Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves

Abstract

Mild traumatic brain injury (mTBI) resulting from exposure to blast shock waves (BSWs) is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB). Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa) initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction (TJ) proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145–323 kPa) causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy (CTE) and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

Neuroimaging as a biomarker in symptom validity and performance validity testing

“…In animal models, neuroinflammation involving white matter may be a factor driven by genetic vulnerabilities to injury and injury severity (Wieser et al 2013). If injury, regardless of how it occurs relates to more chronic inflammatory processes adversely influencing white matter integrity, as demonstrated in animal as well as human studies (E. D. Bigler 2013;Shetty et al 2014;Wieser et al 2013) this could set the stage for numerous adverse outcomes associated with PTSD, mTBI or the two in combination. There are also interesting potential associations between depression, development of age influenced cognitive deficits, neuroinflammation and white matter pathology following some kind of acquired injury to the brain (Nihonmatsu-Kikuchi et al 2013).…”

“…If mild TBI and/or PTSD results in diminished white matter integrity, as depicted in Fig. 9, including subtle chronic inflammatory reactions in some, what does this mean in terms of illness behavior, task engagement and motivation to perform SVT/PVT measures (see E. D. Bigler 2013; Chew et al 2013;Ekmark-Lewen et al 2013;Shetty et al 2014;Smith et al 2013)? Unknown.…”

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

“…Blast shock wave models of mild TBI using animal models suggest that the primary injury not only causes damage from free radical induced oxidative stress resulting tight junction, pericytes and astrocyte end-feet disruption, but also causes vascular lesions. Both of these mechanisms may progress into long term neuroinflammatory damage and chronic traumatic encephalopathy (CTE) [46][47][48].…”

Computational and In Vitro Studies of Blast-Induced Blood-Brain Barrier Disruption

“…This suggests that the injury mechanisms might occur at very small length scales, even at the scale of a single cell. Several hypothesis have been proposed: the disruption of BBB integrity [88,43,76]; cerebral vasospasm mechanotransduced by the blast wave [3]; impairment of axonal functionality [57,58]; shock wave excitation of phonons that decay into lower frequency oscillations [49] and the formation of cavitating bubbles [71,67,66,80,109,74,37], among others.…”

“…This gives rise to an extremely low-permeability cellular barrier that separates the luminal (blood supply) side of the BBB from the abluminal (CNS) side of the BBB. Significantly, there is evidence that BBB disruption may play an important role in the delayed neurologic disorders associated with mTBI [88].…”