Exam #1

T2 weighted MRI

"Fat-suppressed" Shows water-rich tissue better Injured nerves tend to swell, water is white and brain tissue is black

king menes

"smasher of Foreheads", incapacitated his rivals with an ivory mace, killed by a hippopotamus

Alpha motor neurons

("motoneurons") can make a muscle contract or a gland change activity because their axons make contact with the muscle or gland, large dendritic arbors because need lots of information to decide to contract

they cut both vagal nerves on animals and watched to see how they recovered, they recovered when only 1 was cut, had no reaction when just the sympathetic nerve was cut, found the substance reuniting the 2 ends of the cut nerve was regenerated nerve, when waiting longer time periods before cutting the second vagal nerve the dog lived longer, nerves first divided where now firmly united and callous, regenerated nerves were smaller than the original, Haighton - prolongation of life taken to indicate partial regeneration NOT complete, when nerve recut the animal died meaning that it was in fact nerve tissue and that it was not other nerves taking the function of the vagus nerve,

1. Describe the logic behind Cruickshank's/Haighton's experiments? Why were the results surprising?

cranial nerves

12 pairs, left and right, Attached to ventral surface of brain, Optic nerve is actually CNS, Most serve sensory and motor functions of head and neck, One of them, the Vagus ("wandering") nerve, travels throughout thoracic and abdominal cavities and regulates functions of internal organs (Parasympathetic)

seddon and sunderland

2 scales of grading clinical severity of PNI

repair-healing regrowth replace

3 R's

seddon scale

3 criteria grading system, got data from WWII soldiers, neurapraxia, axonotmesis, neurotmesis

spinal nerves

31 pairs, Leave vertebral column and extend to skeletal muscles, branching repeatedly as they go, In the PNS (after exiting the vertebral canal) are mixed containing both sensory and motor fibers

Flaccid Paralysis or Paresis Muscle Atrophy Areflexia or hyporeflexia of deep tendon reflexes Fasciculations Fibrillations

5 major symptoms of LMNS

sympathetic chain

A chain of ganglia that runs along each side of the spinal column; part of the sympathetic nervous system.

DTI

A doctor suspects a patient has damaged the sciatic nerve following an injury a knee several weeks ago, but is unsure of the degree of nerve injury. Which of the following modalities would best be able to assess the presence of myelin, and thereby determine the proportion of axons sparred from Wallerian degeneration?

In both the dorsal root ganglion and the ventral horn

A mixed (motor and sensory) peripheral nerve receives an injury classified as Axonotmesis, where can chromatolysis be observed?

Redlich-Obersteiner's zone

Boundary Between CNS and PNS, a little inside the surface of the brain/spinal cord

dualist: nerve fiber and cell body as separate, reunion concept - fibers on both ends of the nerve splice grow together to reunite the neuron monist: nerve fiber originates from the cell body, outgrowth of nerve fibers connected to the cell body

Briefly describe the two competing theories about how a nerve regenerates.

oligodendrocytes

CNS, myelinate 1 internode of many axons, secrete fewer growth factors, originate from neural tube, cannot proliferate following an injury

T1 weighted MRI

Can detect interruptions in the fascicular structure Good at detecting fat (high contrast) and cartilage, water is black and brain tissue is white

synaptic plasticity

Changes in structure of dendrites and terminals, growth of new terminals and dendrites

Cruikshank studied the vagus nerve in dogs. He hypothesized that peripheral nerve regeneration was possible. He fully transected the vagus nerve on one side and allowed some time to pass before cutting the opposite vagus nerve. If he allowed enough time to pass, the dog lived after the second surgery, and Cruikshank inferred that the nerve had healed. He varied the time between the two surgeries, predicting that waiting longer would prolong survival because it would give the nerve more time to regenerate. He looked at the nerves later and found some type of substance at the injury site on the nerves. His hypothesis was not truly confirmed until Haighton's experiments: After performing the same procedure as Cruikshank (except he divided the vagus nerve rather than transecting it), he cut the original cut sites on both vagus nerves in the dog to determine whether regeneration had actually taken place OR if another nerve(s) was compensating. they recovered when only 1 was cut, found the substance reuniting the 2 ends of the cut nerve was regenerated nerve, when waiting longer time periods before cutting the second vagal nerve the dog lived longer, when cut too soon together the dog would suffer and die, in their suffering they would often lose their bowels, have trouble breathing, vomit, found that when cut about 3 weeks before cutting the second one the dog would be able to survive (to some extent), nerves first divided where now firmly united and callous, regenerated nerves were smaller than the original, when the vagus nerve was recut the animal died meaning that it was in fact nerve tissue and that it was not other nerves taking the function of the vagus nerve

Describe William Cumberland Cruikshank's experiment that demonstrated peripheral nerve regeneration. What nerve did he study? What did he do to it? Describe the experiments, his observations, and how he confirmed his hypothesis

A growth cone is an extension of the proximal stump that explores the environment and guides the growth of the new axon by responding to various guidance cues. A growth cone consists of a foundation of microtubules that supports actin filaments which constantly assemble and reassemble, growing the cone in a particular direction. A growth cone moves via filopodia, feet-like extensions of the cytoplasm that surround growing bundles of actin. Filopodia "compete" to capture the microtubules of the growing axon in the cytoplasm and actin, which causes stabilization of the axon and inhibits growth of neighboring filopodia. Guidance cues involved in growth cone movement may be ECM-bound, secreted, or membrane-bound Either attractive or repellant, at a short or long range May even elicit other responses such as branching or an altered sensitivity to other cues These signals may originate from the ECM and extracellular environment or from the nucleus of a cell (and then transported somewhere) Concentration gradient of neurotrophins keeps the growth cone moving forward. Neurotrophins originate from Schwann cells and targets of the growth cone Myelin is another guidance cue of sorts (myelin usually repels axons) Myelin comes from Schwann cells Netrins, Slits, Semaphorins, Ephrins These guidance cues require receptors on neurons They function as "sign-posts" "Stop, keep out, turn back" "Go, keep growing, come this way" "Start branching" "Change how you respond"

Describe the structure of an axonal growth cone. Where are the different cytoskeletal elements localized, how does it "move"? What types of signals are involved in this process, and from where would they originate?

