Potential Health and Performance Effects of High-Level and Low-Level Blast: A Scoping Review of Two Decades of Research.

Although blast exposure has been recognized as a significant source of morbidity and mortality in military populations, our understanding of the effects of blast exposure, particularly low-level blast (LLB) exposure, on health outcomes remains limited. This scoping review provides a comprehensive, accessible review of the peer-reviewed literature that has been published on blast exposure over the past two decades, with specific emphasis on LLB. We conducted a comprehensive scoping review of the scientific literature published between January 2000 and 2019 pertaining to the effects of blast injury and/or exposure on human and animal health. A three-level review process with specific inclusion and exclusion criteria was used. A full-text review of all articles pertaining to LLB exposure was conducted and relevant study characteristics were extracted. The research team identified 3,215 blast-relevant articles, approximately half of which (55.4%) studied live humans, 16% studied animals, and the remainder were non-subjects research (e.g., literature reviews). Nearly all (99.49%) of the included studies were conducted by experts in medicine or epidemiology; approximately half of these articles were categorized into more than one medical specialty. Among the 51 articles identified as pertaining to LLB specifically, 45.1% were conducted on animals and 39.2% focused on human subjects. Animal studies of LLB predominately used shock tubes to induce various blast exposures in rats, assessed a variety of outcomes, and clearly demonstrated that LLB exposure is associated with brain injury. In contrast, the majority of LLB studies on humans were conducted among military and law enforcement personnel in training environments and had remarkable variability in the exposures and outcomes assessed. While findings suggest that there is the potential for LLB to harm human populations, findings are mixed and more research is needed. Although it is clear that more research is needed on this rapidly growing topic, this review highlights the detrimental effects of LLB on the health of both animals and humans. Future research would benefit from multidisciplinary collaboration, larger sample sizes, and standardization of terminology, exposures, and outcomes.

Self-Reported Concussion Symptomology during Deployment: Differences as a Function of Injury Mechanism and Low-Level Blast Exposure.

Traumatic brain injury (TBI), which can result from either direct impact to the head or blast exposure, has been the leading cause of morbidity and mortality in recent military conflicts. However, little research has compared mTBIs by mechanism of injury. The present research addressed two research questions: (1) Are blast-related mTBIs (mbTBIs) associated with significantly more symptoms than impact-related mTBIs (miTBIs), and (2) are mTBIs associated with more self-reported symptoms among service members with higher (vs. lower) risk of low-level blast (LLB) exposure. We obtained data from 181,423 active duty enlisted United States Marines deployed between 2003 and 2012, who completed the Post-Deployment Health Assessment. We examined the self-reported symptoms of Marines who completed an mTBI screen and could be classified as at high or low risk for LLB exposure, using their military occupation as a proxy (n = 12,013). Symptoms were compared as a function of blast exposure (blast vs. impact), probable mTBI (yes vs. no), occupational risk of LLB (high vs. low), and symptom type (neurological vs. musculoskeletal vs. immunological). Overall, musculoskeletal symptoms were reported more frequently than neurological and immunological symptoms. However, Marines with probable mTBIs (regardless of mechanism of injury) and those with probable mbTBIs specifically reported more neurological symptoms, which rose to the level of musculoskeletal symptom reporting. Among Marines with probable mTBI, those with high risk of LLB exposure also reported significantly more neurological symptoms. Our results indicate that mbTBIs and miTBIs may be fundamentally different, and that LLB may increase susceptibility to injury.

Blast Exposure and Risk of Recurrent Occupational Overpressure Exposure Predict Deployment TBIs.

INTRODUCTION: Traumatic brain injury (TBI) has been the leading cause of morbidity and mortality in recent military conflicts and deployment-related TBIs are most commonly caused by blast. However, knowledge of risk factors that increase susceptibility to TBI following an acute, high-level blast is limited. We hypothesized that recurrent occupational overpressure exposure (ROPE) may be one factor that increases susceptibility to mild TBI (mTBI) following blast. MATERIALS AND METHODS: Using military occupational specialty as a proxy, we examined the effects of high versus low ROPE on mTBI following blast exposure. Initial analyses included 111,641 active-duty-enlisted U.S. Marines who completed the 2003 or 2008 version of the Post-Deployment Health Assessment. Final analyses examined probable mTBI screens among Marines with at least one qualifying exposure as a function of whether the exposure was a blast and level of ROPE (N = 12,929). This study was approved by the Institutional Review Board at the Naval Health Research Center. RESULTS: Blast and ROPE were both independently and jointly associated with a probable mTBI. Marines who experienced a blast (vs other qualifying exposure) and those in high (vs low) risk occupations were 1.07 and 1.23 times more likely to sustain a probable mTBI, respectively. Furthermore, among those who experienced a blast during deployment, those in high-risk occupations were 1.45 times more likely than those in low-risk occupations to sustain a probable mTBI. CONCLUSIONS: Blast exposure and ROPE were independently associated with mTBIs, and Marines with both blast exposure during deployment and ROPE were especially likely to sustain an mTBI. This suggests that ROPE heightens the risk of mTBI following blast. Ongoing research is examining the severity, symptomology, and sequelae of TBIs as a function of ROPE.

