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Injuries from exposure to explosions rose dramatically during the Iraq and Afghanistan wars, which motivated investigations of blast-related neurotrauma and operational breaching. In this study, military “breachers” were exposed to controlled, low-level blast during a 10-day explosive breaching course. Using an omics approach, we assessed epigenetic, transcriptional, and inflammatory profile changes in blood from operational breaching trainees, with varying levels of lifetime blast exposure, along with daily self-reported symptoms (with tinnitus, headaches, and sleep disturbances as the most frequently reported). Although acute exposure to blast did not confer epigenetic changes, specifically in DNA methylation, differentially methylated regions (DMRs) with coordinated gene expression changes associated with lifetime cumulative blast exposures were identified. The accumulative effect of blast showed increased methylation of PAX8 antisense transcript with coordinated repression of gene expression, which has been associated with sleep disturbance. DNA methylation analyses conducted in conjunction with reported symptoms of tinnitus in the low versus high blast incidents groups identified DMRS in KCNE1 and CYP2E1 genes. KCNE1 and CYP2E1 showed the expected inverse correlation between DNA methylation and gene expression, which have been previously implicated in noise-related hearing loss. Although no significant transcriptional changes were observed in samples obtained at the onset of the training course relative to chronic cumulative blast, we identified a large number of transcriptional perturbations acutely pre- versus post-blast exposure. Acutely, 67 robustly differentially expressed genes (fold change ≥1.5), including UFC1 and YOD1 ubiquitin-related proteins, were identified. Inflammatory analyses of cytokines and chemokines revealed dysregulation of MCP-1, GCSF, HGF, MCSF, and RANTES acutely after blast exposure. These data show the importance of an omics approach, revealing that transcriptional and inflammatory biomarkers capture acute low-level blast overpressure exposure, whereas DNA methylation marks encapsulate chronic long-term symptoms.

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.

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 (Aβ42) 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 Aβ42 or in serum levels of NF-L, tau, or Aβ42 (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,  R 2  = 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.

Neurological dysfunction after traumatic brain injury (TBI) is caused by both the primary injury and a secondary cascade of biochemical and metabolic events. Since TBI can be caused by a variety of mechanisms, numerous models have been developed to facilitate its study. The most prevalent models are controlled cortical impact and fluid percussion injury. Both typically use “sham” (craniotomy alone) animals as controls. However, the sham operation is objectively damaging, and we hypothesized that the craniotomy itself may cause a unique brain injury distinct from the impact injury. To test this hypothesis, 38 adult female rats were assigned to one of three groups: control (anesthesia only); craniotomy performed by manual trephine; or craniotomy performed by electric dental drill. The rats were then subjected to behavioral testing, imaging analysis, and quantification of cortical concentrations of cytokines. Both craniotomy methods generate visible MRI lesions that persist for 14 days. The initial lesion generated by the drill technique is significantly larger than that generated by the trephine. Behavioral data mirrored lesion volume. For example, drill rats have significantly impaired sensory and motor responses compared to trephine or naïve rats. Finally, of the seven tested cytokines, KC-GRO and IFN-γ showed significant increases in both craniotomy models compared to naïve rats. We conclude that the traditional sham operation as a control confers profound proinflammatory, morphological, and behavioral damage, which confounds interpretation of conventional experimental brain injury models. Any experimental design incorporating “sham” procedures should distinguish among sham, experimentally injured, and healthy/naïve animals, to help reduce confounding factors.

To investigate the effects of caffeine on psychomotor vigilance and sleepiness during sleep restriction and following subsequent recovery sleep. Participants were N = 48 healthy good sleepers. All participants underwent five nights of sleep satiation (time-in-bed [TIB]: 10 hours), followed by five nights of sleep restriction (TIB: 5 hours), and three nights of recovery sleep (TIB: 8 hours) in a sleep laboratory. Caffeine (200 mg) or placebo was administered in the form of chewing gum at 08:00 am and 12:00 pm each day during the sleep restriction phase. Participants completed hourly 10-minute psychomotor vigilance tests and a modified Maintenance of Wakefulness Test approximately every 4 hours during the sleep restriction and recovery phases. Caffeine maintained objective alertness compared to placebo across the first 3 days of sleep restriction, but this effect was no longer evident by the fourth day. A similar pattern of results was found for Maintenance of Wakefulness Test sleep latencies, such that those in the caffeine group (compared to placebo) did not show maintenance of wakefulness relative to baseline after the second night of restriction. Compared to placebo, participants in the caffeine condition displayed slower return to baseline in alertness and wakefulness across the recovery sleep period. Finally, the caffeine group showed greater N3 sleep duration during recovery. Caffeine appears to have limited efficacy for maintaining alertness and wakefulness across 5 days of sleep restriction. Perhaps more importantly, there may be recovery costs associated with caffeine use following conditions of prolonged sleep loss.