Neuroregeneration is the repair, regrowth, or replacement of nervous system tissue after injury, either by endogenous mechanisms or exogenous intervention. Note, this process takes place after some type of injury to the nervous system, with causes ranging from a slowly progressing disease to immediate trauma. Neuroplasticity is changes in synaptic strength or the generation of new synapses in response to changes in patterns of neuronal activity; it's the ability of neurons to change connections in response to the environment, for example, forming new connections to compensate for a lost function. Neuroplasticity does NOT necessarily take place in response to injury. Neuroplasticity, in theory, is happening throughout one's life as one forms new memories, learns behaviors, and lives new experiences. Neurodevelopment is the development of the nervous system in an embryo. The process involves stem cells differentiating into cell types needed for the nervous system (ex: glial cells, neurons). Neurodevelopment does NOT take place in response to damage of the nervous system. During neuroregeneration, some cells may revert back to a neurodevelopment-like state that allows them to differentiate into a different cell type and/or grow and divide. Neuroregeneration, neuroplasticity, and neurodevelopment all involve growth and change of the nervous system. These three processes, in theory, allow our body to mature and function properly. Not only do these processes overlap in terms of their cellular requirements, effects on behavior, they also overlap in terms of the types of genes expressed, the degree to which these processes overlap is subject to intense debate

How are the concepts of neuroregeneration, neuroplasticity, and neurodevelopment related? How might they be distinguished?

A regenerated nerve May have smaller diameter b/c axons will have smaller diameters Axons may have shorter myelin segments Axon diameter and myelination will affect functionality going forward! Muscle targets may be innervated differently! A different motor neuron type may innervate the muscle target, changing the identity of the motor unit Changes in motor unit identity and distribution

How is a regenerated peripheral nerve different from one that was never injured in terms of its structure and innervation pattern?

Schwann cell memory hypothesis, pruning hypothesis

Hypotheses for how the axon find the right target?

yes! no! no!

Is regeneration a general property of nerves? Can sensory fibers innervate muscle? Can motor fibers innervate sensory structures?

pruning hypothesis

Making contact with the correct target triggers other axonal branches to be pruned, axon sends all different growth cones to each fasicle, correct ones stat and wrong ones degenerate, will retract if connects to the wrong place

schwann cells

Myelin-forming cells of the peripheral nervous system, Also perform many support functions, Known for their role in the regeneration ability of peripheral nerves, support, regulate salt concentration, myelinate 1 internode of 1 axon, secrete basil lamina and growth factors, originate from the neural crest (PNS), can proliferate following injury, can seperate from myelin, break down myelin and make goodies to entice the neuron to regrow in that direction

regrowth

Regrow- if the part is damaged beyond repair, another part might be grown by the body given the right conditions

Schwann cell memory hypothesis

Schwann cells "remember" if they were in a motor or sensory nerve Express factors that preferentially attract those axons GDNF and pleotrophin are expressed more in motor axon Schwann cells NGF, BDNF, Hepatocyte growth factor are expressed more in sensory Schwann cells, some kind of signal that tells/reminds them what they are, evidence to support this

First-order Pseudounipolar Cells

Sensory neurons receive environmental input because their "dendrites" are specialized for detecting physical stimuli, cell bodies off to the side and dendrites look like axon,

satellite cells

Supportive Cells of the Peripheral Nervous System, they share many common features with astrocytes, sit around pseudounipolar sensory cells, cell bodies around in the ganglia, function not sure

false

T or F: CNS neurons undergo a different series of changes

false because you can use a nerve from in the body as a conduit

T/F: Without currently available synthetic nerve conduits, surgeons would be unable to repair gaps in nerves > 5 mm in length

false because reinnervation with another axon can come in and do that job

T/F: Without reinnervation by the original axon, motor recovery cannot take place and myofibrils will degenerate

true! (a patch of skin is left on to monitor how healthy the graft is, if blood supply is not restored it will become evident in this tissue first)

T/F: can you move muscles to other parts of the body?

become narrower over time

The bands of Büngner....

axons (and in more sever injuries, myelin. Schwann cells stick around but leave the axon)

Wallerian degeneration is the process whereby _________ is/are degraded and removed distal to a site of nerve injury

chronic inflammatory conditions, mutations, autoimmune disorders, infection by bacteria, toxic effects, metabolic disorders

What are some causes of peripheral nervous system disease?

Sunderland (Grades 1-5) Seddon (3 Grades: Neurapraxia, Axonotmesis, and Neurotmesis) HINT: Seddon is a shorter name, so it's the scale with only 3 Grades rather than 5 The grades are based on cellular changes caused by the extent of tissue damage, with the lowest grade being attributed to the least damage and the highest grade being attributed to the most damage. The microscopic changes that occur at the site of nerve injury are directly related to recovery potential! Spontaneous recovery: Sunderland Grades 1-3 Surgery required for recovery: Sunderland Grades 4 & 5

What are the two scales of peripheral nerve injury? What is their physiological basis?

