortical upper motor neurons originate primarily in _______

Layer V of the primary motor cortex (Brodman area 4)

Look at these 2 MRI and determine which is Multiple sclerosis

Left Figure: MS lesions tend to be ovoid, 3-5 mm or larger in size, periventricular, juxtacortical, pericallosal ('Dawson's fingers). Right Figure: 'Nonspecific' lesions seen in microischemic states, migraine etc. tend to be small, round, with no predilection for periventricular, pericallosal or juxtacortical regions.

Free nerve endings of sensory neurons

Left: Nociception: Direct activation by intense pressure (cut) and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances. Right: Secondary activation: Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP) which binds to NK1 (Gq) receptors. Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin (BK). Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets.

Hyperalgesia in Chronic Nociceptive Pain: Peripheral Sensitization

Left: Nociception: Direct activation by intense pressure (cut) and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances. Right: Secondary activation: Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP). Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin (BK). Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets. Note: peripheral sensitization can cause increase A-delta/C firing rate and the same temperatures as those non-sensitized

What are the sensory deficits resulting from this small cavitation of 3-4mm?

Lesion level: cord level C2 Deficits: DC modalities intact ALS modalities - bilateral loss of pain/temp sensation with a cape-like distribution at ~C3-C4 ALS modalities intact in dermatomes represented above and below the lesion because ALS intact

What are the sensory deficits resulting from this stab injury at cord level T6?

Lesion level: mid-thoracic - cord level T6 Deficits: DC modalities - ipsilateral sensory loss including and below T6 nerve root level ALS modalities - contralateral loss beginning 1-2 segments below lesion (and below) Ablation of dorsal horn causes ipsilateral loss of incoming sensation via T6 nerve root + ipsilateral band of analgesia extending to T7-T8

Posturing in unilateral UMN lesions (supratentorial)

Lesion to motor cortex and underlying WM -contralateral inf. facial hemiparesis (usually not hypertonic) -contralateral spastic monoparesis Lesion to internal capsule -contralateral spastic hemiparesis/hemiplegia - LE extension and circumduction (brainstem UMN spared) - UE flexion at elbow and wrist -Spastic gait

Bilateral lesion above brainstem, centralized to thalamus, IC

Lesioned: corticospinal, corticoreticulars, corticobulbars UMNs below lesions are spared and disinhibited: rubrospinals (red nucleus), vestibulospinal (vestibular nucleus), reticulospinal (reticular formation) Present with decorticate rigidity (UE flexed, pronated; LE extension with plantar flexion, legs inward, and extended neck)

If descending lesion includes corticospinals + midbrain red nuclei (rubrospinal tracts)

Lesioned: corticospinals, corticoreticulars, corticobulbars, rubrospinals Spared and disinhibited: vestibulospinal (vestibular nucleus) and reticulospinals (reticular formation) Present with decerebrate rigidity with profound extensor one in the neck and all extremities

What causes the major dense and intraperiod lines?

Liken a SC ready to myelinate to a balloon made of a lipid bilayer. The outer leaflet is pink, reflecting its high lipid:protein composition available on the cell surface. The inner leaflet is blue, reflecting different proteins oriented toward the cytoplasmic face of the plasma membrane. To take a peak at the inner blue layer I've cut off the end of the SC/balloon and removed its nucleus. With the left end of the balloon turning inward around the axon as the distal most leading edge of SC membrane, it will encircle the axon and always remain the innermost SC turn of our formative myelin sheath. After all the turns are completed, the subsequent process of myelin compaction does to the SC what deflation does to the balloon. This is shown to the right as an unfurled SC. Extrusion of cytoplasm causes the blue inner leaflets of the balloon/Schwann cell collapse against each other (blue against blue). Peripheral membrane proteins on the cytoplasmic face of the membrane are stained dark by osmium tetroxide = major dense line As the balloon makes consecutive turns around the axon, the outer membrane leaflets of apposing turns of SC membrane also adhere to each other, forming the pink-on-pink intraperiod line as the sheath compacts.

Potency, Onset & Duration of local anesthetics action depends on ____

Lipid solubility L.A. Potency ∞ lipid solubility Onset of action ∞ lipid solubility (non-ionized form) Duration of action ∞ lipid solubility (less cleared by blood flow)

Pain and temp afferents ascends two segments in ______

Lissauer's tract

Pharmacology of Voltage-gated Na+ channels

Local Anesthetics -LIDOCAINE, LEVOBUPIVACAINE Antiarrhythmic drugs Class I - sodium channel blockers (Class IB has Lidocaine) -Local anesthetics have cardiotoxicity Antiepileptics -CARBAMAZEPINE, PHENYTOIN Neurotoxins -Tetrodotoxin, Conotoxin -Local anesthetics have neurotoxicity

Central sensitization ("wind-up") can be blocked by:

Local anesthetics (block NaV 1.8-1.9 channels) Opioids (block release of Substance P and glutamate) Inhibitors of NK1 and AMPA receptor

What directs proliferation, survival and differentiation of migratory neural crest

Local gradient of environmental cues (e.g NGF) Note: vagal/sacral NC -> enteric neurons, postganglionic parasympathetics; Truncal NC -> sympathoadrenal lineages)

Mechanoreceptor generator potentials

Local potential Proportional to simulus strength For some types, peak amplitude declines despite continued stimulus application (=adaptation)

Cuneatus fasciculus in thoracic sections

Located lateral to the Gracilis fasciculus

Cuneatus fasciculus in lower cervical sections

Located laterally to the Gracilis fasciculus Contains the ascending tracts from T1-5 more medially and the cervical ascending tracts from C7-C1 with the lower levels mapping more medially

Cuneatus fasciculus in upper cervical sections

Located laterally to the Gracilis fasciculus separated by the intermediate septum Contains the ascending tracts from T1-5 more medially and the cervical ascending tracts from C7-C1 with the lower levels mapping more medially

Gracilis fasciculus in upper cervical sections

Located most medially, medial to the dorsal horns Separated from the cuneatus fasciculus by the intermediate septum Arranged in the somatotopic mapping

Gracilis fasciculus in lower cervical sections

Located most medially, medial to the dorsal horns Arranged in the somatotopic mapping

Modulation of pain transmission

Locus Coeruleus (LC) releases NE on the interneuron in the dorsal horn activating α2 receptors on its cell body and thus blocking transmission. Note: LC also have self-inhibitory mechanisms via α2 Periaqueductal gray (PAG) interneurons project to the Raphe Magnus nucleus. Via the Raphespinal tract, this nucleus projects to an enkephalin interneuron. This interneuron then projects to the axon of the DRG neuron. Note: there are also interneurons that modulate the PAG interneuron and Raphe Magnus interneuron

Descending modulation of wind-up

Locus ceruleus in pons → ↑ NE in dorsal horn → inhibition of DHN (via α2) Nucleus Raphe Magnus in Medulla → ↑ 5-HT in dorsal horn -Via 5-HT3 (Ca2+ influx)→ Enkephalin Interneuron → Endogenous analgesia (physiological) -Via 5-HT2 (Gq)→ Facilitates "wind-up" of DHN under pathological conditions

First sign of local anesthetic neurotoxicity

Logorrhea (uncontrolled or incoherent talkativeness). Or total silence. The patient stops talking. Therefore, the OR rule rule of local anesthetics is to keep the patient talking

Cord transection

Long tracts that formerly traversed the lesioned area undergo anterograde Wallerian degeneration following a segmental lesion Ascending tracts degenerate (and demyelinate) above lesion level, which disrupts sensation from the segmental and infrasegmental cord. Descending tracts degenerate (and demyelinate) below lesion level, which disrupts motor function segmentally and infrasegmentally.

Webscope Peripheral nerve image

Look for perineurium, epineurium myelinating Schwann cells, myelin sheath, axoplasm.

Akinesthesia

Loss of conscious awareness of position sense

Myelinating Schwann cell EM

Low magnification EM of a SC and its myelinated axon. The electron dense turns of compact myelin are surrounded by the last turn of non-compacted membrane, which contains SC cytoplasm. This cross section through an internode happens to be in the plane of the SC nucleus (most are not). The red arrows indicate a layer of extracellular matrix (ECM) the SC deposits adjacent to its plasma membrane. This is critical to the success of axon regeneration in the PNS and is not made by oligodendrocytes in the CNS.

Examples of motor neuron disease

Lower motor neurons involvement (Spinal Muscular Atrophy) Upper motor neurons involvement (Primary Lateral Sclerosis) Lower motor neurons innervating the bulbar musculature involvement (Progressive Bulbar Palsy) Upper and lower motor neurons involvement (Amyotrophic Lateral Sclerosis / ALS)

"spinal level" in cord lesions

Lowest dermatome with intact sensation to pin-prick

Potency & Induction Speed of Inhalational Anesthetics

MAC (minimal alveolar concentration) makes 50% of patients unresponsive to incision. MAC is a measure of potency. Less MAC = More Potent High blood/gas partition coefficient = High solubility = Low partial pressure = Slower induction (High - High - Low - Slow) More Soluble = Slower Induction Faster induction requires frequent hitting of the protein target by an anesthetic molecule

PROPOFOL, FOSPROPOFOL - Most Common IV Anesthetic, Rapid Emergence

MOA: Agonist for GABAA receptor (promotes chloride entry) Used for maintenance and induction For short procedures, small boluses every 5 min are used For long term maintenance: 100 - 300 µg/kg per min infusion SE: -Elicits pain on injection (Rx: lidocaine) -Decreases cerebral O2 consumption, cerebral blood flow, intraocular pressure. -Hypotension -Respiratory depression

McDonald Criteria

MRI criteria for demonstration of dissemination in space ≥1 T2 lesion in at least 2 of 4 areas of the CNS -periventricular -juxtacortical -infratentorial -spinal cord MRI criteria for demonstration of dissemination in time -a new T2 and/or enhancing lesion(s) on follow up MRI, with reference to baseline scan, irrespective of the timing of the baseline MRI -Simultaneous presence of asymptomatic enhancing lesions along with non-enhancing lesions at any time (no baseline scan needed) Presence of Oligoclonal bands in CSF is supportive but not required for diagnosis -present with other inflammatory conditions, so not specific to MS -95% fo RRMS patients will demonstrate OCBs in CSF

Multiple sclerosis diagnostic workup

MRI is hallmark - dissemination in space Serologic testing to rule out mimics -ANA, RPR, ESR, HIV, ACE level, lyme titers just to start Lumbar puncture (more to exclude mimics than to "confirm" MS) -Elevated IgG index (CSF : serum) -Elevated myelin basic protein -Presence of >2 oligoclonal bands Evoked Potentials -Visual -Auditory -Somatosensory

Tay Sachs imaging

MRI would show thinned cortical ribbon and decreased white matter (T2 images would show areas of white where it should be black) Retina would show Cherry-red spots with white all around it caused by an accumulation of lipid in ganglion cells around the fovea

