Blast-induced traumatic brain injuries (bTBIs) result from explosive events and have been labeled as the "signature injury" of modern warfare. Many reports show compelling evidence that, even in the absence of noticeable symptoms, bTBI can cause long-term brain damage leading to dire mental health and/or neurodegenerative consequences. The often subclinical nature of this "silent killer" is particularly alarming, as it precludes early treatment, missing the ideal therapeutic window to prevent damage progression and the resulting pathological sequelae. A multi-modal analysis is proposed to identify the mechanisms linking bTBI- induced mechanical damage to interceding biological mechanisms which may lead to development of post- bTBI pathologies. With a validated rodent model of bTBI combined with the power of computational modeling and cutting-edge, nanoparticle-based sensor technology, we aim to gain greater insight into the link between the biomechanics of bTBI, structural damage in the brain, and subsequent biological mediators of continued post-bTBI damage. Our hypothesis is that rapid, dynamic intracranial pressure changes produce deformation gradients in the brain that are injurious to neurons and brain microvasculature, initiating the pathologic mechanisms leading to post-bTBI neuronal degeneration and dysfunction. We present preliminary evidence of a novel sensor's capacity to for the first time determine brain deformation in real time during blast injury in vivo. These measurements will guide generation of calibrated, validated whole-brain computational stress/strain models leading to increased understanding of the forces experienced by the brain during bTBI. In addition, we demonstrate evidence of bTBI-induced blood-brain barrier compromise indicative of microvascular damage as well as upregulation of acrolein, a potent neurotoxin, marker of neuronal damage, and pro-inflammatory agent. Acrolein is elevated for at least five days post-bTBI in both brain tissue and urine, suggesting it may be responsible for mediating ongoing brain damage long after the initial injury as a result of structural damage to neurons and microvasculature during blast exposure. Its sustained elevation and capacity for noninvasive measurement identifying it as a potentially viable screening biomarker and treatment target for subclinical bTBI. By exploring the regional relationships between bTBI-induced neuronal and microvascular damage, acrolein elevation, and brain deformation through a unique, multi-modal approach, we aim to unveil new mechanisms linking bTBI mechanical damage to secondary biological mediators of sustained injury. Ultimately, this research seeks heightened understanding of bTBI and new diagnostic and therapeutic targets in hopes of improved quality of life and reduced healthcare burdens for bTBI patients, loved ones, and care providers.

Public Health Relevance

Blast-induced traumatic brain injuries (bTBIs) result from explosive events and have been tagged the silent killer in modern military conflicts. This label alludes to the often acutely subclinical nature of bTBIs progressing to delayed onset of neurodegenerative and/or neuropsychiatric consequences without initial symptoms at the time of injury. By exploring the mechanisms responsible in efforts to uncover viable diagnostic and therapeutic targets, this research aims to improve quality of life and reduce the healthcare burden of injured soldiers, their loved ones, and care providers by alleviating the development and severity of post-bTBI pathologies.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS090244-01
Application #
8808857
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Purdue University
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
West Lafayette
State
IN
Country
United States
Zip Code
47907