L4

Question 1

What is the difference between compensation and recovery?

Answer 1

Compensation is something we do to accommodate the deficit, whereas recovery is our brain physically recovering form the insult.

Question 2

What are the two mechanisms of recovery?

Answer 2

1. more good

2. less bad

Question 3

What are the issues with labelling things as either good or bad for stroke and recovery?

Answer 3

1. things are very rarely just good or bad.

[example]

• • chronic cell death gets rid of cells but also prevents cytotoxicity from lingering dead cells
• • inflammation can cause cell death but can excite neuroprotective functions

2. additionally it is difficult to prove causation (especially from correlation).
3. fuzzy boundaries exist, where timing of events is highly variable and easily influenced by numerous factors.
4. and lastly, relative importance is often hard to determine and varies from case to case.

Question 4

Define: edema (it’s effects), ICP and CBF

Answer 4

• • ICP = intracranial blood pressure
• • CBF = cerebral blood flow
• • edema is an increase in tissue water content

1. edema is cytotoxic which is an early increase in intracellular water that can cause cells to rupture
2. edema is vasogenic which is a later increase in extracellular water derived from blood and related to BBB damage and inflammation

Question 5

Discuss cerebral edema in the context of ICP and CBF.

Answer 5

Brain swelling can cause herniation (midline shift), cell death, impaired CBF (via higher ICP) and the patient’s death.

• • edema varies with insult type and severity, and usually is not bad enough to markedly impair CBF
• • higher ICP may in fact have a tamponade effect on ICH or SAH

– spontaneous recvoery is temporally linked to resolution of edema and raised ICP in the more serious strokes

– can be treated (drugs which remove water or hemicraniotomy, in severe cases)

Question 6

How does ICP factor into outcome?

Answer 6

If ICP is elevated, outcome is poor (correlation)

• • ICP is pressure inside the skull, which increases via the mass effect (if any) and edema
• • reductions in CSF occur to accommodate mass effect and edema

CPP = MAP - ICP
(where CPP = cranial perfusion pressure and MAP = mean arterial pressure)

Therefore, a decrease in CPP is seen with an increase in ICP

• • lower levels of consciousness
• • secondary ischemia and death if reductions in CPP are severe
• • no perfect correlation between ICP and outlook, but high ICP can kill
• • normally resolved in weeks but sometimes days

Question 7

What is normal ICP

Answer 7

~ 10 mm Hg

Question 8

What is the relationship between strokes and inflammation?

Answer 8

1. inflammation occurs after brain injury
   - - complex response by central (microglia) and peripheral (neutrophils and macrophages) immune cells via signalling molecules (cytokines)
   - - occurs rapidly and can persist for months
   - - varies with age, type and severity of stroke, co-morbidities, etc.
2. functions to remove damaged brain tissue and to promote remodeling
   - - phagocytizing dead cells (ie. infarct and blood clots) and wall off damaged areas (glial scar)
   - - promoting neurovascular repair and survival (ie. secreting growth factors)
3. ‘excessive’ inflammation causes brain injury and impedes recovery
   - - causing BBB damage leading to edema, releasing cytotoxic molecules
   - - inhibiting repair (impeding neurogenesis)
   - - anti-inflammatory treatments widely thought to be protective, but no clinical proof yet

Question 9

How might temperature affect inflammation effects in stroke?

Answer 9

Hypothermia can actually mitigate the signalling for micoglial cells to come in

Question 10

What are DAMPs?

Answer 10

Danger Associated Molecular Patterns (ie. release of nucleic acids, certain lipid and proteins from damaged cells)

Question 11

What does the resolution of inflammation look like? Why is timing so important for inflammatory-targeted treatments?

Answer 11

1. resolution of inflammation is:
   - - depletion of inflammatory mediators
   - - increase in anti-inflammatory molecules
   - - induction of anti-inflammatory cells
2. timing is key because there is an acute phase (days to weeks) where inflammation is harmful, and a recovery phase, which is later and a phase which you do not want to impede

Question 12

What is spreading depression?

