S3: Injury and the Potential for Recovery in the CNS

Question 1

List types of injury in the CNS

Answer 1

• Development.
• Traumatic e.g. brain injury and traumatic spinal cord injury.
• Ischaemic injury e.g. stroke.
• Hypoxic e.g. cardiac arrest.
• Inflammatory e.g. MS
• Neurodegenerative conditions e.g, Alzheimer’s, Parkinson’s.
• Infection e.g. meningitis, encephalitis.
• Tumours.

Question 2

What different cell populations are there in the brain?

Answer 2

Most types of injury affect all cell populations in the brain. This includes:

• Neurones.
• Glial cells (astrocytes, microglia, oligodendrocytes (myelin)).
• The blood - brain barrier.
• CSF.

Question 3

What is cerebral palsy?

Answer 3

It describes a group of permanent disorders of the development of movement and posture, causing activity limitations that are attributed to non progressive disturbances that occurred in the developing foetal or infant brain.

Question 4

What symptoms are the motor disorders of cerebral palsy accompanied by?

Answer 4

Sensation
Perception
Cognition
Communication
Behaviour 
Epilepsy
Secondary musculoskeletal problems e.g. scoliosis

Question 5

What is a stroke?

Answer 5

A stroke occurs when there is an acute loss of blood supply which then results in damage to the region supplied by the blocked artery. It takes 6-8 minute of the blood supply being interruted (due to ischaemia or haemorrhage) to cause neuronal death (an infarction).
- Most cerebral vascular occlusions will reopen spontaneously (via removing clot) within 24 hours but for the neurones this will be too late. During this time it has been calculated you lose 2 million neurones per minute.

Question 6

What is hypoxic brain injury?

Answer 6

It is when there is reduction of oxygenation to the whole brain (different to stroke where only a region of the brain is deprived of oxygenation).

e. g. A cardiac arrest can result in too low blood pressure causing too little flow to the brain, with these injuries the areas that tend to be affected are the most metabolically active parts of the brain.
- So the grey matter namely the cerebral cortex and basal ganglia are most affected.

Question 7

What is multiple sclerosis?

Answer 7

Inflammation can also cause brain injury and quite common cause is MS. MS is an autoimmune condition causing inflammation at the myelin sheath of neurones, which results in demyelination of the neurones. This causes neuronal dysfunction so MS affects both the brain and the spinal cord.

Question 8

How do neurodegenerative disorders affect structure of the brain?

Answer 8

They involve a general shrinkage of the brain (atrophy).

Question 9

Symptoms of infection in the brain

Answer 9

Presented with headache, nausea and vomiting, reduced level of consciousness, myoclonic jerks and pyrexia (cerebellar abcess).

Question 10

Two ways neurones are injured

Answer 10

Neurones can either be severed/broken (so lose their target input) or lose their neural input and denervate (and die off!).

Question 11

Two major consequences for neurone due to damage to the axon

Answer 11

• Upstream, the cell body may die via apoptosis (retrograde degeneration).
• Downstream, the distal axon dies via wallerian degeration (anterograde degeneration).

Question 12

Consequences of denervation of a neurone

Answer 12

This is commonly seen in spinal cord injuries.

• Spasticity which is increased tone that is velocity dependent because of hypersensitivity that occurs due to denervation.
• Degeneration of the target cell or transneuronal atrophy (commonly seen in visual and auditory system).

Question 13

What is retrograde degeneration and use cortical stroke as example

Answer 13

• Depending on site there may be rapid degeneration of the projecting neuron.
• E.g. Cortical stroke leads to rapid degeneration of thalamic neurons that project to the cortex.

Question 14

Does hippocampus neurogenesis persist throughout ageing?

Answer 14

• Pools of quiescent stem cells are smaller in aged human hippocampal dentate gyri.
• Proliferating progenitor and immature neuron pools are stable with ageing.
• Angiogenesis and neuroplasticity decline in older humans
• Granule neurones, glia and dentate gyrus volume are unchanged with ageing

Question 15

List mechanisms of spontaneous recovery in the brain

Answer 15

• Glial scarring

- Regeneration

Question 16

What is glial scarring?

Answer 16

After a neurological injury, there is a reactive cellular process involving proliferation of astrocytes and microglia. This is called glial scar formation (gliosis). The purpose of this mechanism is to protect and be part of the healing process however in the context of neuronal injury the formation of a glial scar has both beneficial and detrimental effects.

• As a positive, it helps regenerate a tissue barrier after the BBB has been compromised and it promotes revascularisation of the injured brain.
• However, in the process astrocytes secrete neuro-developmental inhibitors that prevent axon regrowth and regeneration.
• Essentially, glial scarring limits injury but prevents regeneration of neurone.

Question 17

Compare cleaning during regeneration in the PNS and CNS

Answer 17

Severed axons in the PNS can regrow, if their nerve sheath remains intact.

• In the PNS, clean up of damaged parts of the cell is by macrophages and the schwann cells assist in the regenerative process. Time is important so if the cleanup is faster, it aids regeneration.
• The problem in the CNS is that the clean up is slow and oligodendrocytes tend to inhibit regeneration. Consequently the environment is not optimal for nerve healing and therefore most CNS fibres do not regenerate.

