Elevations in Tumor Necrosis Factor Alpha and Interleukin 6 From Neuronal-Derived Extracellular Vesicles in Repeated Low-Level Blast Exposed Personnel.

Objective: The purpose of this pilot study was to determine if military service members with histories of hundreds to thousands of low-level blast exposures (i. e., experienced breachers) had different levels of serum and neuronal-derived extracellular vesicle (EV) concentrations of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNFα), compared to matched controls, and if these biomarkers related to neurobehavioral symptoms. Methods: Participants were experienced breachers (n = 20) and matched controls without blast exposures (n = 14). Neuronal-derived EVs were isolated from serum and identified with mouse anti-human CD171. Serum and neuronal-derived EVs were analyzed for IL-6, IL-10, and TNFα using an ultra-sensitive assay. Results: Serum TNFα concentrations were decreased in breachers when compared to control concentrations (p < 0.01). There were no differences in serum concentrations of IL-6, IL-10, or the IL-6/IL-10 ratio between breachers and controls (p's > 0.01). In neuronal-derived EVs, TNFα and IL-6 levels were increased in breachers compared to controls (p's < 0.01), and IL-10 levels were decreased in the breacher group compared to controls (p < 0.01). In breachers the IL-6/IL-10 ratio in neuronal-derived EVs was higher compared to controls, which correlated with higher total Rivermead Post-concussion Questionnaire (RPQ) scores (p's < 0.05). Conclusions: These findings suggest that exposure of personnel to high numbers of low-level blast over a career may result in enduring central inflammation that is associated with chronic neurological symptoms. The data also suggest that peripheral markers of inflammation are not necessarily adequate surrogates for central neuroinflammation.

A Pilot Study of Whole-Blood Transcriptomic Analysis to Identify Genes Associated with Repetitive Low-Level Blast Exposure in Career Breachers.

Repetitive low-level blast exposure is one of the major occupational health concerns among US military service members and law enforcement. This study seeks to identify gene expression using microRNA and RNA sequencing in whole-blood samples from experienced breachers and unexposed controls. We performed experimental RNA sequencing using Illumina's HiSeq 2500 Sequencing System, and microRNA analysis using NanoString Technology nCounter miRNA expression panel in whole-blood total RNA samples from 15 experienced breachers and 14 age-, sex-, and race-matched unexposed controls. We identified 10 significantly dysregulated genes between experienced breachers and unexposed controls, with FDR corrected <0.05: One upregulated gene, LINC00996 (long intergenic non-protein coding RNA 996); and nine downregulated genes, IGLV3-16 (immunoglobulin lambda variable 3-16), CD200 (CD200 molecule), LILRB5 (leukocyte immunoglobulin-like receptor B5), ZNF667-AS1 (ZNF667 antisense RNA 1), LMOD1 (leiomodin 1), CNTNAP2 (contactin-associated protein 2), EVPL (envoplakin), DPF3 (double PHD fingers 3), and IGHV4-34 (immunoglobulin heavy variable 4-34). The dysregulated gene expressions reported here have been associated with chronic inflammation and immune response, suggesting that these pathways may relate to the risk of lasting neurological symptoms following high exposures to blast over a career.

Neuronally-derived tau is increased in experienced breachers and is associated with neurobehavioral symptoms.

Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aß42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (-0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aß42 or in serum levels of NF-L, tau, or Aß42 (p's > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score (F(1,14) = 7.702, p = 0.015, R2 = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.

Chronic Effects of Breaching Blast Exposure on Sensory Organization and Postural Limits of Stability.

OBJECTIVE: The goal of this effort to investigate if experienced breachers, professionals with a career history of exposure to repeated low-level blasts, exhibited postural instability. METHODS: Postural data were examined using traditional tests of means and compared to normative data. RESULTS: Breachers had significantly lower NeuroCom Sensory Organization Test (SOT) visual scores (within normative limits), prolonged Limits of Stability (LOS) test reaction time (30% of breachers and 7% of controls testing abnormal), and slower LOS movement velocity (21% of breachers and 0% of controls testing abnormal) compared to controls. CONCLUSION: Our LOS test findings are like those previously reported for students in the military breacher training course and seem to indicate that while acute effects of blasts on sensory control of balance fade away, effects on postural LOS persist over time.