Answer 12

[definition] waves of depolarization that slowly spread across the cerebral cortex

• • not the depolarization that you see in ap’s
• • occurs in the days following stroke
• • contributes to injury and perhaps functional impairments in other ways

Question 13

What type of abnormal activity might be seen after a stroke?

Answer 13

1. spreading depression
2. neuronal hypo-activity
3. neuronal hyperactivity

Question 14

What is neuronal hypo-activity (after a stroke)?

Answer 14

It is how some neurons have greatly reduced levels of activity following a stroke.

• • in some cases cells don’t recover (they die)
• • usually gradual recovery occurs in hours to weeks
• • there are various causes of hypo-activity, such as alterations in nt and channels, diaschisis, edema, structural damages (persistently increased levels of tonic, extrasynaptic GABAergic inhibition, shortening of the axon hilloc important for generating ap’s)

Question 15

What is neuronal hyperactivity (after a stroke)?

Answer 15

It is how some cells have an increased spontaneous activity after a stroke (hyper excitable such as from loss of inhibition)
– possibility of seizures

Question 16

What is GABA’s role in hypoactivity?

Answer 16

Can be increased due to diminished uptake by astrocytes, particularly in the peri-infarct neurons! GABA is inhibitory and therefore aids hypo-activity.

So decreased GABA uptake leads to increased extracellular GABA which leads to increased tonic inhibition. This leads to decreased neuronal excitability and therefore diminished recovery.

Question 17

What is the theory of diaschesis?

Answer 17

That behavioural impairments are linked not just to the injured areas but to a reversible functional depression in remote and undamaged (but connected) sites.
– resolution of diaschesis is thought to contribute to recovery

Question 18

What are some forms of diaschesis?

Answer 18

1. projections to the contralateral side
2. projections to the spinal cord
3. associative projections within a hemisphere

Question 19

What targets diaschesis?

Answer 19

various therapies such as amphetamine

Question 20

Describe the lesion study in rats that looked at diaschesis

Answer 20

There was a lesion area, a hypoperfusion area (due to stroke itself; impairment because of the occlusion; affected connections to this region, change in GABAergic tones), a hypometabolism area (quite large, this is regional diaschesis, lasts to day 8)

Question 21

What are collaterals?

Answer 21

[definition] existing connections between blood vessels that can come on-line during a stroke to limit damage and/or functional impairment thereby improving recovery
– changes in blood pressure affect collateral flow

Question 22

What is angiogenesis?

Answer 22

[definition] growth of new blood vessels
– slower than collaterals, but important in supplying an appropriate amount of CBF to compromised tissue and areas undergoing remodeling

Question 23

Behavioural recovery after brain injury is strongly associated with what?

Answer 23

• • unmasking of dormant pathways
• • growth of new dendrites and spines (synaptogenesis; a lot of damage is done to spines, dendrites, axons and terminals in a stroke)
• • generation and lengthening of new acon initial segments
• • axonal and terminal sprouting
• • functional brain re-organization stemming from these changes

– these changes begin quickly, peak, and can persist for weeks before returning to baseline levels (occur in a use-dependent manner and are affected by rehab)

Question 24

How does neurogenesis factor into stroke/stroke recovery?

Answer 24

[definition] neurogenesis is the growth of new neurons; the brain normally produces new cells throughout life

• • spontaneous neurogenesis is increased for days to weeks after ischemia, hemorrhage, and trauma, and is widely thought to contribute to functional recovery
• • new cells diverted to site of injury
• • most don’t survive or are not integrated properly; nevertheless these cells may produce growth factors that madify local circuitry and/or promote survival of injured cells

Question 25

Where are new cells typically produced?