Military Blast Injury and Chronic Neurodegeneration: Research Presentations from the 2015 International State-of-the-Science Meeting.

Blast-related traumatic brain injury (TBI) is a signature injury of recent military conflicts, leading to increased Department of Defense (DoD) interest in its potential long-term effects, such as chronic traumatic encephalopathy (CTE). The DoD Blast Injury Research Program Coordinating Office convened the 2015 International State-of-the-Science Meeting to discuss the existing evidence regarding a causal relationship between TBI and CTE. Over the course of the meeting, experts across government, academia, and the sports community presented cutting edge research on the unique pathological characteristics of blast-related TBI, blast-related neurodegenerative mechanisms, risk factors for CTE, potential biomarkers for CTE, and treatment strategies for chronic neurodegeneration. The current paper summarizes these presentations. Although many advances have been made to address these topics, more research is needed to establish the existence of links between the long-term effects of single or multiple blast-related TBI and CTE.

Ubiquitin carboxy-terminal hydrolase-l1 as a serum neurotrauma biomarker for exposure to occupational low-level blast.

Repeated exposure to low-level blast is a characteristic of a few select occupations and there is concern that such occupational exposures present risk for traumatic brain injury. These occupations include specialized military and law enforcement units that employ controlled detonation of explosive charges for the purpose of tactical entry into secured structures. The concern for negative effects from blast exposure is based on rates of operator self-reported headache, sleep disturbance, working memory impairment, and other concussion-like symptoms. A challenge in research on this topic has been the need for improved assessment tools to empirically evaluate the risk associated with repeated exposure to blast overpressure levels commonly considered to be too low in magnitude to cause acute injury. Evaluation of serum-based neurotrauma biomarkers provides an objective measure that is logistically feasible for use in field training environments. Among candidate biomarkers, ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) has some empirical support and was evaluated in this study. We used daily blood draws to examine acute change in UCH-L1 among 108 healthy military personnel who were exposed to repeated low-level blast across a 2-week period. These research volunteers also wore pressure sensors to record blast exposures, wrist actigraphs to monitor sleep patterns, and completed daily behavioral assessments of symptomology, postural stability, and neurocognitive function. UCH-L1 levels were elevated as a function of participating in the 2-week training with explosives, but the correlation of UCH-L1 elevation and blast magnitude was weak and inconsistent. Also, UCH-L1 elevations did not correlate with deficits in behavioral measures. These results provide some support for including UCH-L1 as a measure of central nervous system effects from exposure to low-level blast. However, the weak relation observed suggests that additional indicators of blast effect are needed.

Impact of RNA editing on functions of the serotonin 2C receptor in vivo.

Transcripts encoding 5-HT(2C) receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT(2C-VGV), exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT(2C-VGV) receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT(2C-VGV) receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT(2C-VGV) receptors. However, enhanced behavioral sensitivity to a 5-HT(2C) receptor agonist was also seen in mice expressing 5-HT(2C-VGV) receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT(2C-VGV) receptors had greater sensitivity to a 5-HT(2C) inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT(2C) receptor binding sites in the brains of mice solely expressing 5-HT(2C-VGV) receptors. We conclude that 5-HT(2C-VGV) receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT(2C) receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT(2C) receptor binding sites in brain. We further caution that the pattern of 5-HT(2C) receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen.

RATIONALE: Hallucinogenic serotonin 2A (5-HT(2A)) receptor partial agonists, such as (+ or -)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent head-twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT(2A) receptor antagonists. In addition to 5-HT(2A) receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT(2C) receptors. OBJECTIVES: We tested for involvement of 5-HT(2C) receptors in the HTR induced by DOI. RESULTS: Comparison of 5-HT(2C) receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT(2C) receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT(2A) receptors in frontal cortex explained the strain difference, including 5-HT(2A) receptor density, Galpha(q) or Galpha(i/o) protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT(2C) receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT(2C) receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. CONCLUSIONS: We conclude that the HTR to DOI in mice is strongly modulated by 5-HT(2C) receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT(2) receptors.