Neuroscience Notes for Medical Students


## Part I ### Major Cell Types in Nervous System #### Cell Type/Function ##### Neuron CNS from neuroepithelium divided into basolateral (dendrites and body) and apical (axon). Overall structure is highly infolded/involuted to increase surface area for increased input. [![Neuron-1](]( ##### Cell body Soma or perikaryon neuronal cell bodies have a prominent nucleus with prominent nucleoli and dispersed chromatin bc they are actively transcribing DNA to make protein. Cytoplasm contains a golgi apparatus, Nissl substance (polysomes-ribosomes) (mainly rER), cytoskeleton, and mitochondria. Also has inclusions: melanin in the sub. Nigra and lipofuschin which is a neurotoxic accumulative breakdown pigment. **Primary function**: Collect information from other neurons. It is the sight of synthesis of macromolecules. ##### Dendrites Extensions of the cell body. Cytoplasm identical to soma except the nucleus. They are highly branched. Identification of dendrites is established via a specific microtubule associated protein MAP-2 (also has MAP-1 and MAP-5- these work for all neurons). **Primary function:** Receiving stimuli from sensory cells, axons, and other neurons. Are cytoplasmic projections from soma. Specialized zones to receive inputs, equipped with membrane receptors, gap junctions, and signal transduction machinery associated with the inner leaflet of the plasma membrane. * In CNS, dendrites have spines- shaft/neck of spine more impt. bc closer to soma. ##### Axon Single process that emanates from a cell body with constant diameter. It begins as the axonal hillock (initial segment) and this part is usually devoid of Nissl bodies or myelin and it initiates APs. Axons contain sER (no rER or ribosomes), mitochondria, vesicles, actin filaments (neurofilaments), motoric proteins (kinesin and dynein), and microtubules MAPs, identified via MAP-3 (also MAP-1 and MAP-5-). Dyenin goes from positive to negative (terminal to cell body) and kinesin moves negative to positive (cell body to the terminal). Some axons are myelinated. **Primary function:** Distal ends are specialized terminal boutons which convert electrical impulse into chemical neurotransmitters. Clear vesicles – small molecular weight molecueles like Ach, GABA, glutamate, glycine. Dark vesicles – heavier NT like enkaphlins, dopamine. NTs can be released on an axon, dendrite or soma. #### Classification of Neurons ##### [![Basic-neuron-types-2](]( Morphology: - **A. Unipolar** – single process; Development - **B. Bipolar** – two process (axon and dendrite) emanating from the cell body; Olfactory epithelium and Vestibular/Cochlear ganglia. - **C. Psuedounipolar** -one process that divides into peripheral and central branch (both axons); Sensor neurons of cranial sensory and DRG (spinal) sensory. - **Mutlipolar**– most common and pyramidal shaped. ##### (2) Function: - **A. Sensory (afferent)** – transmit sensory input and located primarily in PNS - **B. Motor (efferent)** – innervated muscles, glands, and other neurons throughout body in the periphery and originate in CNS - **C. Interneurons**– integrators that establish networks for higher learning and located in CNS ##### (3) Chemistry: – most neurons transmit AA + another NT - **A. Cholinergic** – motor neurons - **B. Dopaminergic** – sub. nigra - **C. Excitatory or Inhibitory** (Glu (+) or GABA (-)) - **D. Peptidergic** – enkaphalins, sub. P
PNS – ganglion Peripheral nerves consist of bundles (fasicile) of axons which may contain sensory & motor fibers Function: Motor: Somatic, autonomic, and enteric. Sensory: somatic and visceral Post-ganglionic cell are multipolar and DO receive synaptic contact. The cell bodies are surrounded by satellite cells derived from neural crest like schwann cellsCellsTypesLocation/Forms
Neuronal cell bodiesSensory – do not receive synaptic contacts; pseudounipolar autonomic ganglionSpinal (DRG) and cranial nerve ganglia, some sensory epithelium Sympathetic, parasympathetic, enteric
PNS Nerve structure- Epinerium- outermost covering (collagen/elastic fibers) - Perinerium- dense connective tissue. Lined by epithelioid cells that isolates neural environment. - Endonerium-loose connective tissue surrounding a single nerve fiber (axon)
Glial Cells – gap junctionsSchwann CellsSchwann cells form myelin sheaths around axons or just envelop the axon and is unlmyelinated. Myelin is the plasmalemma of the schwann cell and is wrapped around the axon , it is intereupted by nodes of ranvier that indicate interface between 2 myelin sheaths (internode) each made by a separate schwann cell.
CNS – nucleus = collection of neurons in CNS versus ganglion in PNSCellsLocationFunction
NeuronsGray matterCollect, & transmit info. Synthesize macromolecules
AxonsWhite matterConduct information
OligodendrocytesWhite (and gray) matterCNS myelin, can cover several axons at once. Postembryologic development
AstrocytesWhite and gray matterThey contain GFAP (kind of intermediate filament). They have processes that expand onto blood vessels and other neurons. They regulate tight jxns to form Blood brain barrier. Adjacent astrocytes couple by gap junctions. They regulate K+ concentration. They have uptake for NT machinery. * reactive astrocytes- activated by injury (astrogliosis), forms glial scar. Happens in an infarct and can prevent regeneration Æ paralysis.
MicrogliaGray (and white) matterMacrophages of CNS, phagocytosis. If CNS damaged, the microglia become enlarged, motile and phagocytic. Play a role in Alzheimers
Ependymal cellsWalls of ventriclesLine ventricles, central canal of spinal cord, and choroid plexus; ciliated cells form a continuous sheet. Remnant of embryonic proliferate neuropethelium; make CSF
Choroid Plexus_Form CSF; made by envagination of the pia and ependymal layers into ventrical spaces. These sacks contain blood vessels that supply fluid and electrolytesSto CSF.
