Posted March 13, 2018

Deborah Shear, Ph.D., Walter Reed Army Institute of Research

Mild traumatic brain injury (mTBI) is a signature injury of military conflicts in Iraq and Afghanistan, affecting over 230,000 US Service members over the last 14 years, due to the use of improvised explosive devices (IED) by enemy combatants. Because mTBI is a closed-head concussive injury, it can often occur without obvious external wounds. This presents a major challenge in determining the alterations a Service member's brain undergoes after mTBI, as well as the time required for the brain to heal, a critical factor in deciding when a Service member is fit for return-to-duty. Moreover, we do not yet fully understand the long-term health effects of multiple mTBIs, which may be particularly damaging if the brain is not allowed adequate time to heal between injuries.

Dr. Deborah Shear was awarded the Applied Neurotrauma Research Award through the Psychological Health and Traumatic Brain Injury Research Program to address the problem of recognizing the markers and long-term effects of single and repeated mTBI. Dr. Shear and her team are specifically investigating how cellular changes resulting from mTBI relate to clinically relevant behavioral and electrophysiological outcomes. In support of these efforts, Dr. Shear's team developed the Walter Reed Army Institute of Research (WRAIR) Projectile Concussive Impact (PCI) model of mTBI in rats. The PCI model generates an mTBI that is comparable to injuries experienced by troops, allowing for the reproducible generation of closed-head mTBI across a wide spectrum of injury severities, and incorporating the use of a custom-designed helmet equipped with pressure sensor film.

Dr. Shear and her team have found that rats that experienced either a single or repeated PCI injury demonstrate acute neurological and sensorimotor deficits, paired with cellular, neuroinflammatory, and metabolic disruptions. The majority of acute disruptive alterations observed in rats with a single concussive injury, including motor deficits, neuronal death, and elevated inflammatory markers and gliosis, were found to be significantly worse in animals with repeated concussive injury and this cumulative effect is highly dependent upon the time interval between hits. This indicates that there is a transient period of vulnerability after an initial concussive event, during which additional concussions may lead to more severe acute outcomes. Assessment at late stages after injury revealed that rats that experienced repeated mTBI demonstrate disruptive and progressive cognitive deficits up to several months after injury. Repeated mTBI also resulted in long-term white matter thinning as well as increases in molecular markers of gliosis.

Overall, Dr. Shear's team found that the functional consequences of either single or repeated concussive injuries resolved more quickly than the underlying cellular and molecular disruptions, highlighting the need to develop clear biomarkers of mTBI to inform the return-to-duty decision. Moreover, their findings lend support to a number of molecular correlates that may be indicative of the period of increased vulnerability after a concussive injury.

This work has contributed to a US patent: �Device and Method for Inducing Brain Injury in Animal Test Subjects� (US 8,973,565 B2); another patent is pending for the helmet sensor system. Additionally, Dr. Shear's research has resulted in several peer-reviewed publications, describing the functional and molecular correlates following single and repeated closed concussive head injury, as well as a novel approach to detecting affective behavioral outcomes of mTBI in rats. The novel and relevant PCI injury animal model may serve as the foundation for future discoveries that improve mTBI diagnosis, prognosis, and treatment, thereby improving Service member care and mitigating long-term damage. This research may also lead to a better understanding of brain healing after trauma, and thus help to determine more appropriate return-to-duty guidelines for Service members who have suffered mTBI.

Publications:

Leung LY, Larimore Z, Holmes L, et al. The WRAIR projectile concussive impact model of mild traumatic brain injury: re-design, testing and preclinical validation. Ann Biomed Eng. 2014 Aug;42(8):1618-30.

Browning JR, Whiteman AC, Leung LY, et al. Air-puff induced vocalizations: A novel approach to detecting negative affective state following concussion in rats. J Neurosci Methods. 2016 Oct 29. (epub ahead of print).

Mountney A, Boutte AM, Cartagena CM, et al. Functional and molecular correlates following single and repeated rat closed-head concussion: indices of vulnerability following brain injury. J. Neurotrauma. 2017 Oct 1. (epub ahead of print).

Link:

Public and Technical Abstracts: A Military-Relevant Model of Closed Concussive Head Injury: Longitudinal Studies Characterizing and Validating Single and Repetitive mTBI

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