Age of individual: greater chance of regeneration in neonatal-early childhood ages because permissive molecules are still present it's easier to have cells in a regrowth state Distance from soma: if the distance b/t growth cone and target is too great, neuron won't be able to regenerate Neuron required to synthesize more cellular components, and more distance makes the growth cone farther away from target derived trophic factors Degree of injury especially in relation to the integrity of the extracellular matrix: think of the Seddon and Sunderland scales Grade 5 injury = no epineurium = no guide for axon growth Also, higher grade injury probably involves more damage at the site of injury as well: vascular trauma, gap b/t proximal and distal segments, fibroblasts proliferate at site of injury and can form dense scar tissue In the most severe injuries, Schwann cells and axons are no longer confined by the peri- and epineurium, Schwann cells and fibroblasts proliferate Time: muscles turn to fat over time, endoneural tubes w/in Bands of Bunger become more narrow, growth factors decrease Axons can wander (loss of axon guidance cues) and can result in neuromas (large masses of axons can accumulate in and around the site of failed regeneration), Axons must reach their targets w/in 1-2 years!!

What are three factors that influence regeneration of a severed peripheral nerve? How do they relate to the sequence of events and/or molecular signals that accompany successful nerve regeneration?

1 mm/ day, about an inch per month; 1-2 years; 2ft

What is the rate of axonal regrowth in the PNS? How long can an axon grow? max length an axon can grow?

microscopes, staining techniques

What new technologies helped resolve the controversy?

in vivo

What type of experiments did William Cumberland Cruickshank perform?

couldn't be 100% sure, didn't have the technology we do to discern if it was in fact nerve, when nerve recut the animal died meaning that it was in fact nerve tissue and that it was not other nerves taking the function of the vagus nerve, judgement based on 1 experiment and 1 study, death occured sometime after making these studies difficult to use as evidence, different animals used across studies, different protocols lead to different results, different nerves,

What were some sources of variability in the efforts to confirm the findings of Cruickshank's/Haighton?

right when they enter the spinal cord, a little inside the surface of the brain/spinal cord (schwann cells cling to the axon as it crosses the white matter but are gone after a few mm)

Where does the CNS become the PNS? (Where does myelination change from oligodendrocytes to Schwann cells)

To give the injured nerve enough time to find its original conduit

Which of the following is NOT a reason why a nerve transfer (neurotisation) would be preformed? -To avoid surgery at the site of injury -To give the injured nerve enough time to find its original conduit -To achieve functional recovery despite high grade injury -Injury < 6 inches from the spinal cord -The presence of a large, scar-tissue filled gap

some injuries recover because of plasticity in the CNS, Additionally, a partial injury to a nerve that preserves some motor innervation can recover without reinnervation from the original neuron via terminal sprouting of adjacent preserved axons

Why do some peripheral injuries recover without reinnervation?

rehabilitation

____________ is needed to prevent neuropathic pain and to overcome effects of disuse

neurotrophins (once they reach the schwann cell and it remyelinates it stops producing these but the schwann cells near it that the axon hasnt reaches are still making some, therefore keeping the concentration of neurotrophins in front of the axon and the axon/growth cone moving forward)

a concentration gradient of __________ keeps the growth cone moving

Tinel's sign

a way to detect irritated nerves. It is performed by lightly tapping (percussing) over the nerve to elicit a sensation of tingling or "pins and needles" in the distribution of the nerve. It takes its name from French neurologist Jules Tinel, tingling in the distribution of a peripheral nerve, suggests regrowth, to tell is a nerve is regrowing, tap the end of the nerve and if there is a tingling sensation the nerve is regrowing.

areflexia

absence of reflexes

mast cells

act as an alarm/damage signal during wallerian degeneration, call scwann and macrophages to clear myelin and clean up the mess of the distal end

transneuronal degeneration

an injury does not happen in isolation, injuries to peripheral nerves have a domino effect on neurons in the communication chain, changes in innervated tissues and other neurons, post synaptic cells effected, glial cells block synapses, neurons in the chain also degenerate because it doesnt have the trophic influence of the neruon before it, injury to a neuron causes several morphological and physiological alterations in the tissue innervated, New "terminals" would sprout from the specialized end portion of the neuron; whereas "collaterals" sprout (collateral sprouting) from the nodes of Ranvier. BOTH mechanisms are responsible for the ability of preserved motor fibers to "take over" when neighboring axons degenerate leaving muscle fibers denervated, can cause CNS reorganization (seek out new means to innervate, may make it harder for the old neuron to connect to CNS because they have rewired

the injury involves more structures, disrupting connective tissues is worse than the axon because these need to be there for regeneration (need to lead axons to correct targets)

as the grade increases...

filopodium

axon bundles looking for signals in the growth cone, if find progrowth signals starts growing in that direction and microtubules grow in that part of the cell, repulsive signals lead to microtubule depolymerization (removal), steering via Differential adhesion (can attach to some things), cytoplasmic streaming (push cytoplasm), Transducing different signals and by Generating Mechanical force (contract, myosin), "compete" to capture the microtubules, Microtubles inhibit the formation of more filopodia, stabilizing the growing axon, once layed with microtubules axon prevents it from forming a side branch,

Diffuse Tensor Imaging (DTI)

axon tracts, (up and down), how water travels/diffuses within neurons, used to study tracts, be able to assess the degree of myelination the best, as it generates a set of 3d vectors (tensors) indicating the direction water diffuses at any given point in the tissue. This is highly directional in myelinated nerves, as water tends to diffuse up and down the nerve. NCS (nerve conduction studies) might be difficult to do depending on the patient, as the nerve is deep and inaccessible in the upper thigh. Credit is awarded for T1 MRI, although the fine resolution and the ability to show directionality would probably make this superior.

glial tissue (gliosis)

because so much protoplasm will be destroyed when the neuron is cut too close to the cell body the neuron will die, they die and are not replaced since differentiated neurons are unable to reproduce. Instead, the space previously occupied by the neuron is replaced by...