Multiple sclerosis imaging

MS can produce potentially unrelated neurological signs attributed random focal lesions (plaques) Plaques in most heavily myelinated tracts typically cause greatest deficits: -subcortical WM (cognitive decline) -dorsal columns (paresthesias, pain) -corticospinal, cerebellar WM (weakness, ataxia) -brainstem (disconjugate eyes; may be lethal) -optic nerve (scotomas, blindness) -CNS part of preganglionic autonomics (incontinence)

14yo female presents with several days of dysarthria and double vision Several months prior had experienced several days of numbness and mild weakness of the right arm and leg that then slowly resolved, and did not prompt evaluation Several months prior to that, had experienced trouble with balance that led to a fall where she broke some teeth requiring surgical repair -No PMH, no bad habits, family history of hypertension, ROS noncontributory On exam: -Vitals within -Mental status AAOx4, able to name/repeat/follow commands -CN: nystagmus on left lateral gaze, mild dysarthria, otherwise II-XII intact -Motor: Strength 5/5 throughout, tone mildly increased in right leg -Sensory: diminished to all modalities in right arm and leg -Reflexes: 2+ biceps and BR, 3+ patellar and achilles, toes downgoing, no clonus -Coord/Gait: Mild dysmetria with both FNF and HKS. Able to ambulate unassisted but gait is somewhat wide-based. Trouble with tandem. Rhomberg nl. Chem 7 nl, CBC nl C-reactive protein 5.5 (nl 0.2-0.9) CSF: -14 WBC, all lymphocytes; 0 RBC -Protein 76, glucose 48 -Cultures and gram stain neg

MS case

Polymyositis

Mainly seen in adults No skin involvement No perifascicular atrophy Multiple muscles involved (note: one muscle involved would just be chronic inflammatory myositis)

Basal ganglia disorders

Manifest as breakthrough of spontaneous, involuntary and inappropriate movements (dyskinesia) -athetosis -chorea -ballismus -dystonias and tics -hyperkinesia -resting tremor or slowed movements with decreased range of movement -akinesia -hypokinesia -bradykinesia -micrographia Motor component to thoughts can be affected -bradyphrenia

When are nerve biopsies useful?

May provide specific diagnosis in; -mononeuritis multiplex: Vasculitis Inflammation: CIDP, other -Hereditary neuropathies: HSMN-I (onion bulb formation/Hypertrophic schwann cell processes) -Infiltration: Amyloid, Sarcoid, Leprosy -Storage Disorder: Metachromatic leukodystrophy, Fabry's , Tangier D

Central Pontine Myelinolysis (CPM) imaging

May see trident sign, caused by hyperintensity at central pontine region with sparing of the corticospinal tracts May also see the piglet sign once it has progressed further

Flexor reflex

Mediates limb withdrawal from painful sitmulus Afferent simulus -cutaneous nociceptors -A-δ pain fibers (NOT Ia, II or Ib fibers) Response -limb withdrawal -multisegmental -Ipsilatearlly raise and flex leg -Ipsilateral extensors reciprocally inhibited

Some of those receptors that have the smallest field diameter include:

Merkel disk with a field diameter of about 0.5mm Note: these confer the greatest acuity

Types of symmetric myelopathies

Metabolic Infectious Neurodegenerative Vascular Congenital Traumatic

Peripheral polyneuropathy causes

Metabolic (diabetic, nutritional, uremia, endocrine Toxic (drugs, heavy metals, organic compounds..) Genetic (CMT, HSN, amyloidosis ...) Infectious (leprosy, HZ, HIV, diphtheria, lyme) Immune mediated (CIDP, GBS, MMN ...) Neoplastic or paraneoplastic (myeloma, lung cancer) Ischemic (vasculitic, Diabetes, vascular insufficiency Traumatic Critical illness neuropathy Cryptogenic or idiopathic (one third ±)

Multiple sclerosis acute treatment for relapses

Methylprednisolone 1000mg daily for 3-5 days Oral Steroids? (a lot of pills!) ACTH 80 units SQ daily for 5 days (used when can't tolerate steroids) IVIg Plasma Exchange

What accounts for the changing size of these funiculi across cord levels?

More dermatomes are represented at progressively higher cord levels. ALS and dorsal columns increase in width from sacral to cervical levels. Fewer myotomes require UMN control at progressively lower cord levels, so LCST gets smaller. UMN tracts diminish in size from cervical to sacral levels as the axons find their LMN targets.

For Cl- anions (-65 mV), an open GABAergic or glycinergic receptor allows Cl- influx and pushes the Vm _____

More negative, thus hyperpolarizing

Second pain

More pervasive, perceived as burning, throbbing, cramping, etc

Opioid analgesics

Morphine Hydromorphone Oxycodone Hydrocodone Fentanyl Sufentanil Remifentanil Meperidine Methadone Codeine Levorphanol

Opioid drug metabolism, principles of use

Morphine is converted to morphine-6-glucuronide (twice as potent as morphine) and morphine-3-glucuronide in liver. Due to first pass metabolism, morphine is 2 to 6-fold less potent orally than parenterally. Increase dose when switching patients from parenteral to oral. Individual response is variable: -Rx. Inj. Morphine sulfate 10 mg I.M. Q4h. - Standard dose effective in 2/3 patients. Use longer acting drugs when less frequent dosing required (METHADONE). For short, painful procedures - quick acting, fast-dissipating drugs (REMIFENTANIL)

radiculopathy

Most common cause is degenerative spine and disc disease Other causes ; Diabetic and inflammatory polyradiculopathy Symptoms are predominantly sensory and pain, motor deficit is less prominent Symptoms distribution follows dermatomes and myotomes More common in patients over age 50 years Diagnosis; clinical history, neurological exam, NCS/EMG and imaging (MRI, CT scan, Ct myelogram, plain X-ray) Treatment; conservative in most cases and surgical in selected cases.

Median Neuropathy (carpal tunnel syndrome)

Most common mononeuropathy Related to diabetes, obesity and rheumatoid arthritis Symptoms include tingling and/or numbness in fingers and hand sometimes an electric shock sensation, weakness and in advanced disease thenar compartment atrophy (abductor pollicis brevis muscle is innervated from the median nerve)

Diabetic neuropathy

Most common peripheral neuropathy , due to diabetes mellitus Symptoms include sensory loss, tingling, burning and sharp pain Symptoms include motor loss, loss of reflexes (ankle), loss of balance and coordination Decreased healing of ulcers and infections leading

Symmetrical Distal Sensory-Predominant Polyneuropathy

Most common type of neuropathy (nearly 50% of pts) Chronic, slowly progressive course, worse in poorly controlled diabetes Length dependent sensory disturbances dominate (Stocking-glove, midline of abdomen) Motor deficit is infrequent (mild distal weakness) Neuropathic pain in nearly one third of patients Autonomic disturbances are often encountered Pathogenesis is uncertain, probably metabolic and microvascular basis

Multiple Sclerosis

Most prevalent, chronically debilitating demyelinating disease of the CNS Most common autoimmune CNS disorder; 400,000 in US Mean age of onset is 32 Female:male incidence 2:1 globally ~0.1% chance of acquiring MS 85% of MS cases begin with a Clinically Isolated Syndrome No cure - can only modify course of disease Mean life expectancy 5-10 yrs less than normal, except for aggressive forms of the disease

Upper motor neurons originate from what two places?

Motor cortex -cortical spinal tract and corticobulbar tract (initiate complex fractionated voluntary movements of extremities and face) - corticoreticular fibers Brainstem (balance and postural maintenance that is reflexive, below level of consciousness and also invovled in voluntary movements of proximal limbs) -rubrospinal tract -tectospinal tract -reticulospinal tract -vestibulospinal tracts

Features of Charcot-Marie-Tooth Disease

Motor findings -Slowly progressive distal muscle weakness, legs before arms, manifest in first 2 decades of life -Problems tripping and eventually severe foot drop with steppage gait -Muscle atrophy leads to "stork legs" and inverted "champagne bottle" legs -Intrinsic foot/hand muscle weakness leads to pes cavis and claw hand -DTRs markedly diminished or absent, disappearing in ankles first then arms Sensory findings -Abnormalities most pronounced in the distal extremities with loss of vibration and position sense; Romberg sign is typical -Numbness is not a complaint, perhaps due to lack of sensory function to begin with (don't know what they're missing) -Pain and temperature is normal because this is carried through non-myelinated C-fibers -Nerve electrophysiological and pathological analysis show intermediate slowing of conduction and length-dependent axonal loss, with more prominent axonal degeneration than de/remyelination which supports the hypothesis that axonal abnormalities precede demyelination.

Cerebellar function

Movement error correction makes movement smooth and purposeful by coordinating stretch and tension of synergistic muscles Effects on truncal and axial musculature stabilize posture and gait Not a source of UMNs or LMNs

Acute Disseminated Encephalopmyelitis (ADEM) Histology

Multifocal white matter lesions on MRI Perivascular inflammation Perivascular, "sleeve-like" demyelination with reactive microglia

Multiple sclerosis epidemiology

Multiple Sclerosis (MS) affects approximately 350,000 individuals in the US and more than 1 million worldwide Predominantly females (2-3:1) Young to middle age onset: rare before 10 and after 50 With some exceptions there is greater incidence of MS at high latitudes Cause unknown -Theories of infection (EBV) and/or vitamin D deficiency have mounting evidence -Genetic component Incidence -1 per 100,000 in areas near the equator -6-14 per 100,000 southern US and southern Europe -30-80 per 100,000 northern US, Canada and northern Europe Heredity -15% of MS pts have an affected relative -Highest rate in siblings Genetic factor -There is thought to be a genetic factor in MS -Twin studies: as high as 35% in identical and 4% in fraternal twins -2-3 X higher in females than males

perineurium

Multiple layers of connective tissue that encases a group of axons Blood vessels and nerves are found in the perineurium, along with inflammatory cells

Perimysium

Multiple layers of connective tissue that encases a muscle fascicle Blood vessels and nerves are found in the perimysium, along with inflammatory cells

Mitochondiral myopathies (MM)

Multisystem disorder -Nervous system: Seizures, spasms, developmental delays, deafness, visual system defects, stroke, dementia -Skeletal muscle: muscle weakness, cramps, (myoglobinuria) -Pancreas: Diabetes -Heart: Cardiomyopathy -Liver: Hepatic steatosis, liver failure -Kidneys: Nephrotic syndrome, Fanconi's syndrome -Digestive tract: dysphagia, diarrhea, obstruction (decreased motility) Present in young adults and presents with muscle weakness Maternal inheritance Will see aggregates of abnormal mitochondria under the sarcolemma called "ragged red fibers" when stained with trichrome EM shows mitochondrial inclusions "parking lot Inclusions" (cristae line up in linear arrays)

Presentation of Charcot-Marie-Tooth Disease

Muscle atrophy -Arms, legs, hands and feet -Foot drop -High foot arch Decreased tendon reflex Later affect sensory Hypertrophic nerve may be felt or seen through skin Family history of similar disease