### Principles of CNS Organization, Terminology, and Course Overview When you first look at an image, distinguish between gray matter (cell bodies) and white matter (axons, etc) **Gray Matter**: Cell bodies primarily. They like in the nuclei (big pictures area of gray matter) or cortex (2nd area of gray matter). **White matter**: bundles of axons wrapped in myelin. Column: in spinal cord going up and down. Fasiculus: bundles, lemniscus: flat bundle/ribbon, capsule: surrounds something, peduncles: stalk/foot. Affert and efferent. Pathways in the CNS: they consist of a series of neurons that are connected through synapses. Often named for their origin and termination. Spinal cord to thalamus is the spinothalamic tract, cerebral cortex to the spinal cord is the corticospinal tract, spinal cord to the cerebellum is the spinocerebellar tract, the pons to the cerebellum is the ponticocerebellar tract, vestibular nucle to the spinal cord is the vestibulospinal tract. Often cross to the other side at some level of the CNS. When you look at a pathway, pay attention to the origin, endpoint, and point of cross over. The major pathways between the spinal cord and the cortex are primarily crossed. Therefore, the right side of the cerebral cortex controls the left side of the body (motor system) and the right side of the cerebral cortex receives information from the left side of the body. This is important when you are understanding the affects of lesions. Pay attention to the: 1. Overall organization of the pathway and function (motor?sensory?etc) 2. Specific location of the pathway within the brain and in brain sections 3. Where the lesion occurs in relation to the crossing of the pathway. #### Neuronal classification: Neurons can be classified by 1. Where the axons are heading (projection neurons…faraway places bs interneuorns: local circuit pathways). 2. Shape: they can be pyramidal, stellate, granular 3. Pattern of axsonal processes: can have basket cells, chandlier cells 4. Chemical identity: neurotransmitters (Ach, glu, GABA, Dopamine, Norepinephrine, serotonin, etc). #### Synapse classification: 1. Peripheral or central 2. Pre and post synaptic elements (axosomatic, axodendendritic or axoaxonic). 3. Excitatory and inhibitory 4. Chemical identity of the presynaptic elements and the postsynaptic receptors
[![blue-and-red-3](]( is motor, red is sensory. Also look at where the tract is going after the lesion. That is how you can tell where the lesion will be 1. The motor problem will be on the left side 2. The motor problem will be on the left side 3. The motor lesion will be on the right side and the sensory lesion will be on the right side 4. The motor lesion will be on the right side but the sensory lesion will be on the left
- Descending systems from cerebral (more) cortex and brainstem centers (upper motor neurons) direct voluntary movements and activate motor programs for basic movements and posture - Lower motor neurons directly innervate skeletal muscles - Cerebellum -& basal ganglia modulate movements (balance and coord ; initiate and control movement)
The frontal cortex stimulates the motor part of the lobe. You go from the cell body through axon all the way down to the spinal cord. The internal capsule (white matter) of fibers form the motor tract. It leaves the fore brain€goes to the midbrain€pons€medulla€spinal cord. Switch it around for the sensory.except, with sensory you go through the brain stem and then thalamus. In the thalamus, it synapses and goes onto the tract.Surface anatomy: cortex can be cerebellar or cortical. The thalamus is located under the lateral ventricles. It is along the midline
Neuromuscular Junction Peripheral NerveRelevant to pharmacology Contains motor and sensory fibers
Spinal CordLocation of motor neurons and associated reflex circuitry, Somatosensory (to cerebral cortex), and Motor (from cerebral cortex). Damage can lean to paralysis
Brain StemMajor divn: medulla, pons, and midbrain.. Contains multiple pathways and cranial nerve nuclei (3-12). 7- Bells palsy
Cerebellumbalance & coord. Cerebellar cortex, deep cerebellar nuclei, & connections to brainstem (cerebellar peduncles)
Basal GangliaGroup of nuclei within the cerebral hemisphere that are associated with motor control and motor planning. Substantia nigra. Parkinson’s – bad initiation VS. Huntington’s – bad control
ThalamusOne part of diencephalon – hypothal, subthal, & epithal. Contain multiple nuclei that form “egg-shaped” that lie on each side of midline within cerebral hemispheres. They receive and process incoming information, and then it is sent to cerebral cortex and then back to thalamus.
Cerebral CortexMajor Lobes: frontal, parietal, temporal, and occipital (and limbic). They each have different functions.
HippocampusMajor region of limbic system, includes Amygdala. Involved in short & long-term memory + learning. Hippo affected in temporal lobe epilepsy and Alzheimer’s disease. Also demonstrates plasticity after injury.
### Normal Synaptic Transmission at the Neuromuscular Junction Schematic
1. Depolarization of the pre-synaptic terminal membrane by AP activates voltage-gated/sensitive calcium channels (VGCC).
2. As calcium flow into the pre- synaptic terminal it triggers fusion of synaptic vesicles with pre- synaptic terminal membrane (SNARE Complex)
3. Ach contained within the vesicles is released into the synaptic cleft.
4. Ach diffuses across the synaptic cleft and bonds to receptors on post-synaptic membrane.
5. These are ligand-gated ion channels (nicotinic Ach receptors) that when a transmitter binds it elicits a conformational change that opens ion channel. Ach and nicotine can bind the channels.