neuroma

big swelling in the nerve, annoying and painful, cut it out so the nerve can reattempt to regrow, occurs after several months of failed recovery, schwann cells and fibroblasts proliferate at the site of the injury and form a dense network of scar tissue, large masses of axons can accumulate in and around the site of failed regeneration, treatment: surgical resection, chaotic information, nerves branching and growing eveywhere

ischemia

blockage of bloodflow that cuts off nutrients to a nerve

central nervous system

brain and spinal cord

rami

branch of the spinal nerve, ventral goes to the front of the body and appendages and the dorsal goes to the back of the body

axonotmesis

breaks axon but NOT nerve itself, mesenchymal structures preserved, occurs when there is complete interruption of the axon and surrounding myelin, the mesenchymal structures are preserved

lower motor neuron syndrome

causes flaccid paralysis or paresis (not total loss of function), muscle atrophies, areflexia (no reflex because nothing to stimulate the muscle) fasciculations (dying nerve signals AP and get random muscle twitches, falls limp and twitches randomly), fibrillations (tiny fasciculations due to accidental release of synaptic vessicles without CNS command), sometimes able to feel it depending on the fiber type severed,

Transdifferentiate

cell changes its type

in vitro

cells and grow cells on a substrate

neuroplasticity

changes in synapse strength or generation of new synapses in response to changes in neuronal patterns, taking what we have and rearranging it (new connection) to replace circuits/new pathways for old activities, e,g phineas gage recovered some function after a couple years, initiated by experience, learning, rearrangement of existing neuronal connections

William Cruishank 1776

chemist, discovered the importance of the lymphatic system, observed the vagus nerve reuniting in mammals, first evidence that PNS regeneration was possible and ruled out other compensatory functions

5-8 weeks

clearing the debri stage can start after several days but can take an average of.... to complete

ganglia

clusters of cell bodies in the PNS, cell bodies of pseudounipolar sensory cells tend to cluster together

Central adaptation after peripheral nerve injury

common cause of neuropathic pain?

peripheral nerve injury

common, yearly incidence: 45 cases per 100,000 people (roughly the same as epilepsy), primarily effects younger people (take more risks with their bodies), over 90,000 people every year in the US, most common causes include motor vehicle accidents, sharp injuries, consequences: results in impaired limb function, loss of ability to work, decreases quality of life,

neurotmesis

complete break inculding mesenchymal structures, involves a total disconnection (all the layers) of the nerve and total functional loss.

lacerations

complete or incomplete, easily produced so most easily studied,

central adaptation

consequence of transneuronal regeneration, motor neuron injury causes changes of innervation of muscle cell which can lead to changes in spinal cord itself, Plasticity and compensation can lead to altered functionality, Persistent weakness, Altered sensations, Common cause of neuropathic pain (changes in spinal cord cause maladaptive neuroplasticity, rewiring using sensory fibers leads to pain), Can be very significant in injuries to newborns and young children whose nervous systems are more plastic Vigorous rehabilitation is needed to prevent neuropathic pain and to overcome effects of disuse

sunderland scale

consists of 5 'grades' of nerve injury, 1-3 can most likely recover spontaneously but parts of 3-5 require surgery

Arm nerves are rerouted to innervate discrete parts of pectoralis major The pattern of activity is read, transformed, and fed to actuators in the prosthetic limb, neurons in new muscle can be read (pattern of activity) and can figure out what is is they were trying to do with their old limb through the new muscle

control of prosthetics using the original nerve?

Enteric nervous system

controls function of gastrointestinal tract, pancreas, and gallbladder, there are no Schwann cells, hence axons are unmyelinated, surrounds digestive tract (layer of muscles surrounding that tube), like a fishnet stocking/web around the digestive tract

growth cones

cross the site of injury, has to get through/across scars to get in the tubes, change rapidly in the search for signals, same as development, need a malleable support during development so use actin fillaments (not as strong as microtubules but help put everything in place), have filopodium

EMG studies

detect functioning in motor units with an electrode, identifies fibrillations, observe signals early on in mild injuries (still hanging on), if severe = flat line, if firing after a couple months when previously flat lined: firing, Detects functioning motor units with an electrode Can identify fibrillations- rapid unsynchronized muscle activity resulting from denervation Signals can be observed early in mild injuries, before Wallerian degeneration retracts the axon Signals cannot be observed early on in injuries where the axon's integrity has been compromised, When done shortly after injury, can help distinguish between neurapraxic and more severe injuries, because there might not be any observable improvement at the beginning stages of regeneration

abraham trembly

discovered regeneration in animals, found through studies on hydra, Wondered if they were plants or animals, They can move BUT they can regenerate lost parts, Swiss scholar hired to teach natural history to the Count's 3 and 6 year old, so essentially he made these discoveries while baby sitting, founder of the modern light microscope

sunderland grade 3

disrupt some of the mesenchymal structures, loss of endoneurium

Santiago Ramon-y-Cajal

drew what he saw from memory to create cells and different cell types, neuronal doctrine - neurons are the functional unit of the nervous system, harsh decree - CNS does not at all regenerate, invented silver staining to stain cell bodies and axons, observed that in cases of central nervous system injury, regrowing axons were absent. Dystrophic neurites were observed that seem to be manning a failed nerve degenerative response growth cones are seeing in the peripheral nervous system.

fasciculations

dying nerve signals and AP, 1 little muscle part tweaks by itself, twitches, random contractions of the muscle, falls limp and twitches randomly