Reciprocal inhibition in stretch reflex

Muscle stretch evokes inhibition of LMN to antagonist muscle via glycinergic interneuron

Mitochondrial Encepalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)

Mutated genes located in mitochondrial DNA Most patients have stroke-like episodes before the age of 40, other symptoms begin in childhood Lactic acid accumulation causing GI symptoms including vomiting, abdominal pain, fatigue Additional symptoms include muscle weakness, difficulty breathing and seizures Note: imaging would show ischemia in multiple vascular territories (mitochondria cannot produce ATP but not really a vascular problem) Note: Histology shows red and dead neurons or even neuronophagia (microglia surrounding the dead neuron)

Congenital insensitivity to pain and temperature with anhydrosis (CIPA) (familial dysautonomia type IV)

Mutation of trkA leaving NGF unable to signal Clinical presentation -difficulty thermoregulating - prone to heat stroke -orthostatic hypotension -cutaneous scars from injuries and burns Dual Phenotype 1. Depletion of pain & temperature-sensing primary sensory neurons in DRG and trigeminal ganglion 2. Depletion of postganglionic sympathetic neurons

Plaque (gliotic scar)

Myelin and OCs are replaced with reactive astrocytes (Creuzfeldt cells), albumin and macrophages to form gliotic scar (plaque) Axons can be intact but axonal damage is more extensive than previously thought Creuzfeldt cells do not maintain BBB, which can be restored in shadow plaques

Galactocerebroside

Myelin glycolipid found exclusively in the myelin membrane oligodendrocyte plasma membrane

Myelin: Decrease CNS energy (ATP) demand

Myelin reduces membrane capacitance - electrostatic force unlike charge attraction across the acolemma is restricted to nodes Decreases Na+K+ ATPase requirement to restore Vm Reduces ATP demand

2 types of Schwann cells

Myelinating Non-myelinating

What is the final indicator of developed brains?

Myelination Myelination is incomplete for upper motor neuron tracts in cord, e.g. corticospinal, until years 2-3, contributing to gait instability and hyperactive plantar reflexes in toddlers Myelination continues in cerebral hemispheres through 2nd decade, when frontal lobe structures serving executive functions become the last to myelinate

Myelin: increase the length constant

Myelination increases rM (no ion channels at internodes) Also expanding axon diameter decreases rI

N-of-1 trial

N-of-1 trials are multiple crossover trials, usually randomized and often blinded, conducted in a single patient. W In ordinary practice, the clinician prescribes treatment and asks that the patient return for follow up. If at the follow up encounter the patient is improving, the treatment is continued. If no improvement is evident, alternative strategies such as a dose increase, switching to a different treatment, or augmenting with a second treatment are implemented This process continues until a satisfactory outcome has been achieved, until intolerable side effects occur, or until no further progress seems possible. In n-of-1 trials, the process is formalized with the aim of achieving balance in the assignment of treatments over time so that treatment effect estimates are unbiased by time-dependent confounders. Randomization of treatment periods is one way of achieving such balance.

Opioid Antagonists

NALOXONE 0.4 -1 mg I.M. or I.V. -Used in I.V. "Coma Cocktail" along with 100 mg Thiamine and 50% Dextrose 50 mL -1 mg I.V. blocks 25 mg of I.V. heroine. -Completely metabolized in liver, therefore only parenteral administration works. -Low dose (0.04 mg spares analgesia) for itching, nausea, vomiting with IV/epidural fentanyl anesthesia NALTREXONE - Oral drug -100 mg P.O. blocks 25 mg I.V. heroine for 48 hours Naltrexone XR I.M. Inj. Methylnaltrexone for constipation in late stage illness Alvimopan for post-op ileus after bowel resection

Nitrous oxide (N2O)

NMDA blocker "Laughing gas" - mild euphoria & recreational use Colorless, Odorless gas. Not flammable. Not Explosive. But supports combustion like O2. Insoluble in blood /tissues -> rapid equilibration -> rapid induction and rapid emergence. Second Gas Effect: Rapid uptake of N2O from alveolar gas → ↑ concentration of co-administered halogenated anesthetics → acceleration of induction. Diffusional Hypoxia: On discontinuation, rapid N2O release dilutes alveolar O2. To avoid hypoxia, 100% oxygen rather than air should be administered when N2O is discontinued. Note: Nitric oxide (NO) is not an anesthetic - it is a vasodilator

Xenon

NMDA blocker Rare gas, cannot be manufactured (yet) Must be extracted from air (very expensive) Inert gas but blocks NMDA Xenon is extremely insoluble in blood and other tissues, providing for rapid induction and emergence from anesthesia. Sufficiently potent to produce surgical anesthesia when administered with 30% oxygen Virtually ideal anesthetic gas

Hyperalgesia in Chronic Nociceptive and Neuropathic Pain: Central Sensitization

NMDA receptors, normally blocked by Mg2+, do not take part in normal pain transmission. Mg2+ block is removed by tissue injury/ inflammation NMDA receptor becomes active in "wind-up" → Ca2+-influx ↑ Ca2+→ ↑ PLA2 activity → ↑ PGE2 -↑ PGE2 → Opening of presynaptic Ca2+-channel → Substance P & Glutamate release -↑ PGE2 → Postsynaptic glycine receptor inactivation → Disinhibition of second order neuron Note: NMDA can be blocked by KETAMINE and DEXTROMETHORPHAN

Is Wallerian degeneration in the CNS follows by axonal regrowth?

NO Axons disintegrate and demyelinate distal to lesion; oligodendrocytes die/don't regenerate Axon retraction bulbs sprout growth cones but don't regenerate axons; no laminin Some types of neurons die - disconnected from target-derived trophic factors Lesions show reactive astrogliosis (hemhorragic stroke) or leptomeningeal cell invasion (cord injury); these cell types express surface chondroitin sulfate proteoglycans causing growth cone retraction

Are C fibers myelinated?

NO!

Does the Anterior spinal artery alone have perfusion pressure adequate for lumbar/sacral segments?

NO!

Are cells inherently good conductors of electrical current?

NO! Cell membranes are poor passive conductors of current. They do not permit conducting of current longitudinally along their extent, unlike copper wire

Do basal ganglia lesions show upper motor neuron signs?

NO! It is not a source of UMNs

Does upper motor neuron damage interrupt reflex arcs

NO! The final common pathway is still intact, but disinhibited Test LMN-muscle reaction to assess upstream UMN dysfunction

Are there synapses in sensory ganglia?

NO, axons of these neurons synapse first in the CNS

Are Endocannabinoids, e.g, anandamide neurotransmitters?

NO, but they modulate the action of neurotransmitters, e.g. DA, by acting on cannabinoid receptors to function as a sort of dimmer switch on NT actions.

Are autonomic nerves myelinated?

NO, they are instead ensheathed

What can accelerate B12-associated demyelination in vulnerable patients, e.g. elderly patient with already subacute levels of B12 asking for gas at the dentist's office

NO2! It oxidizes cobalt which will inactivate cobalamin (B12)

Quantal packaging and release

NTs are released in quanta 1 quantum = 1 vesicle of NT molecules; for Ach = ~10,000 molecules in the postsynaptic cell, 1 quantum of Ach evokes 1 MEPP (miniature endplate potential) 1 MEPP corresponds to the minute depolarization (+1 mV) attributable to Na+ influx through a single nAchR At the NMJ there is a low baseline level of spontaneous discharge of quanta from individual synaptic vesicles, but not enough to trigger an AP However, an AP traveling down motor neuron normally evokes discharge of thousands of Ach vesicles (quanta), or millions of Ach molecules Sufficient nAchRs open to raise Vm from resting potential (~90 mV) to threshold As such the endplate potential (EPP) is large enough to trigger an AP along the myocyte

Axons express voltage-gated ion channel for what 3 cations?

Na+, K+, Ca2+ The Na+ and K+ channels are expressed along the axon up to the terminal face (if myelinated will be expressed at at the nodes of Ranvier, if not myelinated along the entire axon). The Ca+2 channels are expressed only at the terminal face, where neurotransmitter is released

As a whole the membrane potential is a function of three conductances for these ion species

Na+, K+, and Cl- Goldman-Hodgkin-Katz equation considers the three Nernst potentials for Na, K and Cl to calculate resting potential (Vr) for the membrane Vm for a neuron is closest to Nernst potential of the ion to which it is most permeable. At rest this is K+ due to the ever-open K2P channels. The Nernst potential for K+ is -90 mV, not far from the neuronal Vr of -70mV.

______ sets up and restores Resting membrane potential in the wake of an action potential (AP)

Na+K+ ATPase The traveling AP traveling along the axon transiently opens channels allowing Na+ influx and channels enhancing K+ efflux. In the wake of an AP this temporarily reverses the charge balance across the membrane. Na+K+ ATPase will then restore it

Opioid antagonists

Naloxone Naltrexone Nalmefene Methylnaltrexone Almivopan

Which of the following agents via IV administration is used to reverse the NMJ blocking action of pancuronium, cisatracurium and mivacurium? A. Neostigmine B. Physostigmine C. Pyridostigmine D. Edrophonium E. Parathion

Neostigmine The other reversal agent is SUGAMMADEX that reverses steroidal NMJ blocker ROCURONIUM or VECURONIUM action

radiculopathies

Nerve root compressions caused by intervertebral disc herniations, cervical or lumbar, directed -Centrally -Posterolaterally -Far laterally Note: Root compression produces neuropathic pain shooting toward affected dermatomes (radiculopathic pain)

Barbiturate effects

Nervous System -↓ Cerebral blood flow and ↓ ICP -Anticonvulsant. Thiopental - treatment of status epilepticus Cardiovascular System -Hypotension. Due to venodilation and negative inotropic effect Respiratory System -Respiratory depression. Apnea at high doses. -No bronchospasm and safe for asthma patients Other Side Effects -Fatal attacks of porphyria in patients with acute porphyria and are contraindicated -I.V. anesthetics DO NOT trigger malignant hyperthermia (unlike inhalational anesthetics and succinylcholine)

Postganglionic parasympathetic ganglia within the Myenteric plexus histology

Nested between the longitudinal layer and inner circular layer of the muscularis externa of smooth muscle is a nerve plexus, the myenteric (Auerbach's) plexus (circled). Non-myelinated postganglionic nerve fibers and their somata are represented there. The plexus innervates the muscularis externa and produces peristaltic activity.

Oligodendrocytes (OCs) are derived from _______

Neuroectoderm

Neuronal somata of primary neurons features

Neuronal somata of primary sensory neurons are large, 50-70 µm in diameter, with a centrally positioned nucleus (N) containing a prominent nucleolus (NI). Neuronal somata show no detectable branching in the ganglia and are surrounded by a ring of small glia, termed satellite cells (Sat C) Note: Nerve fibers (A) are visible but not contiguous with soma and in general do not intersperse among neuronal soma

Toxicity of local anesthetics

Neurotoxicity - Seizures at lower toxic doses - Not related to Na+-channel block - ? Ca2+-, K+-channel, NMDA receptor block Cardiotoxicity -Cardiac arrest -Requires 3× higher dose than neurotoxicity Methemoglobinemia Allergy

EM of a myelinated axon in the longitudinal plane

Node of Ranvier (red arrows) exists at axolemma between the parallel red lines. Voltage-gated ionchannels and Na+K+-ATPase are expressed there Paranodal loops (green) stack progressively to the side (not on top) of each other with successive turns of myelin and define a paranodal region of the internode immediately adjacent to the Node.