Autoimmune profiling in rats revealed the antioxidant enzyme, peroxiredoxin 6 (PRDX6), as a target for autoantibodies evoked in response to traumatic brain injury (TBI). Consistent with this proposal, immunohistochemical analysis of rat cerebral cortex demonstrated that PRDX6 is highly expressed in the perivascular space, presumably contained within astrocytic foot processes. Accordingly, an immunosorbent electrochemiluminescence assay was developed for investigating PRDX6 in human samples. PRDX6 was found to be measurable in human blood and highly expressed in human cerebral cortex and platelets. Circulating levels of PRDX6 were elevated fourfold over control values 4 to 24 h following mild-to-moderate TBI. These findings suggest that PRDX6 may serve as a biomarker for TBI and that autoimmune profiling is a viable strategy for the discovery of novel TBI biomarkers.

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.

Mesenchymal stromal cells secrete a variety of anti-inflammatory factors and may provide a regenerative medicine option for the treatment of traumatic brain injury. The present study investigates the efficacy of multiple intravenous or intracardiac administrations of rat mesenchymal stromal cells or human mesenchymal stromal cells in female rats after controlled cortical impact by in vivo MRI, neurobehavior, and histopathology evaluation. Neither intravenous nor intracardiac administration of mesenchymal stromal cells derived from either rats or humans improved MRI measures of lesion volume or neurobehavioral outcome compared to saline treatment. Few mesenchymal stromal cells (<0.0005% of injected dose) were found within 3 days of last dosage at the site of injury after either delivery route, with no mesenchymal stromal cells being detectable in brain at 30 or 56 days post-injury. These findings suggest that non-autologous mesenchymal stromal cells therapy via intravenous or intracardiac administration is not a promising treatment after focal contusion traumatic brain injury in this female rodent model.

Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). Isolated concussions frequently produce acute neurological impairments, and individuals typically recover spontaneously within a short time frame. In contrast, brain injuries resulting from multiple concussions can result in cumulative damage and elevated risk of developing chronic brain pathologies. Increased attention has focused on identification of diagnostic markers that can prognostically serve as indices of brain health after injury, revealing the temporal profile of vulnerability to a second insult. Such markers may demarcate adequate recovery periods before concussed patients can return to required activities. We developed a noninvasive closed-head impact model that captures the hallmark symptoms of concussion in the absence of gross tissue damage. Animals were subjected to single or repeated concussive impact and examined using a battery of neurological, vestibular, sensorimotor, and molecular metrics. A single concussion induced transient, but marked, acute neurological impairment, gait alterations, neuronal death, and increased glial fibrillary acidic protein (GFAP) expression in brain tissue. As expected, repeated concussions exacerbated sensorimotor dysfunction, prolonged gait abnormalities, induced neuroinflammation, and upregulated GFAP and tau. These animals also exhibited chronic functional neurological impairments with sustained astrogliosis and white matter thinning. Acute changes in molecular signatures correlated with behavioral impairments, whereas increased times to regaining consciousness and balance impairments were associated with higher GFAP and neuroinflammation. Overall, behavioral consequences of either single or repeated concussive impact injuries appeared to resolve more quickly than the underlying molecular, metabolic, and neuropathological abnormalities. This observation, which is supported by similar studies in other mTBI models, underscores the critical need to develop more objective prognostic measures for guiding return-to-play decisions.

Purpose One in 59 children is diagnosed with autism spectrum disorder (ASD). Due to overlapping symptoms between hearing loss and ASD, children who are suspected of having ASD require an audiological evaluation to determine their hearing status for the purpose of differential diagnosis. The purpose of this article is twofold: (a) to increase audiologists' knowledge of ASD by discussing the challenges associated with testing and interpreting clinical data for children with ASD or suspected ASD and (b) to provide visual supports that can be used to facilitate audiological assessment. Method Eight children (ages 4-12 years) were recruited as video model participants. Videos were filmed using scripts that used concise and concrete language while portraying common clinical procedures. Using the video models, corresponding visual schedules were also created. Conclusion Although obtaining reliable hearing data from children with ASD is challenging, incorporating visual supports may facilitate testing. Video models and visual schedules have been created and made freely available for download online under a Creative Commons License (Creative Commons-Attribution-NonCommercial-ShareAlike 4.0 International License). Incorporating visual supports during clinical testing has the potential to reduce the child's and family's stress, as well as to increase the probability of obtaining a reliable and comprehensive audiological evaluation. Future research is warranted to determine the effectiveness and feasibility of implementing these tools in audiology clinics. Supplemental Material https://doi.org/10.23641/asha.10086434.