Functional and Structural Neuroimaging Correlates of Repetitive Low-Level Blast Exposure in Career Breachers.

Combat military and civilian law enforcement personnel may be exposed to repetitive low-intensity blast events during training and operations. Persons who use explosives to gain entry (i.e., breach) into buildings are known as "breachers" or dynamic entry personnel. Breachers operate under the guidance of established safety protocols, but despite these precautions, breachers who are exposed to low-level blast throughout their careers frequently report performance deficits and symptoms to healthcare providers. Although little is known about the etiology linking blast exposure to clinical symptoms in humans, animal studies demonstrate network-level changes in brain function, alterations in brain morphology, vascular and inflammatory changes, hearing loss, and even alterations in gene expression after repeated blast exposure. To explore whether similar effects occur in humans, we collected a comprehensive data battery from 20 experienced breachers exposed to blast throughout their careers and 14 military and law enforcement controls. This battery included neuropsychological assessments, blood biomarkers, and magnetic resonance imaging measures, including cortical thickness, diffusion tensor imaging of white matter, functional connectivity, and perfusion. To better understand the relationship between repetitive low-level blast exposure and behavioral and imaging differences in humans, we analyzed the data using similarity-driven multi-view linear reconstruction (SiMLR). SiMLR is specifically designed for multiple modality statistical integration using dimensionality-reduction techniques for studies with high-dimensional, yet sparse, data (i.e., low number of subjects and many data per subject). We identify significant group effects in these data spanning brain structure, function, and blood biomarkers.

Hearing Loss and Irritability Reporting Without Vestibular Differences in Explosive Breaching Professionals.

Background: Blast exposure is a potential hazard in modern military operations and training, especially for some military occupations. Helmets, peripheral armor, hearing protection, and eye protection worn by military personnel provide some acute protection from blast effects but may not fully protect personnel against cumulative effects of repeated blast overpressure waves experienced over a career. The current study aimed to characterize the long-term outcomes of repeated exposure to primary blast overpressure in experienced career operators with an emphasis on the assessment of hearing and vestibular outcomes. Methods: Participants included experienced "breachers" (military and law enforcement explosives professionals who gain entry into structures through controlled detonation of charges) and similarly aged and experienced "non-breachers" (non-breaching military and law enforcement personnel). Responses to a clinical interview and performance on audiological and vestibular testing were compared. Results: Hearing loss, ringing in the ears, irritability, and sensitivity to light or noise were more common among breachers than non-breachers. Breachers reported more combat exposure than non-breachers, and subsequently, memory loss and difficulty concentrating were associated with both breaching and combat exposure. Vestibular and ocular motor outcomes were not different between breachers and non-breachers. Conclusion: Hearing-related, irritability, and sensitivity outcomes are associated with a career in breaching. Future studies examining long-term effects of blast exposure should take measures to control for combat exposure.

The influence of traumatic brain injury on the allocation of vertical spatial attention.

Objective: Research on impairments of spatial attention has primarily investigated hemispatial neglect in brain-lesioned patients, revealing decrements in the allocation of attention to right versus left egocentric or allocentric hemispace. Whereas head trauma might injure those parts of the brain that allocate vertical attention, little is known about the influence of trauma on the allocation of visuospatial attention in vertical space. Thus, the goal of this study was to learn if chronic moderate-to-severe traumatic brain injury (m/sTBI) alters the allocation of vertical visuospatial attention as assessed by the Attention Network Task (ANT). The ANT assesses the influence of Posner-type spatial cues and distractors using an Eriksen flanker task.Methods: 12 chronic m/sTBI patients and 12 demographically-matched neurologically-healthy controls (HCs) completed a version of the ANT wherein trials were coded for cue and target locations above and below central visual fixation. Trial-wise reaction times (RT) and accuracy were subjected to mixed-model ANOVAs and planned contrasts.Results: These data were subject to secondary analyses, which revealed that across groups, median RTs were significantly faster when targets occurred above than below the central visual fixation (p < .01); however, only HCs' error rates differed as a function of target altitude. Unlike controls, m/sTBI survivors did not exhibit the anticipated upward error-rate attentional bias.Conclusions: As alteration of spatial attention can be a major cause of disability, present findings suggest that m/sTBI survivors exhibit this loss of normal upward attentional bias. Future studies are need to learn if these patients might benefit from treatment.