Answer 25

1. subgranular zone (SGZ)

2. subventricular zone (SVZ)

Question 26

Why do some argue that the CA1 cells may regenerate spontaneously after ischemic strokes?

Answer 26

Because they can! Only it is a transient phenomenon and goes away after ~ninety days

Question 27

What are growth factors and what are some types?

Answer 27

[definition] proteins and steroids that stimulate cell growth, proliferation, differentiation, and survival

[types]

1. BMP (bone morphogenetic proteins)
2. EGF (epidermal growth factor)
3. EPO (erythropoietin)
4. IGF-1 (insulin-like growth factor)
5. NGF (nerve growth factor)
6. BDNF (brain derived neurotrophic factor)
   - - widely distributed in the brain
   - - highly concentrated in the hippocampus
7. NT-3;NT-4/5;NNT-1 (neurotrophins respectively, novel neurotrophin)

Question 28

How is BDNF beneficial to strokes?

Answer 28

After strokes.

[short-term]

• • neuronal depolarization
• • affects ion channels (ie. NMDA)
• • potentiating transmitter release

[long-term]

• • altering nt production
• • changing excitability, metabolism, enhancing synaptic transmission and increasing LTP
• • modulating neuronal structure (synapses, dendrites)
• • affecting neuronal survival and differentiation (ie. increasing hippocampal neurogenesis)
• • promoting angiogenesis

BDNF also aids in recovery, and is neuroprotective if given soon enough

Question 29

The three R’s

Answer 29

1. restoration (re-engaging silenced areas)
2. retraining (within damaged system)
3. recruitment (other brain regions)

Question 30

What are the general methods to studying contralteral hemisphere involvement for stroke research?

Answer 30

1. anatomical data
   - - existing pathways support a potential role for the contralateral hemisphere in recovery
   - - changes in the non-damaged pathways occur after stroke (ie. sprouting)
2. animal studies using serial/multiple leasions
3. imaging data in patients (fMRI, PET)
4. activation/inactivation studies (using drugs, tDCS [transcranial direct cortical stimulation*], TMS)

Question 31

Describe how anatomical data is used to study contralateral involvement.

Answer 31

• • that descending tracts usually decussate but sometimes projections do not cross (arguably a role for ipsilateral side)
• • can make use of ipsilateral connections to recover function (because motor is contralateral, ipsilateral use recovers function)
• • with small lesion you see rewiring in the contralateral side, with intermediate ones you see stimulation of the ipsilateral hemisphere causing response of the paretic hand, and with large lesions there is no effect of stimulating the contralateral hemisphere, and the ipsilateral one is now driving the paretic hand)
• • likely a case of dormant pathways becoming active

Question 32

What are some issues with imaging data and methodologies?

Answer 32

There is no one perfect technique

• • use of simple tasks in fMRI studies limit generalization to post-stroke deficits
• • results vary by normal laterality (gait vs. finger movement)
• • differences among techniques

There are study problems (such as small numbers, limited patients selection, using only patients with good recovery) and often use correlational data.

Question 33

What is some evidence from animal studies on hemisphere activation in strokes (ipsilateral vs. contralateral)?

Answer 33

1. mild strokes show unilateral deficits but large ones are bilateral
2. compared a large lesion group to a small lesion one
   - - success improves with time and caps around 50% in SHAM
   - - those with small lesions actually do better (the ipsilateral side for forelimb)
   - - those with large legions do worse
   - - link it to changes in synaptogenesis in the undamaged hemisphere
3. in an experiment with rats given MCA stroke and rehab, injecting a local anesthetic into the contralaterally stroked-hemisphere reinstated deficits
4. looking at the MC, RMC, CMC in rats, the CMC has more projections for the limb, so deficits are expected to follow MC > CMC > RMC
   - - findings support this
   - - findings also show that a second lesion can affect recovery that had happened (so if RMC was lesioned than CMC would be – takes out recovered behaviour entirely)
   - - also find that you first rely on lateral cortex and then contralateral