Separating the longitudinally aligned internodes are ______

Nodes of Ranvier These sites are where voltage-gated ion channels exist along myelinated axons

Sensory ataxia

Non-coordinated movement due to aknesthesia

Inflammatory neuropathy/myopathy can be:

Noninfectious Infectious Systemic

Locus coeruleus (LC)

Noradrenergic neurons also contain the pigment, neuromelanin Cell bodies localize to tiny pontine locus coeruleus Project widely to cortex

Normal exception for extensor plantar response

Normal seen in infants up to 1+ years This is because the corticospinals do no myelinate effectively up at least 1 year of age

Hereditary neuropathy with liability to pressure palsies (HNPP)

Not CMT, but caused by a deletion mutation of PMP-22, resulting in transient numbness and weakness affecting the distribution of single nerve due to mild pressure -underdiagnosed

Halothane

Not used in the US Volatile, light-sensitive, not explosive. Not pungent. Used when catheter placement for IV induction is difficult Relatively high blood : gas partition coefficient = slow induction. CYP2E1 oxidation of halothane -> trifluoroacetic acid ->trifluoroacetylation of liver proteins -> autoimmune reaction to altered proteins -> FULMINANT HALOTHANE-INDUCED HEPATIC NECROSIS Side Effects: -Hypotension (due to myocardial depression and reduction in cardiac output) -↑ ICP (cerebral vasodilation)

Histology of Duchenne Muscular Dystrophy

Note: Beckers would likely look the same but the patient would be older Notice the fibrosis of the endomysium IHC for dystrophin would be absent

Histology showing lipofuschin granule accumulations in some of the postganglionic neurons

Note: H&E of sympathetic ganglion at lower contrast shows brown lipofuschin granule accumulations in some of the postganglionic neurons. Notice the interspersed nerve fibers, unlike the appearance of sensory ganglia

Muscle Fiber properties

Note: average muscle is about 50:50

Medial lemniscus in rostral medulla

Note: injury to the ML at this location is above the sensory decussation, so you would interrupt contralateral sensory information

medial lemniscus in mid-medulla

Note: injury to the ML at this location is above the sensory decussation, so you would interrupt contralateral sensory information

Medial lemniscus in pontomedullary junction

Note: injury to the ML at this location is above the sensory decussation, so you would interrupt contralateral sensory information Note: the lateral aperture can be seen here!

Cross section of peripheral nerve histology (H&E)

Note: might be able to identify a Schwann cell nuclei (this is characteristic of the PNS, as an oligodendrocyte would not be seen)

General anesthesia and EEG phases

Note: surgery is done during phases 2 and 3 of general anesthesia

Spinothalamic tract at lower cervical

Note: the ALS contains a somatotopic map with the arms being more dorsal and the sacral being more ventral Note: the ALS also lies within the anterior funicular (AF)

Spinothalamic tract at thalamus

Note: the VPL houses the 3rd order neurons for pain/temperature and 3 order DCML neurons

Pacinian corpuscle histology

Note: the lamellae are holding Na+ ions and pressure causes these ions to be released and reach the Na+ channels and promote depolarization

Multiple Sclerosis autopsy brain

Note: the lesions are often around the ventricles

Medial lemniscus in the rostral pons

Note: the somatotopic map has more of a horizontal orientation now with the upper extremities more medial and the lower extremities more lateral

Medial Lemniscus in caudal pons

Note: the somatotopic map has more of a horizontal orientation now with the upper extremities more medial and the lower extremities more lateral Note: the ML is right at the interface of the tegmentum and the basis pontis

Gracilis nucleus and Cuneatus nucleus within spinomedullary junction

Note: these house the cell bodies of the second order neurons

Peripheral nerve fiber types

Note: they are classified by their diameters and speed of conduction

Examples of amide link local anesthetics

Note: they have 2 I's in their names LIDOCAINE - Epidural, peripheral nerve block, intravenous regional, topical. Rapid onset, medium acting, low toxicity. Do not use for spinal. Transient neurologic symptoms. Potency 4. LEVOBUPIVACAINE - S(-) isomer of bupivacaine. Less cardiotoxic. Epidural for labor, spinal, infiltration, peripheral nerve block. Potency 16. BUPIVACAINE - Same as Levobupivacaine, but ↑ cardiotoxicity ROPIVACAINE - Less cardiotoxic. Epidural for labor. Surgical, postsurgical, and obstetric regional use. Effective in orthopedic surgery. Long acting. Potency 16. MEPIVACAINE PRILOCAINE - Nerve block (dental); Topical dermal use as EMLA Cream (Eutectic Mixture of Local Anesthetics) (Prilocaine + Lidocaine).

Example of ester link local anesthetics

Note: they have one I in their name PROCAINE - Infiltration, Nerve block, Spinal. POTENCY =1. Low toxicity. Short acting. No topical effect. Vasodilatation. Metabolic product is PABA that inhibits sulfonamides. TETRACAINE - Topical, Spinal (with 10% dextrose to increase specific gravity). More toxic, Potency = 16. BENZOCAINE - Topical use for hemorrhoids, toothache, teething. Adverse Effect: Methemoglobinemia COCAINE -Topical use only at 1-4% for upper respiratory tract and ENT surgery (nasal surgery). -Cocaine inhibits reuptake of catecholamines (NE locally, dopamine centrally

Mechanism of Allodynia in Neuropathic Pain

Note: this is tactile sensation that produces pain DRG crosstalk between neuroma and uninjured neurons Aβ (tactile sensor) sprouts into C fiber (nociceptor) laminae -Stimulation of Aβ is perceived as a painful stimulus

Wave forms reflecting current passage at any given spot along a stimulated neuron

Note: using outside of the cell as a reference, the inside of the cell reads negative when impaled with a recording electrode Note: When a potential is generated, Na+ flows into the neuron making it less negative than the rising state Note: local potentials are achieved in the dendrite and diminishes over time whereas action potentials are achieved along the axon and doesn't peter out over time

Cross section of peripheral nerve histology (Sudan Black)

Note: with this view, it is impossible to distinguish nodes of Ranvier

Gracilis nucleus and Cuneatus nucleus within caudal medulla

Note: you can see internal arcuate fibers crossing the midline and being ascending along the medial lemniscus Note: these ascend in a somatotopic fashion such that the lower extremity is more ventral

Upper motor neuron organization in cerebral peduncles

Occupy the middle third of the cerebral peduncles with a somatotopic organization (face is the most medial with the most lateral serving primarily the leg)

Golgi tendon organ mediate reflexes: reflex inhibition

Occurs in response to an abrupt increase in tension -leads to relaxation of the contracted muscle And the antagonist muscle is contracted

Spinal cord perfusion

Off each vertebral artery are little medial branches that fuse to form the anterior spinal artery. This supplies much of the anterior spinal cord with a perfusion pressure that drops about 2/3 of the way down. Therefore it needs collateral perfusion from the spinal medullary arteries that are coming off at various levels (e.g. lumbar artery, sacral artery, etc). This anterior perfusion supplies most of the anterior portion of the cord including ventral horns, some lateral upper motor neurons, spinothalamic tract, etc The posterior spinal artery arises mainly form the PICA and provides roughly about 1/3 of the cord including the dorsal columns and roots blood supply

Multiple sclerosis spinal cord level gross findings

On section, areas of well-demarcated discoloration seen in white matter (Most common in subpial and subependymal locations and at gray-white junction) Often present in the optic nerves (20% of cases) and at the lateral angles of the lateral ventricles but can be anywhere in the white matter Also found in the spinal cord white matter lesions

Nerve fiber = _______ + _______

One axon + its Schwann cell coating

Transverse lesion effects

One or more segments affected All ascending and descending long tracts passing through affected segment(s) are interrupted Lesioned horns destroyed segmentally Descending hypothalamic fibers destined for preganglionics are interrupted (white circles) > loose sympathetic tone>hypothermia due to excessive vasodilation can also loose bowel and bladder function

Anticonvulsants for Neuropathic Pain

Only 2 drugs approved by FDA for Rx of neuropathic pain (postherpetic neuralgia and diabetic neuropathy) -GABAPENTIN -PREGABALIN These: ~Prevents membrane insertion of α2𝛿 subunit of N-type Ca2+-Channel→↓ Glutamate release → ↓ Spontaneous firing ~↑GABA Release. ~ Effective in fibromyalgia ZICONOTIDE (synthetic conotoxin): -N-type VGCC blocker only for intrathecal administration

Merkel's afferents

Only epidermal Slowly adapting (poorly adapting Enriched at finger tips; 0.5 mm acuity 25% mechanosensory hand afferents Only receptors in epidermis Highest spatial resolution of receptors Can detect points, edges, curves, texture

Corticospinal tracts

Only ~50% cortical UMNs originate in 1° motor cx Remainder from PMA/SMA, and sensory areas 1, 2, 3, 5 and 7!! Pyramidal (Betz) cells project directly onto LMNs for digit movements; smaller UMNs project onto segmental interneurons 85% fibers in pyramids decussate -> lateral corticospinal tract (LCST) uncrossed fibers -> ventral corticospinal tract (VCST) LCST lesions disrupt fine digit movements

Symptoms of Multiple sclerosis

Onset may be dramatic or mild Symptoms, often presents with weakness, paresthesia, sensory loss, optic neuritis, diplopia, loss of vision, seizures, cognitive difficulties, Lhermitte's sign, urinary disturbance, scanning speech and vertigo

Peptide neurotransmitters

Opioid peptides -enkephalins -endorphins -dynorphins Peptides mediating nociception -Substance P -Calcitonin gene-related peptide Hypothalamic releasing factors -LHRH -TRH -GRH -CRH Pituitary peptides -Oxytocin -Vasopressin -ACTH Miscellaneous peptides -Neuropeptide Y -Angiotensin -Neurotensin -Cholecystokinin -Vasoinhibitory peptide

Respiratory depression by opioids

Opioids antagonize the effect of 5HT4A in Pre-Botzinger Complex -> decreases RR and tidal volume This causes: - respiratory center less sensitive to CO2 -sensitivity to O2 at carotid and aortic body gloms cells unaltered -oxygen inhalation may produce apnea in opioid toxicity

Neuromyelitis optica (Devics disease)

Optic neuritis (often bilateral) with cervical spine demyelinating lesions spanning 3 levels or more Poorly responsive to therapy -Not treated with interferons; not a variant of MS -IV steroids or plasmapheresis for acute attack(s) -Long term immunosuppressive therapy (cellcept, rituximab) Hallmark diagnostic test is serum NMO-IgG -Antibody to Aquaporin-4 water channel

Administration of Opioid Analgesics

Oral Rectal transmucosal: Morphine, hydromorphone, oxymorphone suppositories available Epidural - direct access to DRG neurons using very low doses Morphine, fentanyl, sufentanil, methadone Subarachnoid (spinal, or CSF - direct access to dorsal horn neurons and brain structures) Morphine, meperidine, fentanyl

Additional Routes of Administration of Opioid Analgesics

Oral transmucosal - Fentanyl dissolvable matrix Transdermal Patch- Fentanyl (200 µg) patch for cancer pain. After permeation, the drug forms a depot in stratum corneum. 12 h onset period. Iontophoresis - transport of soluble ions thru skin by using mild electric current. Has been used with morphine, fentanyl, and sufentanil. One-hour onset period. Inhalation - Using a nebulizer. Constant supervision needed because of variable dosing. Environmental contamination possible.