6. At most synapses, Ach just diffuses, but at the NMJ, is it AchE that breaks it down.
#### SNARE Complex: 1. v-SNAREs (“v” stands for vesicles) correspond to synaptobrevin. 2. t-SNAREs (“t” stands for target) on cytoplasm of pre-synaptic terminal corresponds with syntaxin and SNAP-25 3. v-SNAREs and t-SNAREs bind and lock the vesicles to the terminal membrane allowing SNAPs to bind, which facilitates binding of NSF protein (ATPase that helps) 4. When intracellular Ca is elevated it binds to a vesicle protein called synaptotagmin (it detects Ca levels and binds Ca to somehow complete fusion) #### AchR - Pentameric 2α 1b 1g 1d - α is binding site for Ach, 2 Ach bind for each α. - 2nd transmembrane (M2) domain forms channel - M2 region kinked = inactive - Ach bind causes twisting and lysine moves to open channel - Cation selective (Na, K, and Ca) - Latrotoxin from black widow spider makes the presynaptic terminal swell bc it causes all the vesicles to fuse to it. - Curare & alpha bungarotoxin – AchR blocker - Tetanus and botulinum toxin cleave synaptobrevin. Botulimum also cleaves syntaxin and SNAP 25. causes asphyxiation **End-plate** – specialized site of contact between a motor neuron and a skeletal muscle fiber. Within the cleft there is a basement membrane (synaptic basal lamina) that is composed of collagen and ECM proteins. AchE is in the basal lamina. **End-plate potential (EPP)** – depolarization that’s produced at the neuromuscular junction. Made from near simultaneous release of multiple quanta **Mini (mEPP)** – post-synaptic response to Ach spontaneously released from the pre-syn. terminal. Arise from irreducible units of NT called quanta **Quanta** – equivalent to a vesicle and causes an mEPP. Quantal content (m) determines size of EPP (multiple quanta) **Safety Factor** – the ability of EPPs to elicit AP due to its ability to reach threshold. **End-Plate Current (EPC)** – synaptic current that produces the rising phase of the EPP. Inward current depolarizes – cations going into cell - The size of the EPP depends on the number of quanta released, quantal content, m. - Quantal content is a product of the number of vesicles available for release, n, and the probability that a vesicle will release, p. Magnitude of Ca influx regulates p. Quantal content (m) = np - Current through a channel: I = g(Vm-Erev) current = conductance * driving force. If Vm is more negative than Erev, then their will be inward current bc the driving force will be negative, the + cells will want to go in. If Vm = Erev, no driving force, no net movement. - Iepc = INa + Ik (I = g(Vm-ENa or K – equil potential)) prior to the reversal potential, there is a huge driving for Na, at the reversal potential inward flow of Na is equal to outward flow of K. At rest, Vm = Ek thus, the equation reduces to just Na driving force that produces EPP. Erev is -15mV – 0mV. - EPCs are inward currents at potentials more negative than Erev and outward currents at potentials more positive than Erev. EPPs depolarize the postsyn cell @ potentials more neg than Erev and hyperpolarize when opposite. Postsyn potentials (like EPPs) are depolarizing if their reversal potential is more positive than the postsyn membrane potential and hyper if opposite ### Peripheral Nerves [![ensheathing-of-peripheral-nerves-7](]( - Cranial nerves and spinal nerves – CNS and PNS communicate with each other through the cranial and spinal nerves. Communication happens in both directions: efferent-motor (CNS to PNS) and afferent-sensory (PNS to CNs) - Sensory ganglia and autonomic ganglia - Peripheral nerve plexus #### Conduction of peripheral nerve: Compound AP [![peripheral-nervous-system-8](]( - Measures contraction of near simultaneous contraction of many motor fibers. - Graded phenomena, NOT all or none AP - Dependent on # of axons stimulated - Myelination and larger size (more forward current flow with less resistance) increases Conduction - A fibers are the largest and C fibers are not myelinated, but there are more C fibers - A fibers carry info about proprioception in skeletal muscles - C fibers are mainly pain - Compound Motor AP (CMAP) are a measure of near simultaneous activation of many muscle fibers - Sensory nerve AP (SNAP) measures activity of all sensory fibers stimulated #### EMG - Two stimulation sites are tested (prox and distal) - Nerve conduction velocity is calculate from the difference in latency - SNAP have no synapse between stimulus and record as CMAP do - SNAP are much smaller in volts #### Myelination - Decreases membrane capacitance and increases resistance - Decrease the lateral leak of current - Insulates axon #### Demyelination - slows and blocks AP - slows CMAP and SNAP - amplitude of CMAP and SNAP NOT changed; but if AP fails completely, then there is no CMAP #### Wallerian degeneration - Distal to sight of injury site undergoes active degeneration - Activation of degenerative enzymes such as calpain and leads to balling up of the myelin sheets into myelin ovoids - Area gets infiltrated by macrophages that clean up debris - Proximal cell body undergoes chromolysis – RNA containing strucutures such as polyribosomes and RER are disappearing. In addition, the cell body can then endergoe apoptosis - Unless the soma dies, the proximal axonal stump will start to sprout and the distal Schwann cells proliferate forming Bungers band that helps guide the axon to target #### Schwann Cells Support all axons (unmyleinated and myelinated) in the PNS. Non myelinated axons in the PNS are supported, but not wrapped by Schwann cells. #### Myelinated axons in the PNS Mylinated axons in the PNS are enwrapped by a single, dedicated Schwann cell per segment. 1 schwann€1 axon during development.