In higher grade injuries there is more damage at the actual site of injury acutely More vascular trauma leading to hemorrhage and edema Gap between proximal and distal segments Fibroblasts proliferate at the site of injury and form a dense network of scar tissue within the endoneurial and perineurial space In the most severe injuries, Schwann cells and axons are no longer confined by the peri- and epineurium, Schwann cells and fibroblasts proliferate Loss of axon guidance cues, axons wander And misalignment of the endo/peri/and epineurium can create problems for axonal reconnection Can result in a neuroma

effects of injury severity

NCS (nerve conduction studies) studies

electrode stimulates nerve and records from the nerves target, if signal travels and reaches the target = mild injury, if doesn't = disruption in the axon, detects compound action potential, flat line if complete severance of the nerve, shortly after an injury is no axon is intact, if demylinated, flat-lines but still some data, can do this during surgical exploration itself, if regenerating will see small APs coming back after a few months, One electrode stimulates a nerve, the other records from another site on the nerve Detects compound action potentials Can detect demyelination as well as damage, This can help determine how many, if any, axons remain intact, Usually performed in conjunction with electromyography

repair

endogenous healing or treatments that seek to augment the body's own regenerative capacity

peripheral nervous system

everything outside of the brain and spinal cords emanating from the spinal cord, cranial nerves, spinal nerves, vertebrae surrounds and protects the spinal cord, special sensory receptors, somatic sensory receptors, visceral sensory receptors, supplies sensory information from the external environment and from the internal environment of the body, and transmits motor information to muscles and glands.

in silico

experiment run on computer simulations

SOX2

expressed in stem cells, able to act in the cell cycle, proliferate schwann cells express this

1. Age of individual (greater in children since permissive molecules are still present, lot more plasticity after early childhood, decreased in older adults too) 2. Distance from soma (need to synthesize more cellular components- further away from target derived trophic factors, need to make new stuff, grow out at a fixed growth rate) 3. Degree of injury (especially in relation to the integrity of the extracellular matrix, needs to be in tact because the axons needs to find that nerve) 4. Time (muscles turn to fat over time, endoneural tubes w/n Bands of Bunger become more narrow, growth factors decrease)

factors affecting regeneration

Theodore Schwann

famous for contributions to cell theory and Schwann cells, demonstrated the rabbit sciatic nerve can regenerate

replace

find exogenous biological or non-biological alternatives to the missing part to recover function

Saturday night palsy

from falling asleep with one's arm hanging over the arm rest of a chair, compressing the radial nerve (runs along inside of your humerus) you'd have problems extending your fingers, if compressed for about 8 hours becomes paralyzed, numbness in thumb pointer and middle finger

neurodevelopment

growth of axons, patterning of cell types

intrinsic neuroregeneration

healing, injury has to take place first, axons can regrow, initiated by injury

terminal sprouting

how a muscle can recover function even if its not reinnervated by the regenerating axon, in partial injuries new axon terminals sprout from adjacent uninjured axon's terminals, wallerian degeneration and the removal of the injured axon terminals leads to the release of soluble factors from the motor end plate, 70-80% of the axons innervating a muscle have to be lost for a person to experience clinical weakness, not optimal because of muscle fiber types (could change type of fast/slow twitch muscle fibers because the fiber type is determined by the neuron that innervates it), nearby axons pick up nearby neurotrophic factors from denervated muscles and pick up the slack

According to the cellular changes at the site of injury

how are peripheral nerve injuries graded clinically?

new synapses, new dendrites, birth of new cells, similar genes and growth factors involved

how does intrinsic neuroregeneration, neuroplasticity, and neurodevelopment overlap?

neuroplasticity (Although the CNS lack regenerative capacity, synaptic plasticity can lead to remarkable recovery of function)

how does recovery typically occur?

6inches (shorter for cranial nerves)

if a cell is cut within _______ of the cell body, it will most likely never recover and die

conditioning lesion (see some regrowth in the CNS side because those regrowth signals are spread through the whole cell, has to be close together timing wise)

if both the PNS side and the CNS side of a dorsal root ganglion nerve are cut, what happens?

recover function through neuroplasticity,

if the CNS has no regenerative ability, how do we recover?

Ultrasound(Fast, dynamic, portable), Magnetic Resonance Neurography (Takes a while, Patient needs to hold still)

imaging studies diagnostic techniques

function/modality

in the CNS, what are things sorted by?

based on where they need to go, mixed (sensory and motor travel together)

in the PNS, how are things sorted?

The axons will have a smaller caliber, depending on how much time passed (BoB narrowing, can slow down signal conduction and cause changes in firing speed) The Schwann cells will form shorter myelin segments Muscle innervation pattern will be different (changes in pattern of fiber types in muscle changes the muscle function)

in what ways is recovery not complete?

Parasympathetic nervous system

increases metabolic and other resources during "rest and digest", as the breaks on smooth muscles, cardiac muscles, and glands, some cranial nerves and sacral regions, rest digest feeding and breeding,

necrosis

inflammation, edema (cells take in more water because of salt concentrations, swell), immune cell activation, secondary tissue damage, injured so severely can't even release factors for apoptosis, cell explodes, lots of immune cells respond and cause inflammation, immune cells come in and release toxins that injures other cells

calcium

ion important for the initial damage signal, first to tell axon it has been injured, generally is kept out of cells, if all of a sudden the axon gets cut there is a big whole for this ion to flow into the cell, if too high activates calpain which are apoptosis enzymes,

fibrillations

little/tiny fasciculations, due to accidental release of synaptic vesicles without regard for CNS command

Jiankui He

made the first genetically modified baby, used Crispr to remove HIv-susceptible gene (CCR5) from 2 day old embryos, controversial, could be bad to do this because could cause off-target mutations (can't get just that specific gene, often get nearby genes too),m

MRI

magnets align hydrogen atoms and knock them down with radio signals, get H from water, when placed in a magnetic field they hit them with radio frequency and knock them down and how long they take to stand back up is measured, Body is largely composed of water molecules, the magnetic moments of the water molecules line up, RF energy is applied and then turned off. They respond to this in a way that allows you to predict what's happening.

synthetic nerve conduits

man-made ways to repair nerve lesions, pros: no immunosuppression, doesn't destroy patient's tissue Cons- not as effective, owing to lack of intrinsic growth factors, expensive

extrinsic neuroregeneration

medical intervention, exogenous neurons and glia, exogeneous growth factors, exogeneous tissues, tap into neuroplasticity with physical therapy, overlaps with intrinsic neuroregeneration to encourage endogenous repairs, overlaps slightly with neurodevelopment

sunderland grade 5

mesenchymal completely lost, neuotmesis

non-living membrane

mesenchymal structures are...