Medial vestibulospinal tract

Originate from the medial vestibular nucleus Bilateral projections Target cervical cord LMN pools Coordinates head position and neck movements, especially extension

Reticulospinal pathway

Originates in the brainstem reticular formation It is targeted by upstream corticoreticular fibers It descends bilaterally to LMN pools destined for axial and proximal musculature, and local circuit neurons within cord gray matter Reticulospinals respond to special sensory and somatosensory input with a postural change e.g. start reflex (loud noise causes a person to turn to that noise) May also synapse on gamma-motor neurons

Rubrospinal tract

Originates in the red nucleus It projects contralaterally to flexor LMNs for the upper extremity

Tectospinal tract

Originates in the tectum of them midbrain specifically in the superior colliculus It projects contralaterally Targets medial LMNs at cervical levels that are responsible for coordinating reflexes of the neck and eye movement

Superficial reflexes

Other signs of hyperreflexia, but not DTRs Graded as absent or present Motor responses to scraping of skin Abdominal -Above umbilicus (T8-T10) -Below umbilicus (T10-T12) Cremasteric (L1-L2) Bulbocavernosus (S2-S4) Anal wink (S2-S4) Plantar (Distal LE UMNs) For plantar response -Polysynaptic-signal must reach cord, ascend to brain, and descend via UMNs -Although abolished by severe LMN or afferent damage, superficial reflexes typically test the brain-cord pathway

Descending analgesic pathways: Serotonergic mechanism

PAG Glu neurons co-activate descending 5-HT neurons in the nucleus raphe Magnus (NRM) in the medulla 5-HT neurons then excite enkephalinergic interneurons in the dorsal horn which inhibit secondary pain projection neurons Note: these enkephalinergic are within the substantia gelatinosa

µ receptor locations

PAG interneuron Raphe Magnus interneuron DRG axons

Descending analgesic pathways: Descending noradrenergic mechanism

PAG neurons excite locus ceruleus (dark in color) NE projections descend to dorsal horn and pre-synaptically inhibit primary pain afferents via NE which gates K+ efflux through presynaptic α2 receptors and hyperpolarizes pain afferent terminals, thereby blocking Ca2+ influx-mediated Glu release

Where are the 3 CNS sites where opioid peptides and opiate drugs mediate pain?

PAG, dorsal horn, and limbic controllers

Mechanism of basal ganglia function

PMA/SMA informs basal ganglia of impending volitional movement Basal ganglia signals motor thalamic nuclei to activate specific UMNs in the primary motor cortex to being, scale, and stop execution of desired movement as intended

Primary sensory neurons located in DRG and cranial nerve ganglia convey sensory information from _____

PNS into the CNS Note: Initially these neurons are bipolar. During development, a short segment of axon proximal to the soma fuses with a short segment of axon directing information from the PNS toward the cell body, to form the adult "pseudounipolar" morphology

Studies for various clinical questions

PREVALENCE: Cross sectional studies DIAGNOSIS: Cross-sectional studies THERAPY - EFFICACY OR HARM: Clinical trials (When it comes to treatment harms, post marketing surveillance follow-up (Cohort) studies are also very important. Although they provide the third best type of information, they are usually the first to uncover serious side-effects of drugs.) PROGNOSIS: Cohort studies which follow patients longitudinally SCREENING: Clinical trials Note: However, other observational study designs can also provide information, only it will be not the best or second best (it will be levels 3 & 4 in the evidence hierarchy) - including case-control studies, case series and even case reports.

Some of those receptors that have the largest field diameter include:

Pacinian corpuscle with a field diameter of 10+ mm Note: these are less sensitive but much larger

Modalities transmitted by anterolateral system

Pain (test by pin prick) Temperature Crude touch (itch, tickle, sexual sensation)

What happens without functional trkA?

Pain and temperature neurons dependent on NGF signaling for survival in development disappear from sensory ganglia Postganglionic sympathetics also die out and never innervate sweat glands Note: Functionally distinct primary afferent neurons require different neurotrophins develomentally for survival, they get them from different sources, and express the appropriate receptors

Neuropathic pain: Secondary projection neuron

Pain is perceived in dermatomes below lesion level of the cord (e.g. MS)

Modes of Control of Infusion Analgesia

Patient-Controlled Analgesia (PCA) : Management of breakthrough pain. Patient has limited control of dosing from infusion pump within tightly mandated parameters (demand dose, lockout dose and interval). Short acting drugs are used. Addiction does not develop. Preferred over I.M. injections. Computer-Assisted Continuous Infusion (CACI) - needs continuous measurement of plasma opioid levels with indwelling sensors.

Multiple Sclerosis demographics

Peak age of onset is 20-40 years Most common chronic CNS disease of young people Male:Female ratio ranges from 1.4-3.1 Geographic differences, More common in regions away from the equator Genetics 15-20 fold increased risk in 1st degree relatives, HLA association

Types of neurotransmitters

Peptide NTs Small molecule NTs

Staining of the subset of primary sensory neurons converting pain and temperature

Peptide neurotransmitters mark the entirety of specific producer neurons E.g., Antibodies to the NT's, Substance P (SP) and Calcitonin Gene-related Peptide (CGRP), specifically label a subset of primary sensory afferent neuron cell bodies carrying pain and temperature information. Patients with Congenital Insensitivity to Pain and Temperature (CIPA) lack SP+/CGRP+ neurons otherwise visualized by immunostaining DRG/cranial nerve ganglia

First pain

Perceived as stabbing, pricking

Posterior limb of the internal capsule

Perfused by the anterior choroidal artery and lateral lenticulostriates Carries the ascending axons projecting from the VPL There is somatotopic mapping here as well with the arms being closer to the genu and the lumbar fibers being the furtherest away

Subacute combined degeneration lesion

Peripheral neuropathy plus: -Bilateral demyelination of DCs and LCST/VCST -± cognitive dysfunction if subcortical WM affected -Visual impairment

Two general mechanisms that explain heightened sensations of pain after injury

Peripheral sensitization -occurs at the sensory nerve endings -synergistic potentiation of repose to noxious stimuli Central sensitization -occurs in the dorsal horn of the spinal cord and high CNS relays -Increased excitability of spinothalamic projection neurons

EM of myelin sheaths from oligodendrocytes within optic nerve

Points to remember: OC cell bodies/nuclei are never found in the outer loop of membrane they make. All of these myelinated axons could belong to a single OC, which is not possible to determine. Therefore the outer loop of OC wrapping is typically compact. OCs make no basal lamina, no extracellular matrix. Blue arrow: axolemma Red arrow: inner loop of non-compacted OC membrane

Acute Disseminated Encephalopmyelitis (ADEM)

Poorly understood--autoimmune? Neurological symptoms often preceded (days to weeks) by a viral syndrome Most fatal cases preceded by measles infection 80% occur in childhood (<10 yrs), rare in adults, often in winter and spring Fever, headache, meningeal signs followed by sudden onset of seizures, decreased consciousness, paraplegia, cranial nerves signs 5% could be associated with vaccination Confused with MS presentation Usually monophasic with mortality rate of 20-30%, but recurrent or progressive cases documented

Kinesthesia

Position sense

Lehrmitte's sign

Positive sign Sensation of electrical shock up the cord (often seen in MS and tabes)

Paresthesias

Positive sign Sensation of tingling, burning, prickling, numbness, "pins and needles", "falling asleep"

Neuropathic pain syndrome: Herpes zoster (shingles)

Post-herpetic neuralgia is a big problem as the damaged afferents regenerate; allodynia

Spinal cord partitions

Posterior funiculus Lateral funiculus Anterior funiculus

Functional advantage of the size principle sequence

Postural adjustments in axial musculature (reticulospinals/vestibulospinals) preceded appendicular movements requiring limb flexors/extensors Note: order of action is S -> FFR -> FF

A cortical lesion of the DCML pathway

Presents with intact sensation but with abnormal perception "cortical sensory loss" Contralateral sensory agnosia -astereognosis (can't sense shape) -agraphesthesia (can't interpret what someone writes on their hand)

Signal propagation with myelination

Prevents current leak which allows the speed of conduction to be quick but also the amplitude to remain sufficient enough to reach threshold downstream

Spinomesencephalic tract pathway

Primary neuron (DRG) consists mainly of A-delta fibers enters the dorsal horn. It will will ascend a few cord levels up though the Lissauer's tract before synapsing with the secondary neuron within the dorsal horn The secondary neuron (dorsal horn projection neuron) will cross through the anterior white commissure of the spinal cord and ascend through the contralateral ALS. From the ALS there are collateral branches within the midbrain where it projects to the periaqueductal gray where it regulates the activity of small PAG interneurons

Spinoreticular pathway

Primary neuron (DRG) consists mainly of C fibers enters the dorsal horn. It will will ascend a few cord levels up though the Lissauer's tract before synapsing with the secondary neuron within the dorsal horn The secondary neuron (dorsal horn projection neuron) will cross through the anterior white commissure of the spinal cord and ascend through the contralateral ALS. From the ALS there are collateral branches within the medulla and pons where it synapses with the 3rd neuron (reticular formation) From the reticular formation, 3rd order neurons ascending up to the thalamus where it projects to the intralaminar nuclei The thalamic neuron then projects through the anterior limb of the internal capsule to the frontal lobe and limbic system Note: the affective element of pain utilizes this pathway

Spinothalamic tract pathway

Primary neuron (DRG) consists of C fibers or A-delta fibers and enters the dorsal horn. It will will ascend a few cord levels up though the Lissauer's tract before synapsing with the secondary neuron within the dorsal horn (Lamina I and IV ) The secondary neuron (dorsal horn projection neuron) will cross through the anterior white commissure of the spinal cord and ascend through the contralateral ALS Will will ascend to the thalamus where it synapses with the 3rd neuron (VPL) The VPL will then project through the posterior limb of the internal capsule to the 4th layer of the primary somatosensory cortex

Lissauer's tract

Primary pain fibers ascend a few levels in this tract before synapsing in dorsal horn of the spinal cord Located just below the Pia mater

Praxis

Process by which a learned motor skill is embodied and enacted "practice makes praxis"