–> sheath of membrane grows around the axon . each axon supported by many schwan cells. The key difference is that for unmyelinated neurons, one Schwann cell can envelop multiple axons to support them, but for myelinated neurons only one Schwann cell can myelinate one neuron. Therefore one axon ends up being myleinated by different Schwann cells. the nodes of ranvier are the only parts of the neuron that have the sodium and potassium gated channels. Sodium channels sit in the middle of the nodes while the potassium channels sit adjacent to the node in the paranode. There are cell adhesion molecules from the bits of cytoplasm from the Schwann cell that attach to the axon itself. These are the specialized structures. At non-myelinated ‘nodes of Ranvier’ an AP is generated, the spread through the myelinated part is passive to the next node of Ranvier. #### Compound action potential (CAP) - Stimulation of a nerve bundle; increasing stimulation strength leads to recruitment of increasing number of axons that fire AP’s - Detection limit exists and maximal amplitude is reached once all axons have been recruited - Shape stays about the same - On the left, it is “all or none,” but on the right, it is “graded” - On the left, up is positive; on the right, up is negative - The down swing is not as steep as the upswing because the current of Na comes on faster than the K current goes - So in the up swing, you have a negative difference in voltage measured at the voltmeter - When it crosses zero again, there is no difference - When you are on the down swing, the voltage difference is positive - Conduction velocity - Range from 0.2m/s to >100m/s - If the conduction velocity is the same throughout the axons, there won’t be much dispersion of the CAP readings - Velocity of CAP gives idea of health of nerve fiber - Demyelination decreases velocity - A fibers faster than B fibers faster than C fibers - Compound Motor Action Potential (CMAP) - Motor nerve stimulated and muscle response calculated - Latency includes synaptic transmission, etc. - So we measure from A to C and B to C, then subtract BC from AC to get AB, the velocity over the length of the nerve WITHOUT the latencies - EMGs (electromyographs are more sensitive as a test but require intramuscular electrodes, so they are invasive) - Sensory Nerve Action Potential (SNAP) - Stimulate median nerve in the finger tip of middle finger - Record response over median nerve at wrist - Two stimulation sites are tested and from the difference in latency, the nerve conduction velocity (NCV) can be calculated - Demyelination interrupts signaling - AP conduction uses passive current flow from node to node - If myelination is disturbed, current is lost to charge the membrane capacitance (increased capacitance of membrane!). - Conduction is either slowed or completely interrupted - Repair: - Remyelinate - Add sodium channels in demyelinated region - Nerve Injury and Degeneration - After injury, Nissl bodies disappear in CB - Chromatolysis (can induce apoptosis) - Distal axon begins to actively degenerate—Wallerian Degeneration - Macrophages infiltrate endoneurium after formation of myelin ovoids - Calpain is an enzymes that invades and leads to the “balling up” of the myelin sheets into “myelin ovoids” - Macrophages clean up the debris - The proximal CB undergoes “chromolysis”—RNA containing structures like polyribosomes and rER disappear - Nerve Cut and Regeneration - Proximal axon stump starts to grow cone and sprouts - Distal Schwann cells divide and form a “tube” of cytoplasmic channels—called Bunger’s Band - If crush injury, basal lamina and perineurium might still be intact€easier regeneration than when the nerve is completely cut! - If reconnected, the nerve’s function can be restored! - If reconnection fails, it atrophies over time - CMAP in disease - If demyelinated, the response that arrives at the recording electrode is dispersed, since the axons are arriving at different times: [![cmap-in-disease-10](]( [![demylination-11](]( - If you have demyelination, the distal stimulus arrives smaller and slower - If you have axonal degeneration, the distal stimulus is smaller - If you have conduction block, there is no dispersion (but stim. Is smaller), because those that do get through arrive together - Damage can lead to muscle weakness! ### Neuromuscular Blockers - Used primarily during surgical procedures - NO effect on the CNS, since they do not cross the BBB. - Block transmission from motor nerve to the motor end plate via: - competitive antagonists of Ach (competitive non-depolarizing), - by inducing sustained depolarization of the end plate followed by desensitization (non- competitive depolarizing). - Full doses cause complete paralysis of all voluntary muscles. Sensation is unaffected and anesthesia is needed.
Endrophonium – competitively inhibits AchE Neostigmine and pyridostigmine are carbamate AchE inhibitors All these are quaternary so don’t cross BBB unlike physostigmine which does because its tertiary
Class of DrugPharmacokineticsPharmacodynamicsApplicationAdverse Effects
Competitive Antagonists (Nondepolarizing) i.e. tubocurarine atracurium rocuronium (anything that ends in curium, curonium, or tubocuranine)- Highly polar and inactive (p.o.) - Administered i.v. or i.m. - Limited volume of distribution - Not metabolized at synapse: Some are metabolized by the liver and have relatively short half-life - Some are excreted by the kidney and usually have longer duration of action. - Reversibly bind to nicotinic receptors at the neuromuscular junction by acting on same site as Ach (competitive antagonists) - AchE inhibs will antagonize there effect - To obtain better muscle relaxation in surgical anesthesia; sensation is unaffected and anesthesia must be maintained. - Skeletal muscle relaxation facilitating tracheal intubation. 1. Autonomic- Increase heart contractility, tachycardia, new drugs help devoid this effect 2. Histamine- bronchospasm, skin flushing, and hypotension 3. Longer duration with reduced clearance by the liver or kidneys 4. Enhancement of blockade with antibiotics
Succinylcholine (depolarizing). Succinylcholine is 2 Ach attachted end to end. It is a muscle relaxant- Not metabolized by AchE - It diffuses away from NMJ and is hydrolyzed in plasma and liver by psuedocholinesterase - Rapid onset of action (30-60 sec) and short duration of action (< 10 min) bc metabolized by plasma cholinersterase - Act at as Ach receptor agonists. - Reacts w/ nicotinic R to open channel and cause depolarization. - leads to fasciculations and some muscular contractions prior to paralysis – flaccid paralysis - Depolarized membrane remains depolarized and unresponsive to subsequent stimulus - Flaccid paralysis - Phase 2 block is after AchR changes conformation and now succinylcholine just acts like a non depolarizing muscle relaxant - Drug is used to treat: laryngospasm, endotracheal intuation, and electroconvulsive shock therapy - Dibucaine number- test identifies patients with abnormal plasma cholinesterase - K levels that are already effect via burn, trauma, neurological disorder can be further effect with succinylcholine adminstation. - *malignant hyperthermia
