A Multidisciplinary Study of the Pathophysiology of Blast-Induced Mild Traumatic Brain Injury

The pathophysiology of blast-induced mild TBI is still poorly understood. It is defined operationally by the appearance of temporary symptoms such as headache, nausea, vomiting, dizziness/balance problems, fatigue, sleep disturbances, difficulty remembering and difficulty concentrating after exposure to a blast. Dizziness and headache are reported in more than 70% of cases presenting acutely (<72 hr), sub-acutely (4-30 days) and chronically (30-360 days) post-exposure; vertigo emerges sub-acutely. Other significant sequelae are hearing loss and emergent and delayed post-traumatic balance disorders, and chronic migrainous disorders in the absence of overt histological or standard clinical radiological evidence of damage. These mTBI symptoms are often accompanied by ringing in the ears, sensitivity to light, and sensitivity to sound. These disorders may persist for years following initial or repeat injuries, degrading the patient’s quality of life. Direct tissue damage of blast-induced mTBI includes venous injury (leading to protein extravasation or a small hemorrhage), microthrombus formation (an injury to the tissue ‘blood’) and axonal shearing are specific forms of direct tissue injury. Tissue injury responses include, at the cellular level, engagement and regulated modifications of cellular repair and metabolic pathways and, at the tissue level, multicellular wound healing mechanisms and vascular autoregulatory responses. Biomarkers associated with the responses include substrates from proinflammatory, oxidative stress, DNA repair, angiogenic and anti-apoptotic pathways. Secondary damage or dysfunction includes ischemia and excitotoxic events that reflect imbalances in homeostatic control of both the intracellular and extracellular environments. Permanent functional loss reflects the severity of both primary damage and secondary cell death. Functional recovery reflects successful tissue repair (including regenerative capabilities) and plasticity of residual resources. The project involves use of blast tubes, already built at Naval Medical Center San Diego (NMCSD) and proposed to be built at TMU from designs provided by NMCSD. Open field blasts will be conducted in Israel (Dr. Pick) and animals will be shipped to Taiwan. There is a dedicated research proposal committed to tackle this important military and civilian problem. It should be noted that Dr. Barry Hoffer has recently been appointed as Chair Professor at TMU and will help establish many of the techniques currently in use at NIH/NIDA to the research infrastructure at TMU. Our project will utilize the animal models to (1) identify pathophysiological mechanisms of single low level blast exposures that produce primary and secondary mTBI at the genomic, proteomic, lipidomic, cellular, tissue and system levels and (2) test the hypothesis that effects of repeated exposures on these measures are additive. Neurological, electrophysiological, neurochemical, and behavioral tests in the animal models will be utilized both to help define the pathophysiology and to validate how parallel diagnostic tests may be developed in affected populations.