Association Between Traumatic Brain Injury-Related Brain Lesions and Long-term Caregiver Burden.

OBJECTIVE: To investigate the association between traumatic brain injury (TBI)-related brain lesions and long-term caregiver burden in relation to dysexecutive syndrome. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: A total of 256 participants: 105 combat veterans with TBI, 23 healthy control combat veterans (HCv), and 128 caregivers. OUTCOME MEASURE: Caregiver burden assessed by the Zarit Burden Interview at 40 years postinjury. DESIGN: Participants with penetrating TBI were compared with HCv on perceived caregiver burden and neuropsychological assessment measures. Data of computed tomographic scans (overlay lesion maps of participants with a penetrating TBI whose caregivers have a significantly high burden) and behavioral statistical analyses were combined to identify brain lesions associated with caregiver burden. RESULTS: Burden was greater in caregivers of veterans with TBI than in caregivers of HCv. Caregivers of participants with lesions affecting cognitive and behavioral indicators of dysexecutive syndrome (ie, left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex) showed greater long-term burden than caregivers of participants with lesions elsewhere in the brain. CONCLUSION AND IMPLICATION: The TBI-related brain lesions have a lasting effect on long-term caregiver burden due to cognitive and behavioral factors associated with dysexecutive syndrome.

Association between long-term cognitive decline in Vietnam veterans with TBI and caregiver attachment style.

OBJECTIVE: To examine whether a caregiver's attachment style is associated with patient cognitive trajectory after traumatic brain injury (TBI). SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Forty Vietnam War veterans with TBI and their caregivers. MAIN OUTCOME MEASURE: Cognitive performance, measured by the Armed Forces Qualification Test percentile score, completed at 2 time points: preinjury and 40 years postinjury. DESIGN: On the basis of caregivers' attachment style (secure, fearful, preoccupied, dismissing), participants with TBI were grouped into a high or low group. To examine the association between cognitive trajectory of participants with TBI and caregivers' attachment style, we ran four 2 × 2 analysis of covariance on cognitive performances. RESULTS: After controlling for other factors, cognitive decline was more pronounced in participants with TBI with a high fearful caregiver than among those with a low fearful caregiver. Other attachment styles were not associated with decline. CONCLUSION AND IMPLICATION: Caregiver fearful attachment style is associated with a significant decline in cognitive status after TBI. We interpret this result in the context of the neural plasticity and cognitive reserve literatures. Finally, we discuss its impact on patient demand for healthcare services and potential interventions.

Relation of repeated low-level blast exposure with symptomology similar to concussion.

OBJECTIVE: To investigate anecdotal reports suggesting that repeated exposure to low-level explosive blast has myriad health impacts, including an array of neurological effects. PARTICIPANTS: A total of 184 anonymous survey respondents from military and nonmilitary law enforcement populations (135 exposed to occupational blast and 49 controls). DESIGN: Survey of self-reported history of occupational exposure to repeated low-level blast (breaching blast) and symptomology similar to concussion. RESULTS: Findings suggest that number and severity of symptoms increase with history of chronic blast exposure (F = 18.26, P < .001) and that symptoms can interfere with daily activity (t = 2.60, P = .010). CONCLUSION: Given the prevalence of repeated exposure to blast among some military and civilian law enforcement occupations, the results of this survey study support a role for blast surveillance programs as well as continued research on health impacts of low-level repeated blast exposure.