SpasmolyticsThe drugs under umbrella act in various placesAct in CNS to reduce tonic output of primary spinal motor neurons or in skeletal muscleReduce muscle spasticityDiffer by the drug
CNS Spasmolytics – Musc relaxants Clonodine & tizanidineCentrally acting alpha 2 adrenergic agonists that reduce muscle spasmReinforces pre & postsyn inhib in cord & inhibits nociceptive transmission in dorsal horn.Spasms, cramp & musc tightns in MS, back + spine injuryDrowsiness, hypotension, dry mouth, and asthenia
CNS Spasmolytics – GABA acting Diazepam Baclofen GabapentinAllosteric GABA A – Cl influx; presyn inhib.Needs GABA A to enhance GABA mediated Cl conductance
Allosteric GABA B in spinal cord, increase K conductanceThe hyperpolization causes presyn inhibition of Ca influx – no NT rel
Block v-gated Ca channelsAntagonistAnti-epileptic
Peripheral Spasmolytics (Skeletal muscle) – dantroleneinhibits Ca release from Sarcoplasmic Retic.Binds to Ryanodine receptorMalignant hyperthermia
Peripheral Spasmolytics (Skeletal muscle) – botulinum toxinIrreversible proteaseFor local spasm and Cerebral palsy
Beta 2 receptors are located on the muscle spindle of skeletal muscles and their stimulation increases the tension generated in fast twitch skeletal muscle fibers causing tremors as seen with epinephrine administration. Tremor is result of increased muscle spindle discharge coupled with an effect on contraction kinetics of fibers. This produces instability in the reflex control of muscle length. ### Peripheral Neuropathy: Lesion, Tx, Etiology? - Where is the lesion? - What modalities (motor, sensory, or autonomic) are involved? - Motor pathways have 2 neuron paths - Sensory and autonomic have 3 neuron paths - What fibers (small or large) are injured? - What is disease process (axon or demyelination)? #### The patterns of peripheral neuropathy - Mononeuropathy-like in carpal tunnel syndrome - Mononeuropathy multiplex-multiple isolated nerves, like in vasculitis, lyme disease, diabetes, leukemia - Polyneuropathy-length dependent-often see stocking-glove distribution – We will focus on this pattern for the rest of this lecture - Sensory loss could be peripheral process OR cell body - You get stocking (short sock) and when you get to knees, your fingers start getting involved. One cell is a meter long! We will talk about length dependent. You can have injury to the peripheral process or nerve cell body. If this is a motor neuron disease, but the peripheral processes will be a peripheral neuropathy. I fit is a sensory nerve, this will present like a peripheral neruorapthy but it is a ganglionapthy because the ganglion cells are lost (produce numbness). Injury in peripheral neuropathy may be due to injury of the cell bodies of nerves or to the peripheral process. Two broad categories of peripheral neuropathies are axonopathyes and myleinopthaties. Peripheral nerve is transected, wrapped with the epinerueium, containing fasciles wrapped with perineureum containing individual axons wrapped by Schwann cells. these axons an be myelinated or unmyelinated. Notice here that BV supply fassciles. This is an anatomic basis of mononeuritis multiplex produced by avasculitis. If have an arthritic vessels, will infarct the nerve and have drop out of various fibers. The clinical effect of a polyneuropathy will depedent on three things. 1. What modalities? motor, sensory, autonomic. Some nerves are pure sensory or motors, but most of them are mioxed 2. What fibers are effected? The sensory fibers are divided into large and small fibers. The large fibers: are vibration and propricopetcion the small fibers are autonomics and pain. 3. Are the injuries axonal or demyelinated?
Sensory Large Fiber↓ Vibration ↓ Proprioception Hyporeflexia Sensory ataxia – positive Rhomberg test; piano playing fingers and loss of balance when eyes closedParesthesias – tinglings
Sensory Large Fiber↓ Pain ↓ Temperature Dysesthesias – abnormal sensation Allodynia Autonomic nerves ↓ Sweating Hypotension Urinary retention Impotence Vascular color changes↑ Sweating Hypertension
Axonal neuropathyDemyelinating neuropathy
- Wallerian degeneration – axonopathy where the transected nerve dies distally, myelin ovoids form, macrophages invade etc - Renervation - Wasting - Dying back pattern-axonopathy where there are multiple small injuries of neurons; die at the most vulnerable part, the terminalÆdie back - 6 weeks later on EMG you will see the same picket fence but increased voltage - Schwann cell degenerates and transmission is impaired (lost charge/not insulated or doesn’t have fibers anymore - Hypertrophic nerve on exam - Global areflexia - Weakness without wasting bc no degeneration atrophy - Distal motor latency increases - Conduction velocity decreased - Reduced recruitment without much denevation - loss the myelin but the axon is still intact. You won’t see wasting in the limbs. Put needle in: eventually charge dissipiates: will still get picket fence. But motor units will stay the same. Six months later there will be no change. - Onion bulb formation from increased schwann cells and hypertrophy with no myelin