neurapraxia

mild, no break in continuity, something is still in tact, loss of myelin from injury, compression damaged myelin or ion concentration because of changing vessels, Causes transient functional loss, because normal ion concentrations in the nerve and tissue are disrupted by ischemia and mechanical deformation of the protoplasm

Ras-pl3k - stimulate RhoA - causes growth cone to fall apart, inhibitory,

molecules that stimulate and inhibit growth regrowth

sunderland grade 2

more connective mesenchymal structure, severed axon, wallerian degeneration, axon can grow back, axons in PNS grow about an inch per month (1ft per year), axonotmesis

stretch PNI

most common form of PNI, traction related injury, nerves are elastic but if the force is great enough it can cause damage, have to be a LOT of force, like the dissociation of a limb, to cause rupture or avulsion

stretch (55%), lacerations (30%, complete or incomplete), compression injuries (10%), other (5%)

most common mechanisms of PNS injury?

Loss and reinnervation leads to changes in motor unit identity and distribution, some groups get innervated but atrophy because not enough axons to reinnervate

muscle innervation pattern changes

myelin ovoids

myelin globules inside of phagocytes

retrograde degeneration

myelin is lost from the proximal segment of the axon, but this only goes back a few segments (lose 1-3 myelin), glial cells nearby the cell body seem to interrupt communication to the cells dendrites, cell body undergoes chromatolysis, if neruon recovers, it will issue axonal sprouts (growth cones), prepares the cell body for regeneration, metabolic changes, not as complete,

sunderland grade 1

neruapraxia, no wallerian degeneratio but is condutction block

neurotisation

nerve transfer, reroute nerves all together, do if no proximal end let, leads it to new channel, nearby uninjured nerve, take a part of this nerve, snip it, reroute it to the distal end of the injured nerve, physical therapy needed to remap functions, typically done in severe injuries where reinnervation is not likely, (<6in from cell body), reroute an uninjured nerve and use it to recover function, have the uninjured nerve and have it do the functions that arent working, snip the uninjured nerve and move it to allow a path to reinnervate areas, brain also has to rewire itself to figure out this change

compression

nerve traveling through a space that becomes smaller (e.g. swelling due to infection)

diffusable molecules

neurotrophins and neurotrophin-like molecules are also highly involved in conjunction with canonical family members Ciliary Neurotrophic Factor (CNTF): expressed by muscles and Schwann cells (motor fibers), Glial Derived Neurotrophic Factor (GDNF): expressed by Schwann cells

Apoptosis

no inflammation, quiet death, cell suicide, cascade increase, trophic factor decrease, cells shrivel up and turn into tiny little spheres, if neurons die in a safe way, orchestrated by caspace proteins within the cell that turned on by signals to do this

Waller

observed fragmentation of axons distal to nerve transection, He hypothesized a "trophic influence, as a rivulet supplied by a river, He was right, but became convinced otherwise

early egyptians

observed that injuries to the head produces the longest lasting disabilities, (e.g. aphasia), their solution was to apply grease to head, pour milk into both ears

wallerian degeneration

occurs in the distal end, the response distal to the injury site in a peripheral nerve. The entire axon and its accompanying myelin sheath distal to the site of injury fragment and are phagocytized by schwann cells which themselves shift into a regenerative phenotype, the basal lamina secreted by schwann cells remains an empty tube like structure after the axons and myelin have degenerated, both myelin from schwann cells and the distal portion of the axon break apart, phagocytosis occurs as the distal portion of the axon, schwann cells seperate from their myelin and interact with macrophages to clear myelin and axon debris, mast cells act as an alarm/damage signal to call in schwann and macrophages, macrophages respond to signals of the mast cells and invade the space around the nerve from nearby blood vessels, formation of myelin ovoids, bands of bungner form, loss of ion channels, axoplasm degenerates, clears debris so that a new axon can grow

flaccid paralysis or paresis (loss of feeling)

paralysis in which there is loss of muscle tone, loss or reduction of tendon reflexes, atrophy and degeneration of muscle, and reaction of degeneration; loss of feeling in the muscles, not necessarily total loss of function

Dendrites - receive signal (input) Cell body (soma) - neuron cannot regrow without this Axon hillock - combines and transforms inputs (integration), greater number of sodium channels, transmits and summates signals Axon - conducts signal (conduction) Axon terminals (terminal buttons) - transmit signal to other cells (output)

parts of the neuron

sunderland grade 4

perineurium loss

anti-apoptotic: (often given to those at risk of neuron injury) ALCAR (has been administered to patients with diabetic, HIV and chemotherapy-induced peripheral neuropathies) NAC (in patients with acetaminophen overdose), anti-inflammatory: ibuprofen (Some drugs need to be topically applied, because they are more dangerous when administered systemically)

pharmacological approaches to rehabilitation and regrowth?

