Brain Damage Notes

Understanding Mechanisms of Brain Damage

• Causes of Brain Damage
  • Cerebrovascular Disorders
  • Traumatic Brain Injury
  • Tumours
  • Infections
  • Neurotoxins

Cerebrovascular Disorders: Understanding ‘Stroke’

• ‘Stroke’ is a sudden-onset cerebrovascular accident (CVA) resulting in brain damage.
• Two broad types:
  • Haemorrhagic
  • Ischaemic

Haemorrhagic Stroke (Cerebral Haemorrhage)

• A rupture of a blood vessel leading to bleeding within the brain (e.g., burst aneurysm)

Ischaemic Stroke (Cerebral Ischemia)

• blood supply disruption caused by

  • Thrombosis (at formation thrombus blocks artery)
    • A thrombus can be composed of things like a blood clot, fat, an air bubble, tumour cells, or a combination.
  • Embolism (traveling thrombus lodges in narrower artery)
  • Arteriosclerosis (thickening of blood vessel walls)
  • Sudden drop in blood pressure

• The area of dead or dying brain tissue produced by a stroke is known as an infarct.

• Surrounding the infarct is an area of dysfunction called the penumbra.

• The tissue in the penumbra may recover, or die, in the subsequent days.

Properties of Ischemia-Induced Brain Damage

• Does not develop immediately (couple of days)
• Affects some neurons more than others (e.g., hippocampus)
• Different mechanisms for different brain structures
• Involves brain’s own neurotransmitters (!)
• Results largely from excess excitatory neurotransmitter release
  • Especially glutamate

How Does The Resulting Damage Occur?

• As a consequence of blockage, blood-deprived neurons become overactive and release too much glutamate
• Glutamate over-activates postsynaptic glutamate receptors, esp. NMDA
• Result: Influx of Ca^{2+} (and Zn^{2+} and Na^{+}) into postsynaptic neurons (concentration abnormally high)
• Triggers release of glutamate from postsynaptic neuron (domino/cascade effect)
• Triggers internal reactions that lead to cell death (apoptosis)

Sequence of Damaging Events with Stroke

1. A blood clot stops the flow of blood to a brain region.
2. Without oxygen and glucose, neurons begin to depolarize, perhaps because of loss of the sodium-potassium pump. The neurons reach threshold and produce a barrage of action potentials.
3. Many of these rapidly firing neurons release the excitatory neurotransmitter glutamate. In addition, the lack of energy in the presynaptic neuron causes the glutamate transporters, which normally remove the transmitter from the cleft, to stop working (no reuptake).
4. Postsynaptic neurons, bombarded with glutamate, also produce a barrage of action potentials (which may spread the glutamate flood), so excessive amounts of calcium and zinc enter the cell.
5. The excessive intracellular calcium and zinc trigger cell death (apoptosis), and the neuron has succumbed to excitotoxicity.

Possible Treatments

A. Thrombolytics (drugs that dissolve blood clots) such as tissue plasminogen activator (tPA), may restore blood flow to avoid further damage.
B. Drugs that inhibit the voltage-gated sodium channel may reduce the number of action potentials generated.
C. Drugs that block glutamate receptors may combat the excessive stimulation.
D. Drugs that block calcium channels may avert the intracellular buildup of calcium.

Cell Death: A Morbid Reminder

• Apoptosis
  • Active but gradual self-destructive process
  • Important adaptive process in limiting brain damage
    • cell body shrinks and remainder of neuron dies, any debris is cleared (vesicles), no trauma to surrounding cells
  • Important in development: culling excess neurons
• Necrosis
  • Passive and fast but a more generally destructive process
  • Neuron swells and breaks up (axons and dendrites, followed by cell body)
  • Fragmentation may cause inflammation and damage cells in surrounding tissue

Traumatic Brain Injury

• The pathomechanism of brain injury is typically shearing, stretching, and tearing at the neuron level.
• Broadly, we think of two primary classifications:
  • Penetrating head injury
  • Closed head injury

Closed Head Injury

• Closed head injury may have many different causes, but common to all is that the brain undergoes either marked acceleration, deceleration, or both.
• Contusions
  • damage to cerebral circulatory system, resulting in internal bleeding and a haematoma (bruise/clotted blood)
    • Epidural/subdural haematoma vs. intracerebral haematoma
• Concussion
  • disturbance of consciousness but no evidence of structural damage (e.g., no contusion).
    • lack of evident structural damage does not mean concussion is benign (e.g., CTE)

Cerebral Hemorrhages

• Subdural hematoma
  • Crescent-shaped Blood collection between dura and arachnoid matter
  • Tear in bridging veins
  • Alcoholics and elderly are prone
• Epidural hematoma
  • Biconvex (lens) shaped Blood between dura and skull
  • Tearing of middle meningeal artery
  • Adolescents and young adults (trauma)
• Subarachnoid hemorrhage
  • Blood in circle of Willis, cisterns, and fissures
  • Rupture of berry aneurysm
  • Polycystic kidney disease (risk factor)
• Intracerebral hemorrhage
  • Blood in parenchyma and ventricles
  • Hypertensive vasculopathy
  • Territory of penetrator arteries