[![feet-12](]( This figure shows loss of all three modalities -> pes planus (flat foot) points to acquired problems versus congenital ones This figure shows DM-induced pressure ulcers (skin break down due to decreased pressure perception) Pes cavus indicates that this is probably congenital. Hammering of toes does not necessarily indicate congenital nature of disease [![neuron-13](]( - In this picture, Mr. Green dies…so on an EMG, you will hear drop out (picket fence versus full interference pattern) - When Mr. Red learns to reinnervate Mr. Green’s muscles, the interference pattern will still show loss of Mr. Green, but the voltage of the motor units will be much bigger than they were with original axonal degeneration - CMAP (from surface) will be larger, but maybe not quite normal - No denervation seen, but the signal is SLOW in nerve conduction studies #### Nerve conduction studies [![nerve-conduction-studies-15](]( - Demyelinating may see decreased amplitude in addition to slowed signal because of complete conduction block or because of phasic cancellation - In axonal. You just have less fires (mr. green is gone)-see low CMAP/SNAP. The reason why compound muscle AP is lower even tho axons are preserved, over the long distance you have phase cancellation of the waves. Some of the fibers are positive and others are negative. Secondly there may be a complete conduction block. [![conduction-block-16](]( #### EMG interference with neuropathy With deinnervation or complete conduction block you just got one motor unit left firing (extreme case). This wave form of dimensions is normal. You can get this pattern with axonal injury or complete conduction block with demylination- the same. However six weeks later, there will be bigger units. Looks the same but look at the amplitude. You will have spikes that are five times bigger (increase duration and amplitude). Amplitude five times bigger. This tells you there was a definite axonal injury and it grew back. At least six weeks other. In the first one can’t be sure if it’s axonal or conduction block. - Reduced interference pattern—seen in demyelination or in axonal degenerationÆcan’t tell difference - Reinnervation shows motor unit potentials of increased amplitude and duration - If the motor unit amp’s are increased (say, 5x bigger, eg), shows that there was axonal degeneration with regeneration! (this regeneration is not seen with demyelination) [![neuro-histo-17](]( #### Histology: - Wallerian degeneration-all at the same age, see macrophages, myelin ovoids, regenerative clusters etc. - Dying back -> doesn’t look as uniform - Demyelination-see onion skins due to repeated demyelination/remyelination - Also see hypertrophy of neurves (ex. Great auricular), because there is increased number of schwann cells (minus the myelin!) - May see focal demyelination—focal indicates acquired - Congenital seen with diffuse pattern #### Demyleination: Where a nerve is subjected to myelination , demylination and then recovery. You will see “onion skins” of the nerve. You have an increased number of Schwann cells of the nerve. Which attempt to recover, but there is no myelin in them. This represents hypertrophy of the nerve. The nerve will feel thick on phys exam. **Focal demylination:** if a patient has a congenital dmeylination, you will see the entire nergve demylinated .if it is focal then it is acquired. If ti is not bilateral also hint of being acquired. #### Myelinopathies They’re rare. The clues are hypertrophic nerves (esp greater auricular nerve). Myelinopthies tend to produce global arreflexia, weakness without wasting (b/c motor unit preserved), pattern tends to be more motor than sensory. And nerve conduction studies can discriminate from acquired (non unifirom) from congenital #### Axonopathies - Majority of toxic, metabolic and endocrine causes are axonal degen. - NCV: CMAPS decreased, but minimal or no change in distal motor latency - Legs>>arms - Emg-signs of denervation and reinnervation #### Myelinopathies - Clues-hypertrophic nerves, global arreflexia - Weakness without wasting - NCS can discriminate b/w inherited and acquired (uniform vs. non-uniform) - Emg-reduced recruitment w/o much denervation—fewer motor units, but same motor unit size #### Etiology? - Approach is 6 D’s! #### Duration? - Acute (<1month) vs chronic (>1 mth) - Most polyneuropathies are chronic - Acute polyneuropathies-Guillain Barre syndrome or vasculitis) - Relapse and remission-from intermittent drug exposure or diabetes control #### Distribution - Asymmetry-mononeuropathy or mononeuritis multiplex-eg. Vasculitis - Symmetric-polyneuropathy (mild-stocking only…more severe glove-stocking) #### Deficits - If mostly motor-think GBS, lead toxicity, charcot-marie-tooth disease (aka hereditary motor-sensory neuropathy, HMSN) - If pure sensory/severe proprioceptive deficit, think carcinoma or vitamin B6 toxicity - If autonomic, think of diabetes, amyloid, or drugs #### Disease pathology? - Axonal or demyelination - If demyelin. Is uniform, think of charcot-marie… - If unremarkable chronic sensorimotor axonal polyneuropathy, must exclude: - Alcohol - Diabetes - Hypothyroidism - Uremia - B12 deficiency - Monoclonal gammopathy #### Developmental neuropathy? - Orthopedic deformities - Long duration - Indolent progression - Family history #### Drug/toxin exposure? - Demyelinating-glue sniffing, arsenic - Axonal-cancer drugs, antibiotics, cardiac meds #### Ethanol Neuropathy-common axonal polyneuropathy - Among most common worldwide - Chronic - Numbness, paresthesias, pain in stocking distrib. - Sensory>>motor loss - Loss of ankle reflexes - Ethanol toxicity and/or VitB1 nutritional deficiency #### Guillain-Barre Syndrome-common demyelinating polyneuropathy - Rapid, severe, typically ascending paralysis - Post-infectious in 60%cases - Paresthesias, pain, numbness - Autonomic nerves too - Reflexes lost - Cytoalbuminologic dissociation in CSF (proteins without cells) #### Diabetic polyneuropathy (uremia can do it too)-common mixed axonal and demyelinating polyneuroapthy - Sensory>>motor - Autonomic involvement common - CSF protein frequently elevated ### Meninges [![meninges-18](]( - On the left, the meninges are left in place - We can see arachnoid granulations, which are where CSF is absorbed into venous circulation - If there is scarring/abnormality of these granulations, CSF can’t get absorbed, and we will see hydrocephaly result - in removing meninges, we can see the gyri and sulci, which will show mass lesions and swelling or shrinkage of the brain - edema will be seen by obliteration of the sulci [![brain-19](]( is the pons, blue is the basilar artery (which are atherosclerotic) and pink is the medulla. When you remove the meninges, look for atrophy (in alzhehimers you will have shrinkage of the birain), gross