Bystander effect

Process by which uninjured tissue diffuses to uninjured tissue activating nociceptors

CNS noradrenergic neurons

Produced in one place in the CNS: the Nucleus ceruleus of the rostral pons They diffusely project throughout the CNS

Thalamocortical fibers

Project from the thalamus VPL to layer IV of the postcentral gyrus at their appropriate level of the homunculus

Somatosensory association cortex (area 5/7)

Projection target of layer IV neurons in S1 = superior parietal lobule- perception here Tactile association cortex (area 5) Visual association cortex (area 7)

Somatosensory afferent fibers

Proprioceptive and mechanoreceptive class heavily myelinated Excitatory - glutamatergic Neurons (DRG & cranial nerve ganglia) are pseudounipolar Conduction of electrical activity bypasses cell body Primary afferent properties are rate-limiting to sensory perception

ProOpioMelanoCortin (POMC) Gene Products

Proteolytic processing of praopiomelanocortin (POMC). After removal of the signal peptide from pre-POMC, the remaining propeptide undergoes endoproteolysis by prohormone convertases 1 and 2 (PC1 and PC2) at dibasic residues. PC1 liberates the bioactive peptides adrenocorticotropic hormone (ACTH), β-endorphin, and γ-lipotrophic hormone (γ-LPH). PC2 cleaves ACTH into corticotrophin-like intermediate lobe peptide (CLIP) and α-melanocyte stimulating hormone (α-MSH) and also releases γ-MSH from the N-terminal portion of the propeptide. The joining peptide (JP) is the region between ACTH and γ-MSH. β-MSH is formed by cleavage of γ-LPH. Some of the resulting peptides are amidated or acetylated before they become fully active.

Adamkiewicz artery

Provides collateral to the ASA originating only from one side around T10-T12 This may occasionally become occluded as a result of graft and surgical management of inferior aortic aneurysm. Must be conscious not to clamp aorta above the level of this artery to prevent cord ischemia

Crossed extension reflex

Provides postural support during limb withdrawal in flexor reflex Interneurons crossing midline (anterior gray commissure) drive extension of the non-stimulated contralateral leg by: -stimulating inhibitory interneurons that hyper polarize flexor LMNs -stimulating excitatory interneurons that depolarize extensor LMNs

Treatment of Acute MSK Pain Superimposed on Neuropathic Pain

Pulse therapy (1-2 week) with corticosteroids (PREDNISONE) or NSAIDs (e.g., ASPIRIN) Chronic therapy with corticosteroids/ NSAIDs ineffective in neuropathic pain Topical NSAIDs (e.g., DICLOFENAC) for rheumatoid pain

Common peripheral neuropathies distribution and common causes

Radiculopathy; Degenerative, inflammatory, diabetic, trauma, neoplastic Plexopathy; Trauma, post infectious, birth injury, hereditary, neoplastic, Mononeuropathy; Trauma, entrapment, infiltration, infectious, vascular, compressive radiculopathy Multiple Mononeuropathy; Vascular, infiltration, infectious, post infectious, entrapment, hereditary, immune-mediated. Polyneuropathy; Generalized, symmetrical usually distal in distribution (stocking-glove), due to a systemic disorder (metabolic, toxic, nutritional, inherited, immune related, infectious, post infectious, paraproteinaemic or paraneoplastic.

Leukodystrophy

Rare genetic diseases that cause an abnormal development and/or progressive loss of central nervous system white matter and storage Autosomal recessive Symptoms and outcome depends on type of disorder

Progressive Multifocal Leukoencephalopathy (PML)

Rare multifocal inflammatory white matter disease (often just under the gray matter) Viral etiology inferred from the presence of inclusion bodies Caused by the reactivation of JC virus, a papovavirus, a common asymptomatic viral infection Largely seen in immunocompromised patients Variable signs and symptoms due to multifocal lesions -blindness, hemiparesis, cognitive decline, brainstem signs Usually little mass effect

Metabotropic receptors

Receptors that are associated with signal proteins and G proteins Note: these are slower than inotropic receptors Ex: those neurons involved with some autonomic functions

General anesthetics: Ion channel modulation

Reconciliation with lipid theory: -Alteration in lateral pressure alters ionotropic receptor conformation Direct binding to ionotropic (GABAA, iGlu, Glycine) receptors -ETOMIDATE and PROPOFOL produce: ~Sedation by binding to β2 on GABAA receptors ~Analgesia by binding to β3 subunit on GABAA receptors. -Barbiturates, benzodiazepines, propofol, and volatile anesthetics act as GABAA agonists -Barbiturates block Kainate & AMPA but not NMDA type of glutamatergic receptors -KETAMINE, NITROUS OXIDE, CYCLOPROPANE, XENON block NMDA -Glycine, N-cholinergic (both NM and NN) and 5-HT3 are also modulated Voltage-Gated Channel Modulation -Volatile anesthetics block VGCCs (L, T, N, P, Q type) -Background (leak) K+ channels (TREK/TASK/TRESK) activated by volatile and gaseous agents -Hyperpolarization-activated CNG channel (HCN) blocked by KETAMINE & PROPOFOL

Summation

Refers to the net effect of all EPSPs + IPSPs at the initial segment of a neuron(site where v-Na+channels are initially expressed), to potentially trigger an AP if threshold depolarization is reached.

Conus medullaris syndrome vs cauda equina syndrome

Reflexes CM: Ankle jerks affected but knee jerks spared CE: Ankle and knee jerks can be reduced or absent Radicular pain CM: Less severe CE: More severe •sciatica Motor strength CM: Typically symmetric hyperreflexic paresis of distal LE (ankle jerks) if isolated injury to S1 CE: Only LMN Sx; asymmetric hyporeflexia/areflexia to LE Sensory Sx and symptoms CM: Numbness localized to perianal area; symmetric and bilateral CE: Numbness/paresthesias more localized to saddle, asymmetric or lateral involving specific dermatomes Impotence CM: More severe and acute CE: Less severe and later Sphincter dysfunction CM: Urinary retention > overfill incontinence/atonic anal sphincter - early CE: Urinary retention later

3 types of multiple sclerosis

Relapsing-remitting with secondary progressive (70%) Benign relapsing remitting (10%) Primary progressive (20%)

Astrocytes and microglia as potentiators of Wind-up

Release mediators of sensitization (e.g., cytokines) Propagate mediators via gap junctions Populate sensory ganglia in chronic and neuropathic pain Glial fibrillary acidic protein as marker Fluorocitrate (astrocyte cytokine production blocker) - inhibits hyperalgesia MINOCYCLINE (microglia cytokine production blocker) - inhibits hyperalgesia

Side effects of N2O

Replaces N2 in cavities faster than N2 can escape -> cavity expansion (contraindicated in pneumothorax, obstructed middle ear, air embolus, obstructed loop of bowel, intraocular air bubble, pulmonary bulla, and intracranial air). Negative inotropic effect on heart is cancelled by sympathomimetic effect Modest increase in respiratory rate Does not affect muscle tone or muscle relaxants Oxidizes cobalt atom in Vitamin B12 → inhibits Vitamin B12-dependent enzymes methionine synthetase (myelin formation) and thymidylate synthetase (DNA synthesis) -Prolonged exposure → bone marrow depression (Megaloblastic anemia) and peripheral neuropathies -Subacute Combined Degeneration

substantia gelatinosa

Represents enkephalingeic interneurons which mediate the degree of pain sensation by dampening the inputs

Ouabain

Resembles digitoxin but poisons rather than enhances the activity of Na+K+ ATPase. Loss of of ATPase function causes depolarization of all excitable cells leading to a loss of all muscle and neural signaling

P2X receptor (purinergic receptor) on nociceptors

Responds to elevated levels of released ATP

Lower motor neuron signs

Results of muscle wholly or partly disconnected from the "final common pathway" Examination shows: -weakness (power <5/5) (paresis or plegia more precise than paralysis) -hypotonia (flaccidity) - fasciculations (twitches) - significant atrophy (>70% muscle mass) - Hyporeflexia (<+2) Note: cranial LMN damage produces similar signs to facial muscles

Optic nerves have myelin but their cell bodies are in the _____

Retina

Cannabinoids are ____ messengers

Retrograde 2-arachidonylglycerol and anandamide are endogenous retrograde messengers Released at the postsynaptic membrane Bind to CB1-receptors on the presynaptic membrane and inhibit the presynaptic neuron (block the release of Substance P or Glu)

Surgical intervention for neuropathic pain syndromes

Rhizotomy - chemical or surgical ablation of nerve root ALS tractotomy Stereotaxic ablation of thalamic nuclei

Cortical connections within somatosensory cortex

SI areas project to SII (secondary somatosensory cx) located in the parietal operculum overlying the lateral sulcus just posterior to SI SII integrates the sensory experience and projects it to limbic structures (hippocampus and amygdala) that establish tactile learning and memory SI neurons also project to somatosensory association cx (area 5), where tactile and proprioceptive information are also integrated Area 5 in turn projects to area 7, where somatosensory info integrates with visuospatial info coming in from the occipital lobe Area 5/7 project to motor cx in frontal lobe such that sensory Input guides voluntary movement

Vesicles containing fast-acting neurotransmitter anchor to the presynaptic membrane via

SNARE proteins

Glutamate

SYNTHESIS -doesn't cross BBB -synthesized in CNS from glutamine -via mitochondrial glutaminase (rate-limiting) STORAGE -loaded into synaptic vesicles by glutamate transporter (VGLUT) GLUTAMATE RECEPTORS -ionotropic subtypes: AMPA, Kainate, NMDA -metabotropic form (many variants) TERMINATION -reuptake into perisynaptic astrocytes (EATT) -astrocytes convert GLU to glutamine FUNCTION -most important and predominant excitatory CNS NT, ~95% of CNS neurons use GLU TOXIC extracellular levels achieved in seizure and stroke

Acetylcholine

SYNTHESIS -esterification of acetyl COA + choline in terminal -via choline acetyltransferase (CAT) (rate-limiting) -Ach-producing neurons in CNS localize to the basal forebrain and midbrain STORAGE -loaded into small round clear synaptic vesicles via ACh transporter ACh RECEPTORS -nicotinic (bind nicotine; nAchR) ~ionotropic, fast -neuronal type: α-bungarotoxin-insensitive ~sk. muscle type: α-bungarotoxin-sensitive -muscarinic (bind muscarine; mAchR) ~metabotropic, slow ~smooth and cardiac muscle; secretory cells ~some CNS synapses TERMINATION -hydrolyzed by acetylcholinesterase (AChE) -AchE is inactivated by nerve gases and some pesticides

GABA

SYNTHESIS -glutamate decarboxylase (GAD) decarboxylates glutamate to GABA (rate-limiting) -GAD requires pyridoxal phosphate (vit. B6) co-factor -B6 deficiency, like GAD mutations, decreases [GABA], increasing the likelihood of seizure TRANSPORT -loaded via vesicular inhibitory AA transporter (VIATT) RECEPTORS three types -GABAA and GABAC are ionotropic and inhibitory; activation causes Cl- influx and hyperpolarization -GABAB (metabotropic); also inhibitory, but open K+ channels, allowing K+ efflux (also hyperpolarizing) REMOVAL -high-affinity GABA transporters uptake GABA into perisynaptic astrocytes

Glycine

SYNTHESIS -from serine via mitochondrial serine transhydroxymethylase RECEPTORS -ionotropic, Cl- channels -pentameric, resemble GABAA receptors -Inhibitory, like GABA (antagonized by strychnine) TERMINATION -astroglial re-uptake LOCALIZATION -synapses restricted mainly to cord

Postganglionic parasympathetic ganglia within the Submucosal plexus histology

Scattered within the vascularized, dense irregular connective tissue of the submucosa are islands of postganglionic nerve fibers and their somata (arrow). They make up the submucosal (Meissner's) plexus and innervate submucosal glands contributing to intestinal secretions.