Neurological exam Nerve conduction studies Electromyography (Usually performed together)

physiological studies diagnostic techniques

sympathetic nervous system

prepares body for "fight or flight", acts as the gas on smooth muscles, cardiac muscles, and glands, fear flight freeze fight, emerges in thoracic and lumbar segments, send preganglionic axon (1st neuron in the chain) to long post ganglionic nerve (sits outside of the vertebral column), goes to organs and parts of the body

Axons can get lost Axons can get stuck Axons can go to the wrong place The target can degenerate The repair signals can "dry up" The Bands of Büngner narrow The Bands of Büngner deteriorate

problems if PNI left untreated (time)

axon gets cut, calcium floods in, waves back propagate to the cell body and lead to a prolonged elevation of calcium, signals for repair (voltage gated channels propagate calcium waves back into the neuron), stimulated growth cone formation (membrane sealing - done by vesicles, cytoskeleton formation, activation of enzymes)

process of calcium in injury signaling

neurorrhaphy

putting the ends of the cut nerve back together, hopefully allows axon to regrow into distal stump so it can't wander out, can be done in ends closely opposed, (0-5mm), cut should be fairly clean, a cuff is used to stabilize the connection (usually biodegradable), allows the nerve to find its natural conduit, line up fascicles so you dont put them in the wrong spot and the axons grow into the wrong place

1. [Calcium] becomes very high 2. Other second messengers, like cAMP, are activated (quick) Retrograde transport of growth factors stops (slow) (Kinetics could allow the cell body to "determine" how much axon is lost) 3. Retrograde transport of molecules modified by calcium activated enzymes at the site of injury begins (slow) (E.g. CREB2, Calpains, are calcium activated caspaces) 5. Together... this activates signaling pathways that ultimately decide between life and death (mTOR PKA DLK-1 (other MAPKs and ERKs), survival signals and death signals are integrated by proteins) 6. In surviving neurons pathways ultimately activate transcription factors controlling regeneration associated genes (100's) (Different genes control discrete elements)

regeneration protocol in the neuron

neuroregeneration

repair, regrowth or replacement of nervous system tissue either by endogenous or exogeneous intervention (body healing itself or modern medicine), also prevention, PNS has some ability to regenerate and the CNS generally lacks that ability, The branch of regenerative medicine that concerns the nervous system,

enteric glia

sheath axons in ENS, similar structure and markers to astrocytes, appear to be able to make new neurons following injury, can turn into neurons, The glia are similar to the CNS, There are differences though: -60% express GFAP -The other portion do not -Almost all express PLP

basal lamina

sheets of proteins blocking/changing growth cone patterns, not in CNS, orderly structures surround the endoneurium,

non-diffuse signals

sign posts, membrane bound or ECM bound molecules, netrins, slits, semaphorins, ephrins, require receptors on neurons, can tell you to stop, go, branch out, or change how you respond

hydra

small animals with tentacles and a foot, when cut in half they both become new hydra, regenerate new nervous systems,

Hyporeflexia

small reflex response

1. minutes --> hours, sense something is wrong, changes in cell signaling 2. begin regeneration protocol, wallerian and retrograde, start, reach max, taper off 3. clear the way for new axons, sprout a growth cone, remove debri 4. reconnect and remyelinate, weeks --> months --> yeats, axon growth and target finding and reconnecting, once reconnected signals to myelin it is ready to connect

stages of nerve damage

can be successfully transplanted into a peripheral nerve, where they can survive and extend axons that not only replace lost endogenous motor axons but also reinnervate denervated muscle fibers, use of optogenetics in helping with regrowth.

stem cell neuron regrowth?

transplantation

stem cell therapies for PNI

1.Put the ends back together (Neurorrhaphy) 2.Bridge the gap (Nerve grafts or nerve conduits) 3. Reroute nerves altogether (Neurotisation (Nerve transfer) Like a new traffic route) 4. Forget about the whole "having nerves" thing and figure out some other way to operate the muscle or a prosthetic device

strategies for extrinsic PNI repair?

galen 200 ACE

studied sheep brains, described nerves and when a nerve was divided it could not be repaired, Concept of motor and sensory nerves Concluded that the brain was responsible for, memory, motor action and sensation, Thought he could differentiate motor and sensory nerves by palpating them, nerves that carried will to the muscles had to be harder, origin of the term "nerves of steel"

neurotrophins

subclass of nerve growth factors, released by a cell other than the neuron, schwann cells make CNTF, exercis and BDNF help axons regrow, a family of closely related signaling molecules that include Nerve Growth Factor (NGF) - CNS and PNS Brain Derived Neurotrophic Factor (BDNF) Neurotrophin 4/5 (NT4/5) Receptor Tyrosine kinases p75 TrkA, TrkB, TrkC, cause a piling of effects inside the cell that gets amplified, selective based on type of fiber

Perineurium

surrounds fascicles of different fiber types (separated by modality) within the nerve, small vessels, within the epineurium, middle layer of the mesenchymal structures, Epitheloid myofibroblasts

Endoneurium

surrounds individual neuron axons, innermost mesenchymal structure, most delicate layerSchwann cells establish delicate extracellular matrix (ECM), regulate fluids

Epineurium

surrounds the entire nerve, tough, allows for stretch, large vessels, outside layer of the mesenchymal structure, Surrounds the entire nerve it also surrounds blood vessels, fibroblasts and adipocytes, two layers, allows for nerves to stretch

nerve conduits

synthetic mesenchymal structures, newer ones biodegradable,

ex vivo

taking a piece/organ out and growing it in an artificial setting

bands of bungner

the basal lamina secreted by the schwann cells and fibroblasts remain as empty tube like structures after the axons and myelin have degenerated, these basal lamina tubes serve as a scaffold for regenerating nerves and schwann cells, as a result of axonal injury the schwann cells proliferate and align along the basal lamina tubes that can accept regenerative axons, the schwann cells are spindle shaped and resemble fibroblasts, NO myelin in these schwann cells!, tubes leading axons to regrow, scaffold for regenerative nerves, schwann cells make lines in the endoneurial tubes and form a pathway in the degenerated nerve

neurogenesis

the birth of new neurons from intermediate progenitor or stem cells, how we can obtain more neurons for repair

synaptogenesis

the formation of a stable synaptic contact with a responsive muscle shifts the neuron back into 'transmit mode, muscle cells release neurotrophins and neurons will grow to those and the axon will reinnervate and switch back to transmittion mode and make neurotransmitters