lesions (cancer), integrity of the sulci and gyrus (if you have severe edema, you will see swelling of the gyri and olbteration of the sucli…you can get edema as a result of hydrocephaly. You can see arachnoid granulations…this is where the CSF dumps into the venous system. If you have a blockade of this, can get hydrocecphaly). Also look at the bottom of the brain for edema. Here you ccan see evidence for cerebral edema or herniation. [![brain-20](]( is the basal ganglion. On the upper side of the internal capsule (bunch of axonsw) there is the caudate nucleus. Id ont know what the area is called below. You can clearly see the distinction between white and gray matter. Huntington’s disease is the loss of the caudate nucleus- the medial portion of basal ganglion. Common demylinating diseases are selective for the white matter (spares the gray matter) this is typical for neural pathologies. The disease will target a specific area of the brain…the nucleus basis (see the printout) is selectively target ed in some diseases. MRI is very good…nearly replicates the neuroanatomy ##### Myelin-staining sxn [![brain-21](]( - the tip of the arrow points up and right to the nucleus basalis - right above that, the dark mustache looking structure is the anterior commisure - Bodily function pattern of distribution in cerebral cortex (motor) - the basal ganglia are grey matter in this image, but do show some darkness, which indicates a decree of white matter in there - classic “homunculus” [![brain-22](]( - legs on medial aspect of frontal lobe - hands/arms on superior aspect - face on the lateral aspect of frontal lobe [![brain-23](]( blue is the lateral geniculate nucleus (6 layers) and the purple is the hippocampus (purple- 3 layers). Black is corpus callosum. The hippocampus is important as it is involved with memory. It is selectively impacted in alzhemiers and in conditions of anoxia. Hippocampus is important in epilepsy as well. ##### Posterior Fossa Contents: - Cerebellum and brainstem - Covered by tentorium cerebelli—dense fibrous structure that separates diff. compartments of brain - If there is transtentorial herniation–>tentorium does not budge when there is cerebral swelling ### Histology and the CNS ##### H&E stained section of cortex: [![histo-24](]( Junction between cortex and white matter (shown as dark red below) should be very distinct - Neocortex has hexilaminar architecture, but itis difficult to appreciate in a normal section ##### neuropil vs neuron distinction - Neuropil-fibrillar material that is extracellular - Sitting in dense fibrous meshwork surrounding neurons, astrocytes and oligos. - Components of cells, but different from the cells themselves
[![histo-25](]( stain to differentiate white matter (dark blue) from cortex
[![histo-26](]( stained section to show alzheimer’ s lesions: neurofibrillary tangles (green) and senile plaques (red).
[![histo-27](]( the red circle is a senile plaque stained in the neuropil
[![histo-28](](, can stain with anti-tau immunostain to show neurofibrillary tangles (Alz dx)
[![histo-29](]( of Substantia Nigra with neuromelanin accumulations in cell bodies (neuromelanin is a breakdown produce of dopamine)
##### ### Cellular players Table: [![histo-30](]( #### Astrocytes Supporting cells in the CNS. They regulate fluid and ionic balance within the brain. They have a major role in regulating glutamate levels. It undergoes gliosis in response to CNS injury. This is when it proliferates and hypertrophies. This is the CNS equivalent of scar formation. Astrocytic gliosis represents a relatively pernanet irreversible change and may be one factor that interferes with CNS regeneration aftr injry. #### Oligodendrcytes Small, round cells, they provide myelin for multiple CNS axons. Loss of oligodendroglia is the defining component ofprimary demyelinating diseases of the CNS (common one is MS). In histo sections, oligodendroglia often look like fried ggs. #### Microglia They are scavenger cells (they are macrophages). They proliferate in response to CNS injury but represent a more subacute type of reaction (to be contrasted with the more slowly evolving astrocytic gliosis). Both microglia and astrocytes proliferate in response to insults of brain injury/necrosis/inflammation (astrocytes more slowly than microglia). When microglia phagocytose necrotic debris in the brain (eg inan infract) they take on a round shape, become distended, and have a granular cytoplasm with no active GFAP. ##### Markers and staining: - Some generic markers will mark all neurons - Some markers will mark just specific cells-e.g. purkinje cells Glial “scar”—can see the astrocytes (which have extensive processes):
[![Glial "scar" - can see the astrocytes (which have extensive processes)](]( “scar” – can see the astrocytes (which have extensive processes)
[![Microglial activation is rapid in hippocampus of mouse with injury](]( activation is rapid in hippocampus of mouse with injury
### Patterns of Injury [![brain-33](]( When a neuron is cut, two major events occur. 1. Breakdown of the axon (and myelin if present) as a result of wallerian degeneration. The degeneration of the myelin sheath because of the axonal destruction is called secondary demyeliantion. Primary demylination is when there is an intact axon and just the degeneration of the sheath. Proximal to the cut the neuronal cell body undergoes central chromatolysis (the neuron body swells and its nucleus and NIssl (RER) bodies are pushed to the periphery of the cell body. Central chromotolysis may be reversible or may progress to death of the neuronal cell body. Chromatolytic neurons is below. [![brain-34](]( - This image shows central chromatolysis in anterior horn cells (spinal cord) - Is a result of widespread carcinoma that invades the subarachnoid space in spinal cord—has gone through the nerve roots [![brain-35](]( - wallerian degeneration of right corticospinal tracts (through pons and medulla) - see shrinkage of the tract, atrophy of the pyramids, etc.ois a result of RIGHT-sided cerebral hemisphere stroke, as can be seen below: Retrograde degeneration (die back degerneration): this is when neuronal cell bodies atrophy if there is a progressive injury to