Title: Improving Outcomes after Repetitive Mild Traumatic Brain Injury from Shock Wave Exposure or Stretch Injury
Description: The prevalence of injuries from improvised explosive devices (IEDs) in recent U.S. military conflicts has highlighted the lack of knowledge of the acute and long-term consequences of blast exposure. Real-world blast exposure is complex and multi-phasic. It is unclear whether the shock wave component of blast exposure (primary blast) can cause traumatic brain injury (TBI); however, other blast components, such as tertiary blast (inertial loading mechanics), have known potential to injure the brain. Clinical and in vivo studies suggest that complex blast loading of the whole body and head can result in acute and delayed behavioral deficits and neurodegeneration, yet tertiary blast exposure or injury to the body can initiate a systemic response that complicates understanding of this pathology. To set safe thresholds for primary blast exposure and design headgear that can guard against primary blast, tolerance criteria for primary blast specific to brain must be defined. We developed and validated a model of primary blast injury for use with in vitro organotypic hippocampal slice cultures (OHSCs) and determined that primary blast without concomitant tertiary blast loading or systemic response can injure isolated brain samples.

This work was the first to define a cell death tolerance criterion for OHSCs to primary blast and report that the threshold for deficits in neuron function was below the threshold for cell death. Mild TBI (mTBI) or concussion, by definition, results in an altered mental state that can include loss of consciousness (LOC) for less than 30 minutes, dizziness, confusion, and retrograde amnesia. These symptoms typically subside within a week after injury; however, for some patients who experience multiple concussions over a relatively short period, these symptoms can persist for a year or longer; persistence of mTBI symptoms is called post-concussion syndrome (PCS). Studies suggest an initial mechanical trauma to the brain can initiate a period of time during which the brain is more vulnerable to additional injury. Little is known about this phenomenon; therefore the current standard of care for patients suffering from concussion is rest and removal from activities with a risk of additional brain trauma.

During combat deployment, over 89% of service members reported an incidence of altered mental state and over 86% reported LOC following 2 or more exposures to blast. We evaluated the response of OHSCs to repetitive primary blast (shock wave loading) and repetitive tertiary blast (stretch injury) separately, characterizing the period of vulnerability that follows an initial insult to define safe rest-periods after blast-exposure and better understand pathologies of more complex injuries, i.e. combined primary and tertiary blast. Long-term potentiation (LTP) was significantly reduced by 2 primary blast exposures delivered 24 hours apart. An initial shock wave exposure increased tissue vulnerability to subsequent exposure, which lasted as long as 72 hours but not longer than 144 hours. Repetitive primary blast exposure also increased microglial activation. Similarly, a single mild stretch injury initiated a period of heightened vulnerability to subsequent mild stretch that lasted at least 72 hours but not longer than 144 hours long.

Repetitive stretch injury significantly increased cell death, nitrite concentration, and astrogliosis and significantly reduced LTP. We also tested delayed administration of memantine as a treatment for repetitive stretch injury. Memantine is approved by the Food & Drug Administration for the treatment of Alzheimer’s disease, and preclinical studies suggest memantine may be neuroprotective following TBI. Cell death was reduced and LTP was rescued by delayed memantine treatment. Along with further preclinical and clinical investigation of repetitive primary and tertiary blast exposure, these studies may aid in setting safe rest periods and identifying new therapies for service members exposed to blast. This research has shown that primary and tertiary blast exposure can injure OHSCs causing cell death, altering neuron function, and increase vulnerability to a subsequent exposure. These studies expand our understanding of the neuropathology of primary and tertiary blast loading and evaluate methods to improve outcome after repetitive injuries with complementary strategies including rest periods and drug-treatment.