Abstract

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.

Highlights

  • Traumatic brain injury (TBI) resulting from blast exposure affects combatants and civilians around the world [1,2,3]

  • Recent estimates indicate that 10 to 20% of the 2.5 million US military service members deployed to Iraq and Afghanistan may be affected by TBI and the majority of these injuries are associated with blast exposure

  • Recent research has uncovered neuropathological and mechanistic connections between blast exposure and chronic traumatic encephalopathy (CTE), a progressive tau protein neurodegenerative disease documented in athletes with repetitive concussive and subconcussive head injury [44,45] and in military veterans with history of blast exposure [21,22]

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Summary

Introduction

Traumatic brain injury (TBI) resulting from blast exposure affects combatants and civilians around the world [1,2,3]. Rational development and clinical implementation of safe and effective diagnostics and therapeutics for blast traumatic brain injury, related sequelae, and associated comorbidities will require detailed mechanistic understanding of the underlying pathology (clinical science) and pathogenic mechanisms (basic science) across all stages of the disease (initiation, progression, interaction, termination). A caveat is required in experimental circumstances in which deployment of a pathobiologically informed animal model provides superior mechanistic insights (that is, construct validity) and explanatory generalizability (that is, external validity), such that derivative biomechanical analyses are more rather than less clinically relevant This is the case in recent studies that have combined military-relevant blast exposure conditions with animal models that exhibit clinically relevant acute and chronic blast-related neuropathology and functional sequelae [22,39]. Critical appraisal and expert consensus regarding these translational issues will go a long way towards fostering progress in the field

Conclusions
28. Elsayed NM
66. Mesulam MM
76. Bigler ED
81. McAllister TW
86. Kuhn TS
Findings
89. Willner P
Full Text
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