Neural Repair

Question 1

Peripheral Nerve Repair

1. Scaffolding - This is non-axonal element of nerve - Schwann cells are the key element for rebuilding the scaffolding - If the nerve is severed, ____ (the size of the gap) determines the repair options.
   - End to end repair is optimal.
   - If less than 3 cm ___ and ___ grafts can be used.
   - If greater than 3 cm, then ___ grafts should be used, usually the ___ nerve.
2. Proper Milleu (local physiologic environment) - This is ___cell driven.
   - They revert to a more primitive state and begin to produce ___ and ___, thus creating an ECM for axonal growth.
   - They also up-regulate growth genes to stimulate axonal growth and express cell adhesion molecules and receptors, primarily ____. This leads to CN proliferation and development of bands of Bunger, thus supporting axonal growth.
   - Requires substantial nutrients and cofactors, including __, __ and ___ (many people with carpal tunnel will get better if you just give ___!).

3. Time

1. ___ Degeneration- ____ degeneration is a process that results when a nerve fiber is cut or crushed, in which the part of the axon separated from the neuron’s cell body degenerates distal to the injury.
2. ___ ___ proliferation - this make take up to ___ weeks
3. Axonal regrowth - axons grow at a rate of __ mm/d

Answer 1

Peripheral Nerve Repair

1. Scaffolding - This is non-axonal element of nerve - Schwann cells are the key element for rebuilding the scaffolding - If the nerve is severed, neurotmesis (the size of the gap) determines the repair options.
   - End to end repair is optimal.
   - If less than 3 cm allografts and synthetic grafts can be used.
   - If greater than 3 cm, then autologous grafts should be used, usually the sural nerve.
2. Proper Milleu (local physiologic environment) - This is schwann cell driven.
   - They revert to a more primitive state and begin to produce laminin and collagen, thus creating an ECM for axonal growth.
   - They also up-regulate growth genes to stimulate axonal growth and express cell adhesion molecules and receptors, primarily interleukin-1. This leads to CN proliferation and development of bands of Bunger, thus supporting axonal growth.
   - Requires substantial nutrients and cofactors, including vit c, b6 and b12 (many people with carpal tunnel will get better if you just give b6!).

3. Time

1. Wallerian Degeneration- wallerian degeneration is a process that results when a nerve fiber is cut or crushed, in which the part of the axon separated from the neuron’s cell body degenerates distal to the injury.
2. schwann cell proliferation - this make take up to 3 weeks
3. Axonal regrowth - axons grow at a rate of 1-4 mm/d

Question 2

Things That Are BAD For Regeneration

1. General overall health - ____ use, ____
2. DM, ___ failure, ___thyroidism, ___. deficiencies, copper deficiencies
3. Medications, heavy metals, industrial solvents, chemo drugs
4. Utilization of the end organ - if you use the end organ (muscle, joint, bone) they wil be enticed to grow back.

Use it or lose it! Full recovery is ___, due to thinner ___and shorter nodal length

Answer 2

Things That Are BAD For Regeneration

1. General overall health - tobacco use, alcohol
2. DM, renal failure, hypothyroidism, vit. deficiencies, copper deficiencies
3. Medications, heavy metals, industrial solvents, chemo drugs
4. Utilization of the end organ - if you use the end organ (muscle, joint, bone) they wil be enticed to grow back.

Use it or lose it! Full recovery is unlikley, due to thinner myelin and shorter nodal length

Question 3

Spinal cord repair

• based on __ of ___ (wt. matter) at the time of injury and limiting secondary injury in the first ___ hours after injury
• Several inflammatory biochemical and enzymatic processes that we currently can not adequately limit that cause significant secondary injury
• Brain neural plasticity plays a role in motor recovery
• If the person has an ____ lesion, defined as some sensory of motor function below the level of trauma, they may have near __ recovery

Answer 3

Spinal cord repair

• based on sparing of tracts (wt. matter) at the time of injury and limiting secondary injury in the first 48 hours after injury
• Several inflammatory biochemical and enzymatic processes that we currently can not adequately limit that cause significant secondary injury
• Brain neural plasticity plays a role in motor recovery
• If the person has an incomplete lesion, defined as some sensory of motor function below the level of trauma, they may have near full recovery

Question 4

How to prevent 2ndary Injury?

Control ____ cascade

• This is ___ driven and leads to cellular edema and ____ influx.
• This causes ___ damage which leads to repair thus driving up cellular ____ demands, which leads to cell ___ starvation and death.

Limit ___ - maintain proper CBF

Answer 4

How to prevent 2ndary Injury?

Control excitotoxicity cascade

• This is glutamate driven and leads to cellular edema and calcium influx.
• This causes DNA damage which leads to repair thus driving up cellular metabolic demands, which leads to cell ATP starvation and death.

Limit ischemia - maintain proper CBF

Question 5

CNS Plasticity - changes in brain organization and function that can be mediated by structural alterations in brain maps and morphological and biochemical changes that can be sustained over time. Can be __ or not.

