Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Abstract

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

Blast effects on post-concussive and mental health outcomes: Data from Canadian Armed Forces breachers and snipers

“…2,26 Self-reports of breachers reveal concussion-like symptoms including headaches, sleep disturbances, and memory impairments. 27,28 Furthermore, impairments appear not to arise in relation to a single exposure, but rather accumulate as a function of repetitive exposure to multiple blast events. For example, the number and severity of symptoms increases with a history of repeated blast exposure, which is more common in instructors than students.…”

“…For example, the number and severity of symptoms increases with a history of repeated blast exposure, which is more common in instructors than students. [27][28][29] In an investigation of the effects of repetitive expos ure to blast on health and performance, Canadian Spe cial Operations Forces Command (CANSOFCOM) breachers scored higher than sex-and age-matched Can adian Armed Forces (CAF) controls on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). [30][31][32][33] In contrast, there was no difference between the two groups on the emotional well-being sub-scale of RAND SF-36.…”

Eagle-449: A volumetric, whole-brain compilation of brain atlases for vestibular functional MRI research

“…Neuroimaging research which incorporates not only cortical areas but also structures in the basal ganglia, thalamus, and posterior fossa would therefore contribute considerably to vestibular systems neuroscience and patient care. Large neuroimaging consortia comprised of datasets from both normative adults and adolescents, including the Human Connectome Project 42 , UK Biobank 43 , and Adolescent Brain Cognitive Development studies 44 , as well as those with mild traumatic brain injury, such as the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium, or LIMBIC-CENC, effort 45 – 47 , are available for comprehensive exploration and hypothesis testing. To date, however, no neuroimaging atlas offers the extensive coverage necessary for researchers to explore vestibular system-associated connectivity across the cortex, subcortical structures, cerebellum, and brainstem.…”

The Multiple Functions of Melatonin: Applications in the Military Setting

“…These injuries are particularly devastating when they involve the brain, which they often do [124,125]. When the CNS is involved, such damage is referred to as traumatic brain injury (TBI); the neural alterations are a consequence of the direct energy transfer of a shockwave [126]. Although there is still much to be learned about the molecular events that initiate TBI, signature processes resulting from such damage are perturbations of mitochondrial physiology, including impaired bioenergetics, faulty oxidative phosphorylation, and elevated oxidative stress [127,128].…”