their distal axon. Viincristine is often a culprit Trans synaptic degeneration is a process where a neuron (commonly a group of neurons) undergoes atrophy when its major synaptic input is lost (due to an infarct, trauma (surgical, neoplastic, etc) or any other cause). The atrophy of nerve cells following damage to the axons that make synaptic connections with them. An example of trans synaptic degeneration of the lateral geniculate nuclei (above the hippocampus) when the optic nerve is cut. Since this area of the brain gets all of its innervations from the optic nerve. Trans synaptic degeneration is a long process and occurs over months to years. #### Types of injury: Anoxic-ischemic: change which results from inadequate oxygen/blood delivery to the high energy dependet neuron. Excitotoxicity: neurons become overstimmulated because of excessive glutamate stimulation. Apoptosis: different stimuli initiate this. ### Overview of the Spinal Cord [![brain-37](]( #### What’s wrong with this illustration? - Length of spinal cord-should have stopped at L1/L2 - Orientation of nerve roots-should not be coming out directly..should go down and then out - Diameter of spinaloA better diagram - Cauda equina is a collection of nerve roots! - A better diagram: [![brain-38](]( #### Spinal cord in cross section [![brain-39](]( - Dark purple-white matter on the outside - Lighter white/violet is gray matter on the inside (reverse of brain!) - The ventral horns are at the bottom of the image, and dorsal horns are at top - Gray matter is “horns” - white matter is columns or fasciculi - Columns are dorsal side (dorsal columns) can be divided into fasciculus gracilis (slender bundle)-FG and fasciculus cuneatus (FC-wedge shape) [![brain-40](]( #### Distinct sensory and motor pathways are present in white matter of spinal cord: - Dorsal column – contains major sensory pathway: the dorsal column can be divided into the FC and FG present only at thoracic level - Lateral and ventral columns contain motor and sensory tracts - Propriospinal system of fascicuus proprius is a separate region of white matter distinthe grey matter. It contains fibers that interconnected teh differnent spinal cord levels. - Anterolateral (spinothalamic) pathway - Motor pathways (including lateral corticospinal) - Others exist, but those are the 3 we will cover - Dorsal-sensory; DRG’s are collection of cell bodies just outside CNS - The info comes in and makes a synapse-where some sort of modification/integration occurs - Ventral-motor #### More of the dorsal horn: - Associated with somatosensory function - Receive input from the DRG cells - Nuclear subdivisions (6) seen in dorsal horn of spinal cord - Substantia gelatinosa – major sensory receiving area (VERY light) – very few myelinated fibers (if any?) – like gelatin-gluey - Dorsal horn can be divided into lamina-Rexed’s cytoarchitectonic classification-but we are not really going to go into them - SG correlates to the second laminar level #### Ventral horns: - Control of the skeletal muscles - Motor neurons in this region send their axons to the central roots - Some of the motor neurons are large and are called alpha motor neurons which innervate striated muscle and smaller ones called gamma motor neurons innervate the muscle spindle (sensory structure) gamma neurons do not directly cause contraction of skeletal muscles - Can see pools (pink) of nuclei for motor neurons: [![brain-41](]( - Organization is an example of somatotopic organization: flexors dorsally and extensors ventrally too [![brain-42](]( - They use Ach as the neurotransmitter-also see some collection in the lateral horns (autonomic neuron bodies!) – see black circle below [![brain-43](]( Lateral Horn - Preganglionic sympathetic neurons from T1->L2,L3 make up the intermediolateral cell column in the lateral horn - Lateral horns mediate teh visceral motor function [![brain-44](]( - Spinal cord levels [![brain-45](]( 171. Starting with C3 in upper left, we see LOTS of white matter 172. This is because you start collecting sensation in the feet, move up through arms, etc.–>as you go up, you bring more and more axons (myelinated) up to the brain..and also because motor neurons branch off progressively, so the most axons will be higher up too 173. Ventral horns are going to be larger at some levels rather than others, because there will be the need for a lot of motor innervation in, say, the extremities (brachial plexus-cervical and leg muscles-lumbar?) Fibers are classified as follows: [![brain-52](]( - Can classify by roman numeral or by lette–used interchangeably - Just be familiar with them, don’t memorize #### Extra add-on’s from her handout: - Each DRG has cell bodies of primary sensory neurons from specific region of the body - 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1 coccygeal - For motor neurons, there are the alpha motor neurons that are large in diameter, and then there are the gamma motor neurons, which are smaller - Gamma motor neurons innervate the muscle spindle - Contribute to regulation of muscle tone, but do not DIRECTLY cause contraction - With the motor pools (the arm in the spinal cord picture), the flexor muscles are located more dorsally and extensor muscles located more ventrally - Intermediate gray matter-located b/w dorsal and ventral horns - Region contains interneurons that link sensory function of dorsal horn with motor function of of ventral horn - Many polysynaptic spinal reflexes involve the interneurons - Also, descending pathways can form contacts with these neurons - T and L segments have the lateral horn, where preganglionic sympa neurons form a column of cells called the intermediolateral cell column - White matter FG goes all the way down, but FC is only C1-T6 #### Extra Dorsal Horn – Nuclear subdivisions include substantia nigra, also can be divided into Rexed’s cytoarchutectonic classification Ventral Horn – contains nuclei (pools) of motor neurons Cervical levels – no later horn and dorsal column FG & FC Lumbar levels – anterior horns large and white matter decreased Thoracic level – dorsal horns are skinny and ventral horn/lateral horn Sacral level – fat horns and decreased white matter, may see spinal roots