1. __ __ - Some higher level skills may be more limited because of CORTICAL CROWDING (visual spatial skills)

–> AGNOSIA

2. ____ of __ __ - Very common in visual and auditory cortex because of so much redundancy.
3. Decrease of ___ - Decreased ___ from cortex to thalamus to BS nuclei
4. __ ___ Phenomenon - redundancy in pathways that assume a greater role after injury. - Seen in the VLF and VC of spinal cord. These are pathways that do the same thing. One overrides the other unless there is injury.
5. ____ of Hemispheres - particularly seen in the fetus, and young childrens after age 2 and before 5
6. Substitution of ___ - Non-injured brain takes over function of the injured brain. This is seen with vicariation in sensory cortex. Maladaptation can come into play here because it can cause chronic pain syndromes

Answer 5

CNS Plasticity - changes in brain organization and function that can be mediated by structural alterations in brain maps and morphological and biochemical changes that can be sustained over time. Can be beneficial or not.

1. Corticol crowding- Some higher level skills may be more limited because of CORTICAL CROWDING (visual spatial skills) –> AGNOSIA
2. Reliqushing of funtional territory - Very common in visual and auditory cortex because of so much redundancy.
3. Decrease of gradient - Decreased gradient from cortex to thalamus to BS nuclei
4. Parallel Circuit Phenomenon - redundancy in pathways that assume a greater role after injury. - Seen in the VLF and VC of spinal cord. These are pathways that do the same thing. One overrides the other unless there is injury.
5. Equipotentiality of Hemispheres - particularly seen in the fetus, and young childrens after age 2 and before 5
6. Substitution of Function - Non-injured brain takes over function of the injured brain. This is seen with vicariation in sensory cortex. Maladaptation can come into play here because it can cause chronic pain syndromes

CREP GF

Question 6

Using Plasticity for Good

• ___ input directly enhances rapid reorganization of cortex maps.
• Intensive ___ stimulates expansion of cortical maps.
• Experience induced ____ is very powerful and not physical activity dependent. i.e. virtual training.
• Cortical maps initially ____ and then ___ as a function is mastered.
• Localized functions can be altered by affecting the ____ hemisphere. Thus, the use of ___ therapy.
• It takes time- reorganization has been documented for up to __ years after TBI and is ongoing throughout life

Optimizing Plasticity:

• Use of ____ neurotransmitters: Alpha-____, ___phenidate, a___, _-___
• ___- ___has the most evidence for benefit, all the B vitamins, alpha-tocopherol (vit E), CDP-choline, creatine, resveratrol and a ketogenic diet all have shown benefit.
• ____enrichment- benefits seen in mice in the lab and in adults clinically. There is a threshold in mice of about 6 hrs/d.
• ____ agonists- donepezil. - Avoid drugs that inhibit- anti___, benzodiazepines, ETOH, tobacco.
• Optimize health.

Answer 6

Using Plasticity for Good

• Sensory input directly enhances rapid reorganization of cortex maps.
• Intensive training stimulates expansion of cortical maps.
• Experience induced reorganization is very powerful and not physical activity dependent. i.e. virtual training.
• Cortical maps initially expand and then condense as a function is mastered.
• Localized functions can be altered by affecting the opp. hemisphere. Thus, the use of mirror therapy.
• It takes time- reorganization has been documented for up to 2 years after TBI and is ongoing throughout life

Optimizing Plasticity:

• Use of catecholamine neurotransmitters: Alpha-amphetamine, methylphenidate, amantadine, L-dopa
• Neutucitals - Mg has the most evidence for benefit, all the B vitamins, alpha-tocopherol (vit E), CDP-choline, creatine, resveratrol and a ketogenic diet all have shown benefit.
• Environmental enrichment- benefits seen in mice in the lab and in adults clinically. There is a threshold in mice of about 6 hrs/d.
• Acetylcholine agonists- donepezil. - Avoid drugs that inhibit- antipsychotics, benzodiazepines, ETOH, tobacco.
• Optimize health.

Question 7

Things that are bad for neural plasticity:

Anti____ and _____ inhibit plasticity. ____ is the key driver of neural recovery, so a ____ antagonist would also inhibit neural plasticity.

___ __ prevents axonal targeting… they blocks this repair mechanism: Astrocytes proliferate and produce an extracellular matrix of chemicals that inhibit axonal growth, particularly ___ ___ ___.

Possible Interventions: - ____ antagonists block the excititoxic cascade. Options include Mag, glycine site antagonists, hypothermia, dextromethorphan, phenobarbital.

• Blocking the ____ (programmed cell death) pathway by blocking ___ cascades.
• Control HTN, Temperature( possibly hypothermia), blood glucose and P__.

Answer 7

Things that are bad for neural plasticity:

Antipsychotics and benzodiazapenes inhibit plasticity. cAMP is the key driver of neural recovery, so a cAMP antagonist would also inhibit neural plasticity.

Glial scars prevents axonal targeting… they blocks this repair mechanism: Astrocytes proliferate and produce an extracellular matrix of chemicals that inhibit axonal growth, particularly chondroitin sulfate proteoglycans

Possible Interventions: - NMDA antagonists block the excititoxic cascade. Options include Mag, glycine site antagonists, hypothermia, dextromethorphan, phenobarbital.

• Blocking the apoptosis (programmed cell death) pathway by blocking kinase cascades.
• Control HTN, Temperature( possibly hypothermia), blood glucose and Po2