Why is PNS axon regeneration possible?

Schwann cells promote axon sprouting because they are coated with laminin, unlike oligodendrocytes

What is the myelinating cell of the rootlets?

Schwann cells! Note: this might seem weird since they are still within the dural compartment

Monitoring the depth of anesthesia

Sedation: -Diminished cognition (cortical activity): Low-dose hypnotic or sedative -Brainstem function (respiratory & cardiovascular functions) intact Anesthesia Induction: -Higher dose hypnotic or other GA drugs -GABAA agonism in inhibitory interneurons and NMDA-receptor antagonism in cortex, thalamus, striatum, and brain stem -Paradoxical excitation may occur -Apnea, Loss of oculocephalic, corneal reflexes -Pupillary light reflex remains -Increase in HR -Anesthesia Phase 2-3 Maintenance: Hypnotic agents, inhalational agents, opioids, muscle relaxants, sedatives, and cardiovascular drugs plus ventilatory and thermoregulatory support -Pupillary light reflex remains -With inadequate anesthesia: Increase in HR and BP and Perspiration, lacrimation, movement Anesthesia Phase 4: -EEG flat (isoelectric) - brain death -Loss of pupillary light reflex -May be purposely induced by the administration of a barbiturate or propofol to protect the brain during neurosurgery or to stop generalized seizures

Other effects of opioids

Sedation: Drowsiness (hence the name - somniferum) ↓ Cough reflex: Suppression of cough center in medulla → aspiration pneumonia. Miosis: Stimulation of Edinger-Westphal nucleus of CN III →"PIN-POINT" pupils. No tolerance develops to this effect. Truncal rigidity: Supraspinal effect→↑ trunk muscle tone → ↓ Thoracic compliance →↓ Ventilation (seen with Fentanyls). Nausea and vomiting: Direct stimulation of chemoreceptor trigger zone. Vestibular component may be involved because ambulation increases nausea IgE-independent Mast Cell degranulation: release of histamine, heparin, tryptase, and eosinophil chemotactic factors. Euphoria: Decreased anxiety and pleasant floating sensation. KOR effects are opposite. Convulsion: Due to inhibition of GABA release in interneurons. Endocrine: -↓ LH, FSH -↑ Prolactin, ADH -↓ libido, sperm motility, and ejaculate volume -Anovulation, amenorrhea. GI: -Constipation (historical use of opium poppy for diarrhea) -Spasm of Sphincter of Oddi CVS: Decreases preload, inotropy, and chronotropy and thus reduces oxygen consumption of myocardium. Morphine is used in angina pectoris and acute myocardial infarction.

Anterior cord syndrome

Seen in flexion injuries e.g. burst fracture, flexion tear drop fracture, and herniated disk Presents with immediate paralysis, because the corticospinal tracts are located in the anterior aspect of the spinal cord Ex: ASA infarction, Artery of Adamkiewicz infarction Note: bilateral lesion

Motor neuron disease variants (e.g. ALS)

Seen mostly in middle age men, usually with no other significant neurologic history dx: must have both UMN and LMN signs not attributed to other disorders and exhibit no sensory deficits

Clark nucleus

Seen within thoracic sections and houses the 2nd order neurons of the dorsal spinocerebellar tract Note: the dorsal spinocerebellar tract in this section as well

Major issues with cohort studies

Selection bias from loss to follow up Selection bias from healthy volunteer effect When prospective, usually requires long periods of follow up Strengths: When prospective, it can substantiate a temporal relationship between exposure and outcome Note: the measure of association is Relative Risk (RR)

Major issues of case-control study

Selection of appropriate comparison group Observation bias if study personnel not blinded to case or control status of participants Non-response, particularly from exposed cases or from non-exposed controls Retrospective nature Note: Odds ratio (OR) is the measure of association

Acute Disseminated Encephalomyelitis

Self limiting disease, managed supportively Usually follows viral illness or less commonly vaccine (molecular mimicry) Scattered areas of demyelination widely distributed throughout brain and spinal cord More common in childhood than MS Seizures/AMS more common at presentation than with MS Improves over weeks to months CSF nonspecific elevated WBC count and protein; negative OCB

Duration of sensory stimuli

Sensation as a function of a sustained stimulus diminishes for some receptors -> adaptation

Placebo effect

Sensory cx sees, smells, tastes or feels stimulus that looks like a dosage form Association cortices relay information to brain's Reward Center = Nucleus Accumbens NA relays info to the PAG to elevate the descending analgesic pathway activity

Peripheral neuropathies manifestations

Sensory loss or disturbances Weakness and muscle atrophy Tendon reflex loss and reduced muscle tone Trophic changes Autonomic dysfunction

Local anesthetics interfere with what general steps of pain perception

Signal conduction Note: can have effects in other places depending on the site of injection

NSAIDS interfere with what general steps of pain perception

Signal generation

4 general steps of pain perception

Signal generation Signal conduction Synaptic transmission Conscious perception

Testing for hyperalgesia and allodynia in neuropathic pain

Simply touch the patient and pin-prick the patient -should elicit little to no pain In allodnynia and hyperalgesia, there will be increased pain with these actions

Active zone

Site of neurotransmitter release Note: located near the voltage-gated Ca2+ channels

The Hierarchy of Evidence Pyramid

Situates studies from bottom to top according to the quality of evidence they provide (highest quality on top) It is based on the intrinsic methodology of each study and the resulting capacity to minimize bias.

The Levels of Evidence Table

Situates studies from left to right based on how well they perform in answering specific clinical questions, e.g.; diagnosis, therapy, prognosis, etc.

Stretch reflex

Skeletal muscle responds to stretch due to work load by contraction (works to maintain constant muscle length) Circuitry is the simplest: monosynaptic = myotatic Example: Deep tendon reflex (DTR)

Types of loss of consciousness

Sleep (physiological) Coma (pathological) Brain death (pathological)

Chordoma

Slow-growing, low grade, but invasive primary bone tumor located from the skull base to sacrum believed to arise from notocordal remnants Note: Fate of the notochord is the nucleus pulposus of the intervertebral disc H&E shows soap-bubble pattern

Ruffini afferents

Slowly adapting Oriented parallel to skin Sensitive to stretch 20% hand mechanoreceptors Involved in finger position; hand conformation

What provides the highest fidelity representation of fine touch?

Slowly adapting Merkel's discs

Aδ fibers

Small and thinly myelinated Subtype that is stimulated by intense mechanical/chemical or thermal stimuli Transmit fast- early, sharp perception of well-localized painful stimuli Do NOT evoke an affective component

Central cord deficit continuum

Small lesion possible in syringomyelia -Shawl-like distribution of ALS sensory loss -Suspended bilateral sensory deficit -If lesion expands, sacral sensation spared the longest Large-to-complete injury lesions: -LMNs signs segmentally -UMN signs infrasegmentally -DCML signs at and below lesion -ALS signs below lesion; sacral sparing possible

Microscopic identification of Synaptic vesicles containing small molecule NTs and those containing peptides neuropeptides

Small molecule transmitters vesicle = 40-60 nm a. Excitatory: Glu, Asp or Ach (round, clear) b. Inhibitory: Gly, GABA (ellipsoidal, clear) c. ±: Catechols/Indoles DA, NE, Epi/5-HT (round, not clear - medium density) Neuropeptides vesicle = 100~250 nm very dense cores POTENCY -small molecule transmitters ~ [µM] -neuropeptides ~ [pM-nM]

Potency of small molecule neurotransmitters vs neuropeptides

Small molecule transmitters ~ [µM] Neuropeptides ~ [pM-nM]

What are the 2 sites for neuronal replacement in the CNS?

Small niches of neural stem cells and committed neuronal Progenitor cells are all that remain in the adult brain; otherwise, neurons are post-mitotic These are found in the lateral wall of the lateral ventricle and the hippocampus The LV cells are of unclear significance Hippocampal progenitor cells produce new neurons daily and are important to learning/memory

C fibers

Smaller and unmyleinated Subtype collectively polymodal Transmit more slowly- perception of a duller, long lasting pain Evoke affective response

Cellular basis for the size principle

Smallest LMN cell bodies are easier to depolarize than larger ones so they reach threshold sooner

As the strength of synaptic signaling in the ventral horn increases, LMNs are recruited in what fixed order?

Smallest motor units (S fibers) with the lowest threshold activate first Increased signaling leads to recruitment of the FFR fibers and then ultimately recruits the largest units (FF fibers) which have the highest threshold for stimulation Ex: S fibers: postural maintenance FR fibers are added: walking FF fibers are added: running

Neruomatrix of neuropathic pain

Somatosensory cortex: increased blood flow Anterior cingulate cortex: remapping of pain matrix, and perception of pain Prefrontal cortex/insula: decreased metabolism Note: there is generally recruitment of additional areas

Neuromatrix of nociceptive pain

Somatosensory cortex: sensory-discriminative features of pain Insula/anterior cingulate cortex: affective-motivational aspects of pain Prefrontal cortex: perception of pain

Treatment of peripheral neuropathies

Specific therapy is dependent on establishing the neuropathy cause Treatment of neuropathic pain and QOL Monitoring respiratory and autonomic function, nursing and skin care in GBS Physical therapy and passive movements Splints, casts, and orthotics support Family counseling in inherited neuropathy Good skin care in sensory neuropathy

________ signaling protects from danger during sleep

Spinoreticular Signaling from the NTS signals for wakefulness; however this signaling is blocked during general anesthesia

Spinoreticular tract in the medulla

Spinoreticular fibers project into Reticular Formation, where synaptic networks link pain to cranial motor programs for: grimace, phonation, movement

Mechanisms of Hyperalgesia in Neuropathic Pain

Spontaneous firing of axons and DHN -↑ Ca2+ channel expression (α2𝛿 subunit of N-type VGCC) -↑ Na+ channel expression (following nerve injury, expression of novel Na+ channels in DRG neurons restyles in spontaneous firing- hyperexcitability) (Low dose IV lidocaine that does not block nerve conduction blocks neuropathic pain because of Na+- channel overexpression) Note: there can also be gain-of-function mutations in the Na+ channels in DRG neurons lowering the threshold for activation- hyperexcitability) -↓ K+ channel expression -↑ Receptors of neurotransmitters Hypersensitivity of neuroma to cytokines (e.g., TNFα)

Clinical stages of general anesthesia

Stage I: Analgesia Stage II: Excitement -Amnesia -Delirium, Vocalization, ↑ HR, ↑ BP, ↑ RR Stage III: Surgical anesthesia -↓ HR, ↓ RR → Apnea -Four planes of surgical anesthesia based on changes in ocular movement, eye reflexes, pupil size Stage IV: Medullary depression -Vasomotor (RVLM) collapse, Respiratory center depression -Death may ensue

Romberg sign

Stance requires learned position sense via DCML pathway + visual guidance; challenged on escalator! DCML lesions affecting lower extremity cause postural instability and a steppage gait due to manual plantar flexion and compensation Visual correction of postural instability = Romberg Sx implies DCML lesion

Babinski sign (extensor plantar response)

Stimulation of the S1 dermatome causes dorsiflexion of the big toe and possible fanning of the others Caused by damaged corticospinal tract which no longer facilitates intersegmental inhibition of L4/L5 anterior horn cells in response to S1 dermatome stimulation Normal response: -Stimulation of the S1 dermatome normally causes a flexor plantar response mediated through the S1 nerve root -Corticospinal tract normally prevents stimulation of the S1 dermatome from spreading to other nerve roots.

