A6 TBI / diffuse axonal injury

Topic

Nervous tissue tolerates a certain amount of mechanical deformation without sustaining damage, thanks to its elastic properties. In cases of traumatic brain injury involving diffuse axonal injury, mechanical acceleration-deceleration forces deform the nervous tissue beyond this elastic limit; it is this mechanical deformation of the tissue that determines whether axonal injury occurs. The likelihood of nervous tissue sustaining such axonal injury depends on both the magnitude of the mechanical deformation and the speed at which it occurs, following a dual-condition model: axonal injury occurs only when both the magnitude and the velocity of the mechanical deformation exceed their respective thresholds.

Within the nervous tissue, the axon itself is the structure that directly sustains this injury: mechanical deformation of the tissue activates mechanosensitive ion channels in the axonal membrane, and the opening of these channels triggers an abnormal influx of calcium into the axon—a mechanism similar to the calcium influx observed in cerebral ischemia. This abnormal calcium influx activates a group of calcium-dependent proteases known as calpains within the axon; these enzymes degrade the axonal cytoskeleton and block axonal transport.

When axonal transport is blocked, proteins that normally travel along the axon cease to move normally and accumulate at the site of the blockage, forming a characteristic protein accumulation known as a retraction bulb. The longer the axonal transport blockage persists, the greater the protein accumulation that forms within the axonal retraction bulb.

At a macroscopic level, the diffuse axonal injury sustained by axons within the nervous tissue contributes to secondary cerebral edema developing in the surrounding nervous tissue. This secondary cerebral edema increases the volume occupied by nervous tissue within the skull; since the skull cannot expand to accommodate this extra volume, the expansion of the nervous tissue raises intracranial pressure, in accordance with the volume-pressure relationship within the cranium known as the Monro-Kellie doctrine.

This same mechanism—whereby an increase in volume within a fixed space raises the pressure inside it—also describes the behavior of nervous tissue when a brain tumor occupies space within the skull. Ultimately, the mechanical deformation of nervous tissue during traumatic brain injury leads—through diffuse axonal injury and secondary cerebral edema—to an increase in intracranial pressure, which determines the severity of the damage sustained by the nervous tissue.

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