Question 18

What does regeneration of our NS mean?

Answer 18

When referring to regeneration we mean the regrowth of severed axons, it occurs in non-mammalian vertebrates and occurs effectively in mammals PNS only.

Question 19

Why is myelin critical to regeneration of our NS?

Answer 19

It provides a guide tube for the sprouting of a severed neuron to its destination as it develops.

Question 20

Why is true regeneration of axonal projections in CNS rare?

Answer 20

1. There is a developmental loss of regeneration ability due to down regulation of growth related genes.
2. Due to enviroment. This is for example, the balance between tropic factors vs inhibitory factors or the presence of glial scars.

Question 21

What is neurogenesis?

Answer 21

It is the birth of new neurones. The nervous system could repair itself if it could grow new neurones and this does occur in many non-mammalian vertebrates e.g. amphibians, songbirds.

Question 22

What two places have evidence of neurogenesis in adult mammals?

Answer 22

1. The subgranular zone (SGZ) within the hippocampus (dentate gyrus).
2. Near the lateral ventricles (subventricular zone - SVZ) supplying the olfactory bulb.
   Both locations are important for memory so perhaps memory does “grow” and it occurs via stem cells.

Question 23

Describe neurorehabilitation

Answer 23

By neurorehabilitation we are referring to the clinical speciality that is devoted to the restoration and maximization of functions that have been lost due to nervous system injury from whatever cause. Rehabilitation is learning.

• The CNS continuously remodels its neural circuitry throughout our lives in order to encode new experiences.
• Everything that we learn is hardcoded in the brain as a change in synaptic strength in some region of the brain.
• Neurorehabilitation capitalises on the way the brain normally learns in order to relearn lost function. This approach of using learning, alone and in combination with other therapies promotes adaptive neural plasticity.
• We learn by observing others performing a task - same population of neurones are active when someone is doing a task and someone is watching someone else perform a task

Question 24

What is neural plasticity?

Answer 24

Neural plasticity is the ability of the brain to change structurally and functionally as a result of input from the environment.
This is a normal phenomenon underlying brain function and is widespread in that it can affect all parts of the brain; sensory, visual, language, motor etc.
- It can help with the recovery of function after an incident e.g. stroke.

Question 25

What is somatotopy?

Answer 25

Somatotopy is the fact parts of the brain correspond to specific functions. Point for point correspondence of an area of the body to a specific point in the CNS.
Specific areas of the brain that help us move, allow us to sense things etc.

Question 26

What do discrete areas of the cortex do?

Answer 26

• Control motion of specific small groups of muscles
• Receive sensation from specific areas of the body
• Subserve vision from specific areas of the visual field
• Subserve audition for specific pitches of sound

Question 27

What is a homunculus?

Answer 27

It is a graphical representation of the parts of the brain associated with different parts of the body (graphical somatotropy).

Question 28

Are there specific areas in the brain for specific functions?

Answer 28

Yes and No.

• We know there are areas of the brain that do specific things, sometimes tasks are shared. So it isn’t JUST one specific area.
• There is flexibility in the brain, and changes are subject to neural plasticity. These can be changed in peripheral/central injury, electrical stimulation and in learning and experience
• For example a person who plays violin will have greater cortical representation of their left hand finger - the homunculus is not fixed and can change over time

Question 29

Ways to fix brain if it can’t grow neurones?

Answer 29

A lot of this fixing is through compensation:
- This is having one brain area take over the functions that the damaged area was doing.
- This is the simplest neural recovery, where uninjured tissue takes over the functions of lost neurones.
Another technique is that presynaptic neurones may sprout more terminals, this forms additional synapses with their targets and postsynaptic neurones.
There can also be addition of more receptor cells to increase sensitivity.
There can be reorganization as well, this is a more dramatic form of neural recovery and can involve major brain areas.

Question 30

What is constraint induced movement therapy (CIMT)?

Answer 30

If you force a stroke victim to use their affected side, then it can drastically improve function in motor function.

Question 31

What is transcranial magnetic stimulation?

Answer 31

Put magnetic field through brain, producing electrical currents which enhances ability to grow nerve cells (induces repolarisation of neurones in cortex).It makes a long term change in excitability of the brain.

Question 32

2 types of stem cells

Answer 32

Embryonic Stem Cells (ESC), these are totipotent and can become any cell type. We get these by harvesting embryos and aborted embryos.
Adult Stem Cells (ASC), these are pluripotent meaning they can’t turn into all cells but can turn into a lot of different cells.
We can also get them through the umbilical cord/placenta

Question 33

What are Inducing pluripotent stem cells (iPSC)?

Answer 33

This is reprogramming mature cells to become stem cells

Question 34

What effects do the stem cells being transferred into injured part of NS seem to be having?

Answer 34

• Anti-inflammatory
• Anti-apoptotic
• Neuroprotective
• Aiding trophic factors and overcoming natural inhibitors

Question 35

What are brain machine interfaces?

Answer 35

• If we can’t regenerate the brain and fulfil the recovery we were hoping we need to try get those brain signals to become the movement we want.This is the idea of having an interface, between brain and computer.
• So the brain sends a signal which is detected by a detector which sends a signal to an electronic device to perform the function.
• The most widely used example is cochlear implants.