Intensity of sensory stimuli

Stimulus strength

Causes of B12 deficiency

Strict vegetarian diet Inability of stomach acids to aid in B12 absorption -Chronic antacid use in elderly should be taken with B12 supplements. -Overuse of H2 receptor antagonists or proton pump inhibitors. Autoimmune diseases Pernicious anemia Ileal resection, Crohn's disease, HIV infection, gastritis, gastric or small intestine surgeries Malabsorption syndromes Malnourishment associated with elderly

Hierarchy of evidence

Study designs in ascending levels of the pyramid generally exhibit increased quality of evidence and reduced risk of bias. Confidence in causal relations increases at the upper levels. Randomized controlled clinical trial (RTC) sits above observational studies because it is the study design with the best built-in design elements to minimize chance, bias and confounding. Note that observational studies can also have high value if designed well. In fact, randomized controlled clinical trials can only provide evidence amenable to experimentation, e.g.; therapeutic or preventive research questions. But in clinical practice not all questions are about therapy or prevention. Questions about diagnostic tools, course of disease (prognosis), value of screening for specific diseases and long-term side effects of drugs are best answered through observational studies.

Genetic Metabolic Disorders

Subset of genetic diseases affecting the nervous system of children normal at birth but miss developmental milestones -Neuronal storage diseases -Leukodystrophies -Mitochondrial encephalomyopathies

Anatomic sites for general anesthetics: Autonomic nervous system

Suppression of respiratory neurons in medulla (HALOTHANE) → bradypnea Blunting of baroreceptor reflex and reduction of sympathetic activity (PROPOFOL, ISOFLURANE) → bradycardia Hypothalamic thermoregulation neurons inhibited by ISOFLURANE → hypothermia

Receptive field of sensory stimuli

Surface area of skin serving a single primary afferent and tis collaterals were deformation produces an electrical potential It is that region of skin within which a sensory afferent detects a tactile stimulus and generates a response

Topical local anesthetics

Surface of wounds, burns, mucous membrane (not effective on skin). Effective in nose, mouth, airways, cornea, urinary tract. LIDOCAINE - for Herpes zoster blisters EMLA = LIDOCAINE + PRILOCAINE for venipuncture BENZOCAINE - Wounds and ulcers PROPARACAINE, LIDOCAINE, TETRACAINE - Ophthalmic TETRACAINE - ENT COCAINE - Nasal Systemic toxicity in high concentration and large areas of application

Neurotrophins regulate what three aspects of neuronal development

Survival vs programmed cell death Differentiation (biochemical and morphological effects e.g. promotes arborization) Chemotaxis (growth cone steers toward NGF gradient)

Sevoflurane

Sweet smelling, pleasant odor Volatile, not flammable, NOT explosive Vapor pressure lower; conventional vaporizer used Low blood : gas partition coefficient (0.65) Its pleasant odor, lack of pungency, and potent bronchodilating characteristics make sevoflurane administration via the facemask for induction of anesthesia in both children and adults a reasonable alternative to IV anesthetics -Used in outpatient surgery. 4%-8% Sevoflurane + 50% N2O + balance% O2 → 1 min induction

Complex Regional Pain Syndrome (CRPS)

Sympathetically Maintained Pain manifests as: -CRPS type I (reflex sympathetic dystrophy): without obvious nerve injury, after fractures of bone, soft tissue trauma, myocardial infarction, and stroke -CRPS type II (posttraumatic neuralgia or, if severe, causalgia): after identifiable nerve injury Clinical features: -Spontaneous "burning" pain in the region of innervation -Pain typically begins after a delay of hours to days or even weeks -Swelling of the extremity, periarticular bone loss, and arthritic changes in the distal joints -Relieved by sympathetic block

Polyneuropathy Evaluation; Helpful Clues

Symptoms specificity; sensory, motor and/or autonomic Evolution (acute, subacute or chronic) Past and present medical history Family history Physical examination findings (deficits distribution, reflexes, skin changes, musculoskeltal deformities, nerve enlargement) Diagnostic test (electrodiagnostic tests, blood tests, neuroimaging studies, CSF analysis and nerve biopsy

Opioid-NSAID Combination Drugs

Synergy between opioids and NSAIDs: NSAIDs block COX -> more arachidonic acid available for lipoxygenase -> lipoxygenase products facilitate opening of K+-channels by opioids -> hyperpolarization -> block of pain signal transmission. Hydrocodone + Acetaminophen (VICODIN, LORTAB) Hydrocodone + Ibuprofen (VICOPROFEN) Oxycodone + Acetaminophen (PERCOCET) Oxycodone + Aspirin (PERCODAN)

The lateral horn in present from _____

T1-L2

Misfolded TDP-43 role in neurodegenerative diseases

TAR DNA-binding protein 43 (TDP-43) is involved in the regulation fo RNA processing There is a prion-like spread of misfolded TDP-43 in diseases like ALS, Alzheimer's disease, and Parkinson's disease Spread may occur from neuron to neuron or glial cell to neuron Note: it should normally be seen in the nucleus, but in those diseases it is often within the cytoplasm

Barbiturate IV anesthetics

THIOPENTAL METHOHEXITAL Agonist for GABAA & Glycine receptors Sodium thiopental: A common IV anesthetic because of good safety record

Antispastic & Other Drugs in Neuropathic Pain

TIZANIDINE Central α2-agonist, inhibits release of excitatory neurotransmitters -Indications: Chronic muscle spasm, tension-headache -SE: Sedation, dry mouth CLONIDINE Central α2-agonist; α2 is on presynaptic C fibers and postsynaptic on DHN -Gi → Open K+ → Hyperpolarization -Indications: CRPS. BACLOFEN -GABAB agonist -Indications: Chronic muscle spasm, paroxysmal pain -Adverse effect: Sedation; Abrupt withdrawal → seizures -Intrathecal baclofen pump in spinal cord injury CLONAZEPAM, DIAZEPAM -GABAA agonist; opens Cl- channel -Adverse effect: Sedation MEXILETINE (Class 1B antiarrhythmic)

Thoracic Outlet Syndrome (TOS)

TOS is a group of disorders that occur when blood vessels and/or nerves are compressed usually in the costoclavicular space Causes include trauma, repetitive work or sports related injuries, anatomical defects and pregnancy Symptoms depends on if the TOS is neurogenic and/or vascular

T/F? The thicker the myelin and the larger the diameter of the axon, the faster the rate of impulse propagation along the axon

TRUE

High resolution PET scan of striatal dopamine transporter (DAT) activity

Targeted by the nigrostriatal pathway, the striatum (caudate + putamen) contains the highest [DA] due to the high density of DA-producing nigrostriatal axon terminals. The yellow/orange signal corresponds to radioactive DA that labels these terminals by reuptake via the DAT.

Which drug classes are most problematic in Chemotherapy induced polyneuropathy (CIPN)

Taxane class, e.g. docetaxel, taxol Vinca alkaloids, e.g. vincristine Platinum compounds, e.g. cisplatin, carboplatin Note: all disrupt microtubule assembly

Tetanus toxin

Tetanospasmin (150 kDa protease) hematogenously distributed from infection site to NMJ Binds ganglioside (receptor) on LMN - subsequently endocytosed Transported retrogradely by axonal transport (via dynein system) along LMNs into cord and brainstem Note: intra-axonal toxin is not accessible to antibodies

In formulating the Practice Guidelines for the management of conditions, it is important to specify two things:

The "class of evidence" that forms the basis for the recommendation. The strength of the recommendation.

What explains the use-dependent block

The 3 statuses of the voltage-gated Na+ channel Guarded receptors for local anesthetics will have increased accessibility in the open state Another theory is that the local anesthetic receptor has increased affinity in the inactivated state

Tetanus toxin cleaves

The SNARE protein synaptobrevin to prevent vesicle docking and NT exocytosis

The BBB protects the endoneurial compartment in what two places?

The aforementioned ring of perineurial tight junctions limits diffusion of solutes into the compartment from the vaso vasorum. In addition, capillaries coursing within the bundles have tight junctions that seal their endothelial cells.

Muscle rigidity can be a side effect of which intravenous anesthetic? (A) fentanyl (B) midazolam (C) ketamine (D) propofol (E) thiopental

The answer is A: fentanyl. Fentanyl is a potent opioid agonist given as part of balanced anesthesia. It can cause chest wall (truncal) rigidity because of interactions in the striatum. This effect has not been noted for B, midazolam, C, ketamine, D, propofol, or E, thiopental.

Which of the following characteristics is used to quantitate and compare the potency of gaseous general anesthetics? (A) blood: gas partition coefficient (B) minimal alveolar concentration (C) blood: brain partition coefficient (D) rate of uptake and elimination (E) relative analgesic potency

The answer is B: minimal alveolar concentration. The minimal alveolar concentration value, which is used for inhalational agents to determine potency, is defined as the percent concentration in the administered air that produces no response to surgical incision in 50% of the subjects. Answers A, C, and D are measures of the characteristics of anesthetics but do not give the potency. Answer E, relative analgesic potency, is a term used when comparing analgesic agents

Which one of the following inhalational anesthetics can provide anesthetic effectiveness only under hyperbaric conditions? (A) enflurane (B) nitrous oxide (C) halothane (D) methoxyflurane (E) isoflurane

The answer is B: nitrous oxide. Although nitrous oxide has the fastest rate of induction and is safe to use, the potency is such that one would have to administer the gas under hyperbaric conditions for it to be the sole inhalational agent. It is often used in dental procedures for its analgesic effects and as an adjunct in other procedures.