Brain Tumours

• A tumour (neoplasm) = independently growing cell mass without any physiological function
• Types of tumours:
  • Meningiomas: ≈ 20% of tumours; grow between meninges; encapsulated (within own membrane), usually benign
  • Infiltrating tumours: Most tumours are infiltrating. Grow diffusely through surrounding tissue, typically malignant, can be difficult to remove or destroy
  • Metastatic tumours: ≈ 10% of brain tumours; originate elsewhere, usually lungs, skin, breast tissue

Brain Infections

• Inflammation resulting from infections is called encephalitis
• Bacterial infections
  • Often lead to cerebral abscesses
  • May inflame meninges → meningitis
• Viral infections
  • Some viral infections preferentially attack neural tissues (e.g., rabies), others can attack neural tissues but not preferentially (e.g., herpes, mumps)

Neurotoxins

• May enter general circulation from gastrointestinal tract, lungs, or through the skin
  • Heavy metals such as mercury and lead can lead to toxic psychosis
  • Some antipsychotic drugs have toxic effect and can produce a motor disorder - tardive dyskinesia
  • Neurotoxins can also be endogenous (think glutamate)

Neurophysiological/Neuroplastic Responses to Brain Damage

• Neural degeneration - deterioration
• Neural regeneration - regrowth of damaged neurons
• Neural reorganisation

Neural Degeneration

• Axotomy (cutting axons): method to study responses to neuronal damage
• Cutting a neuron’s axon results in two forms of neural degeneration
  • Anterograde degeneration
  • Retrograde degeneration

Neural Degeneration

• Anterograde:
  • Distal portion of neuron degenerates quickly
• Retrograde:
  • Proximal portion of the neuron may degenerate or regenerate slowly (depending on reaction of cell body)
• Transneuronal degeneration:
  • Degeneration transmitted from damaged neurons to intact neurons via synaptic connections

Neural Regeneration

• Not successful in mammals and other higher vertebrates - capacity for accurate axonal growth seems to be lost in maturity
• Regeneration is virtually nonexistent in the CNS of adult mammals and unlikely, but possible, in the PNS

Regeneration in the PNS

1. Re-growth starts 2-3 days after injury
2. Nature of injury determines course of events
   1. If original Schwann cell myelin sheath is intact, regenerating axons may grow through them to their original targets (mm per day)
   2. If the nerve is severed and the ends are separated, they may grow into incorrect sheaths towards incorrect destinations
   3. If ends are widely separated, no meaningful regeneration will occur

Why Do Mammalian PNS Neurons Regenerate?

• CNS neurons can regenerate if transplanted into the PNS, while PNS neurons will not regenerate in the CNS → PNS environment
• Schwann cells (PNS) promote regeneration through
  • Neurotrophic factors - stimulate new axon growth
  • CAMs (Cell Adhesion Molecules) - provide a pathway
• Oligodendrocytes (CNS) release substances actively blocking regeneration

Neural Reorganisation

• Reorganisation of the primary sensory and motor systems has been observed following damage to:
  • peripheral nerves
  • primary cortical areas
• Example 1 - animals: Lesion one retina and removal of other
  • V1 neurons that originally responded to lesioned area now responded to an adjacent area
  • remapping occurred within minutes (Kaas et al., 1990)
• Example 2 – humans: Imaging studies with vision impaired participants
  • auditory and somatosensory cortex is comparatively larger (Elbert et al., 2002)
  • superior performance on relevant tasks compared to sighted individuals (Gougoux et al. 2005)

Mechanisms of Neural Reorganisation

• Two-stage model of neural reorganisation:
  • Release from inhibition strengthens existing connections
  • Collateral sprouting results in new connections

Understanding Recovery

• ‘Recovery’ following brain injury is poorly understood
• Difficult to partial out what is true ‘recovery’ (i.e., healing of the neural tissue damage itself) from other mechanisms such as artefact recovery or compensation
• In the early stages, cerebral swelling (oedema) can be a complicating factor.
• In addition, disturbance of neurotransmitter functions may result in what is known as ‘neural shock’.
• These effects may reduce over the days and weeks following an event and lead to a recovery of cognitive functions that were being suppressed by these mechanisms.
• This is often referred to as ‘artefact recovery’ because functions were not actually lost in the first place (just suppressed).
• The concept of cognitive reserve is another example of improvement after brain damage that is not due to true recovery.
• Rather, cognitive reserve (education, intelligence) may allow patients to more easily adapt or compensate for lost functions.
• Functional adaptation and compensation may contribute more substantially to recovery than neurophysiological or neuroplastic responses.