Chromatolysis

the immediate response that sustains the proximal segment if the nerve and later on regeneration of the distal axon, the reaction of the neuronal cell body following damage to its axon and is a retrograde change that may accompany nerve injury. The rough ER (nissl substance) upregulates protein synthesis, turns off proteins for enzymes making, packaging, and releasing neurotransmitters, and upregulates proteins for growth, initiated by a massive influx of calcium, neuron switches from transmission mode into regrowth mode, occurs during retrograde degeneration, what occurs: the soma swells due to too much water intake, dissolution of the rough ER (use nissl to see this, nissl substance covers more surface area, increasing protein synthesis) (rough ER doesnt go away, just spreads out more to increase protein synthesis but is no longer consolidated in 1 space, hence the color decrease), nucleus moves in the soma as rough ER expands, all protein manufacturing aparati are maintained, increased enzyme levels for protein production, Changes in a neuron coinciding with its attempt to repair (part of survival, neuron stops communicating with targets), proteins involved in transmission get down regulated, nucleosome increase size, increased mRNA synthesis, increased protein synthesis, increased slow axonal transport

2. loss of trophic signals (blocking of survival genes from reaching the cell body) and 3. retrograde transport of damage signals from the site of injury and initiation of regenerative program transcription factors through signaling cascades, leading to induction of regeneration-associated genes (flow to the cell body), modified proteins travel in the opposite direction (calcium activates enzymes to modify proteins which then get shipped to the injury site)

the switch from transition mode to regrowth mode is initally dependent on calcium signaling, but later comes to involve...

cellular

there is a _______ but not a functional distinction between the PNS and the CNS

slow

type 1, dark meat, aerobic, postural control, lasts long not strong

fast-twitch

type 2, white meat, anaerobic, brief contraction, fast power that doesnt last long

autografts

using a healthy nerve from the person's own body to repair a damaged nerve, pros: easily tolerable, gold standard, 80% recover cons: function may be lost in sacrificed nerve, and fascicle structure may not be the same

allografts

using a nerve from an organ donor to repair a damaged nerve, pros: doesn't destroy the patient's tissue, not limited in supply cons: requires the patient to be on immunosepressive therapies because the body will attack it but it could cause infection or tumors

the PNS can die following an injury and usually aren't replaced, CNS neurons rarely if ever reinnervate their correct target, most areas of the human nervous system cannot generate new neurons in adulthood,

ways Santiago Ramon-y-Cajal was right

some areas of the PNS does not grow new neurons (olfactory neurons, enteric nervous system), PNS neurons can regrow their axons and reconnect, CNS axons can regrow but only up to 1mm but do a bad job, some brain areas CAN TOTALLY generate new neurons in adulthood (hippocampus), many types of glial cells are capable of regenerating/being generated anew

ways Santiago Ramon-y-Cajal was wrong

compression, low concentrations of toxic substances, disease (neuropathies, due to underlying conditions), (compensation occurs overtime with the slow diseases, a large amount of damage can occur unnoticed, and the "clock" or the time frame after which recovery is unlikely, may have already been running for some time)

ways in which peripheral nerves get damages fast (days --> years, more time for compensatory nerves to take over)

trauma, ischemia, burns, frostbite, electrocution, toxic substances at high concentrations,

ways in which peripheral nerves get damages fast (seconds --> hours, lead to immediate nerve loss and function)

laminin, fibronectin, collagen; depends: endoneurium = schwann cells, perineurium and epineurium = special fibroblasts

what ECM (extracellular matrix) proteins are growth cones capable of detecting (permissive substrates the growth cone can gown on)? who makes them?

physical therapy and electrical stimulation

what can help activity dependent processes that prevent atrophy?

the nerve that innervates the muscle, experience of the muscle fiber changes how axons respond making the axons specific to the fiber type

what determines muscle fiber identity?

adipose tissue (fat)

what do myocytes (muscles) become replaced with after 2 months following an injury?

basal lamina and schwann cells (able to degrade environment such as scar tissue)

what form permissive tubes

neurons switch from transition mode to a regenerative state, saves neurons from further damage, and begins regeneration, initially depends on calcium signaling but later comes to involve retrograde transport of damage signals (cell body reals in these signals after calcium signal expires), from the site of injury and the initiation of regenerative program transcription factors through signaling cascades, new growth cone sprouts from the proximal stump, they begin to regrow in a fashion similar to development, dependent on both fixed and diffusable signals

what happens within the first 24 hours following an injury?

apoptosis is a quiet cell death that does not cause inflammation and occurs when neurons die in a safe way, whereas in necrosis the cell doesn't have time to release apoptosis factors and explodes violently causing the influx of immune cells that cause inflammation and release toxins that cause damage to other cells and causes edema

what is the difference between apoptosis and necrosis?

bone, meninges, CSF

what surrounds the CNS that DOES NOT surround the PNS?

autographs come from the person's own nerves which is good because it is easily tolerable but bad because it may cause a loss of function and the fasicle may not be the same. Allografts come from a donor nerve which is good because the patient won't lose function but bad because the patient would have to be on immunosuppressive therapies leaving them open to infection, etc.

whats the difference between autographs and allografts

rupture

when the Peripheral nerve gets stretched so far it gets pulled apart

avulsion

when the peripheral nerve gets stretched so hard it pulls off the spinal cord

PNS not including the ENS

where are schwann cells found?

the intermediate horn (above motor neuron and below the ventral horn)

where does the sympathetic nerve cell body live?

in the dorsal root outside of the spinal cord

where is the dorsal root ganglion cell body?

ventral horn of the spinal cord

where is the motor neuron cell body live?

in vivo

whole organism is studied, done in the organism

because axons and muscles provide mutual trophic support to one another

why does atrophy occur so quickly in PNI?

makes nerve axon travel in the same direction at the same time, clearing myelin has to happen because they would repel away otherwise

why is it adventageous that myelin usually repels axons?