DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Combined Effects of Primary and Tertiary Blast on Rat Brain: Characterization of a Model of Blast-induced Mild Traumatic Brain Injury

Principal Investigator: LONG, JOSEPH B
Institution Receiving Award: THE GENEVA FOUNDATION
Program: PH-TBI
Proposal Number: 10112005
Award Number: W81XWH-11-2-0127
Funding Mechanism: PH/TBI-IIRA-Broad Agency Announcement
Partnering Awards:
Award Amount: $1,792,768.00


TECHNICAL ABSTRACT

Blast has emerged as the predominant cause of casualties in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), with the majority of these injuries resulting from blast propagated by improvised explosive devices (IEDs). Among these casualties, the large majority (98%) of neurotrauma patients have closed head (i.e., nonpenetrating) injuries that predominantly result in mild traumatic brain injury (mTBI). These statistics highlight the urgent need to advance medical care targeting head-injured warfighters and the growing numbers of veterans with disabilities stemming from blast-induced mTBI. This includes efforts to preclinically define the pathophysiological mechanisms underlying blast-induced TBI, to devise improved means to mitigate the risk of brain injury after blast exposure, and to identify rational therapeutic interventions.

The etiology of blast-induced TBI is at this point largely undefined. This proposal addresses the development and initial validation of a rodent model of blast-induced mTBI. We hypothesize that the biomechanical perturbations of the brain that yield blast-induced mTBI in injured warfighters can be recreated with reasonable fidelity in rats under carefully controlled experimental conditions and that several of the characteristic sequelae of blast-induced mTBI observed clinically can be reproduced in a rodent injury model. In many, if not most, circumstances yielding blast mTBI, brain injury results from a combination of blast overpressure (BOP) (i.e., primary blast) and head acceleration and/or impact (i.e., tertiary blast). In addition, the mTBI resulting from these combined insults may be fundamentally different from that seen from either insult alone. By generating a closely associated insult to the brain (and other organs as well), BOP may interactively exacerbate the pathophysiological effects of impact acceleration associated with tertiary blast injury and compromise the brain's resilience to this additional insult. Consequently, accurate experimental recreation of blast-induced mTBI must account for these multiple contributions to the resultant injury. Both primary and tertiary blast injuries are elements of a blast exposure and should therefore both be incorporated into a valid blast mTBI model. Rats will be exposed to carefully controlled and monitored primary blast generated in an air-driven shock tube alone and in combination with impact acceleration injury, which will be generated by weight drop as well as by piston impact. Sensory, motor, and cognitive functional evaluations will then be used to sensitively detect severity-dependent blast-induced brain dysfunction in conjunction with histopathological evaluations of brain tissue. Development and validation of this animal model of blast-induced mTBI will provide a valuable experimental tool to assist ongoing efforts to mitigate the risks and consequences of blast-induced mTBI in warfighters.