Neural Response to CNS Injury

• Mechanisms of injury to the central nervous system

  • Acute physical trauma (e.g. motor vehicle accidents, boxing, hockey/football hits, falls, explosions)
  • Lack of oxygen due to diminished blood flow or ischemia (e.g. stroke)
  • Neurodegenerative diseases (e.g. Alzheimer's, Parkinson's, ALS)
• Neural injury usually involves both focal damage or damage at the site of the injury and secondary remote damage below the initial injury.

  
• Most injuries to the neurons at the site of the injury damage the axons.
• Sequence of physical degeneration of the axon


  1. Nerve terminal begins to degenerate

  2. Distal stump separates from cell body and undergoes Wallerian degeneration

  3. Fragmentation of myelin

  4. Lesion site invaded by phagocytic cells

  5. Cell body of damaged neuron swells and nucleus moves to eccentric position

  6. Withdrawal of synaptic terminals in contact with damaged neurons

  7. Synaptic cleft invaded by glial cells

  8. Atrophy and degeneration in adjacent input and target neurons

  
• Loss of a neuron at the site of injury has a cascading effect resulting in degeneration along neuronal pathways which increases the extent of neuronal disruption.

  
• Damaged axons affect function and play a role in injury and recovery after acquired brain injury.
• Excitotoxicity


  • Excessive glutamate release by oxygen-deprived neurons is toxic to neurons in high concentrations
  • Glutamate activates calcium channels releasing excessive intracellular calcium
  • Calcium causes glycolysis, increased intracellular water, and activated protein enzymes
  • Lactic acid, cell swelling, and oxygen free radicals injure the neurons resulting in cell death
• Excitotoxicity contributes to neuronal damage in persons with stroke, traumatic brain injury, neurodegenerative disease, spinal cord injury, and acquired immunodeficiency syndrome.
• Diaschisis


  Transient functional changes in brain structures connected to white matter tracts at a remote distance from the site of focal brain damage, due to decreased blood flow and/or metabolism

  
• Cerebral edema


  • Local or generalized accumulation of intracellular fluid and swelling
  • Increased permeability of capillary endothelial cells with leakage of proteins and fluid from damaged blood vessels into the extracellular space (vasogenic edema)
  • Compression of axons and physiological blocking of neuronal conduction

  
• Decreased edema restores a part of the functional loss.
• Regenerative capacity in peripheral vs central nervous system


  • Peripheral nerve: Perineural sheath reforms rapidly, Schwann cells produce trophic factors and adhesive proteins that promote axonal growth, new functional nerve endings formed, myelin sheaths remyelinated, cell bodies return to normal position
  • Central nervous system: Distal axon segment degenerates and myelin fragments, astrocytes and macrophages form glial scar that inhibits axonal regeneration

  
• Intercellular responses to injury


  • Recovery of synaptic effectiveness
  • Denervation hypersensitivity
  • Synaptic hypereffectiveness
  • Unmasking of silent synapses

  
• Recovery of synaptic effectiveness


  Reduction in local edema that interfered with action potential conduction, allowing normal cellular function and neurotransmitter synthesis/transport to resume

  
• Denervation hypersensitivity


  Postsynaptic neurons develop new receptors at remaining terminals, resulting in increased response to neurotransmitters
• Synaptic hypereffectiveness


  Neurotransmitter accumulates in undamaged axon terminals, resulting in excessive release at remaining terminals
• Activation of silent synapses occurs in response to injury.

  
• Regenerative synaptogenesis


  Injured axons begin sprouting and reestablishing connections with target neurons
• Reactive synaptogenesis (collateral sprouting)

  Neighboring normal axons sprout to innervate synaptic sites previously activated by injured axons
• Axonal remodeling


  Spared and previously masked corticospinal fibers become unmasked and increase collateral sprouting to contact more target motor neurons, contributing to partial recovery of function after lesion

  2. Damaged corticospinal fibers extend new collaterals to contact preserved interneurons

  3. Previously masked propriospinal pathways which connect with lumbar motor neurons, become more strongly activated

  
• Neurogenesis


  The process by which new neurons are formed in the brain
• Damage to axons can lead to death of the cell itself, so mechanisms designed to support neuronal survival as well as axonal regeneration are critical
• Neuronal death is a common consequence of severe neural insults, so mechanisms supporting the retention or replacement of neurons are critically important
• In adult humans, development of new neurons is possible but is limited to the hippocampus and olfactory bulb
• Neurogenesis can be decreased in the presence of depression or stress and increased by physical activity or an enriched environment
• Traumatic or ischemic injury to the brain can stimulate the generation of new neurons even in the cerebral cortex, however, recovery of function remains poor

  
• Stem cells in the adult human brain are capable of becoming new neurons, and are suspected to be involved in brain remodeling following neurologic injury
• Neural precursor cells migrate along blood vessels toward the ischemic area following stroke, but many do not survive due to inflammation and the physical and chemical barrier of glial scars

  
• Researchers are examining how and why neurogenesis occurs, what drives neural precursor cells to their target location, how to create a conducive environment for them to survive, and whether they can be used for treatment of neurologic injury and neurodegenerative disease

  
• Functional reorganization of the cerebral cortex


  • Cortical areas retain the ability to develop new functions
  • Changes at individual synapses can reorganize the brain and have significant functional consequences

  
• Cortical reorganization occurs after peripheral injury such as amputation or central nervous system injury such as stroke or traumatic brain injury

  
• Cortical plasticity and reorganization drive functional recovery following stroke
• Persons post stroke experience reorganization of the sensorimotor cortex representation into surrounding motor areas, which can progress over 2 years

  
• A focal lesion opens a window of increased plasticity in the central nervous system
• A person's genetic makeup influences the plasticity of the brain, with some variations associated with decreased motor map reorganization, altered brain activity, and poorer recovery
• Changes in cortical maps after lesions

  • Damage to central neural structures results in alterations to cortical maps and changes in neural activation patterns
  • Focal damage can increase the capacity for structural and functional changes within the central nervous system

  
• Motor recovery following damage to the primary motor cortex may be mediated by other cortical areas in the damaged hemisphere, through the use of either redundant pathways or new regions that take over the function of the damaged area

  
• Contralesional motor pathways can be active during hand movements on the paretic side, but their role in recovery of function is not clear, and some evidence suggests they can impede recovery through increased intracortical inhibition

  
• The cerebellar hemisphere opposite to the damaged corticospinal tract can contribute to motor recovery via establishment of automatic motor skills, related to the cerebellum's role in motor learning

  
• Activation of brainstem pathways following stroke-related damage to the corticospinal system contributes to and constrains recovery of function, with recruitment of reticulospinal pathways resulting in broad, bilateral activation of muscles rather than fine fractionated control