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Chronic mental health problems are common among military veterans who suffered blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns with most DEGs unique to one condition. Six DEGs (Hapln1, Grm2, P2ry12, Ccr5, Pbld1 and Cdh23) were found in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast vs. sham. In particular, amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor α (TNFα) signaling in blast-related effects in amygdala and anterior cortex. EIF4e, an upstream regulator of P2ry12 and Ccr5 was predicted to be activated in amygdala. qPCR validated longitudinal changes in two TNFα regulated genes (Ctsb, Hapln1), P2ry12 and Grm2. These studies have important implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

The consequences of blast-induced traumatic brain injury (bTBI) on the blood–brain barrier (BBB) and components of the neurovascular unit are an area of active research. In this study we assessed the time course of BBB integrity in anesthetized rats exposed to a single blast overpressure of 130 kPa (18.9 PSI). BBB permeability was measured in vivo via intravital microscopy by imaging extravasation of fluorescently labeled tracers (40 kDa and 70 kDa molecular weight) through the pial microvasculature into brain parenchyma at 2–3 h, 1, 3, 14, or 28 days after the blast exposure. BBB structural changes were assessed by immunostaining and molecular assays. At 2–3 h and 1 day after blast exposure, significant increases in the extravasation of the 40 kDa but not the 70 kDa tracers were observed, along with differential reductions in the expression of tight junction proteins (occludin, claudin-5, zona occluden-1) and increase in the levels of the astrocytic water channel protein, AQP-4, and matrix metalloprotease, MMP-9. Nearly all of these measures were normalized by day 3 and maintained up to 28 days post exposure. These data demonstrate that blast-induced changes in BBB permeability are closely coupled to structural and functional components of the BBB.

Mild traumatic brain injury (mTBI) has been linked to mental health disorders (MHDs) and pituitary function alterations. Due to the complex relationship of mTBI, the neuroendocrine system, and MHDs, we propose that neuroendocrine dysfunction (NED) may play a role in negative long-term health outcomes. The goal of this study was to determine if blast-concussed service members (SMs) have a stronger likelihood of developing NED. We hypothesized that NED either pre- or post-injury is associated with poor mental and physical health outcomes. Serum samples from the Armed Forces Health Surveillance Branch were obtained from concussed (n = 59) and non-concussed (n = 72) SMs treated at the Concussion Restoration Care Center (CRCC) in Afghanistan. Serum was collected within 2 years prior to deployment and one or two times within 3 years following their CRCC visit. Samples were analyzed for luteinizing hormone (LH), testosterone, human growth hormone, cortisol, and prolactin to assess post-injury neuroendocrine function. Results indicate that SMs who incurred an mTBI exhibited long-term LH and testosterone deficiencies 3 years following injury compared to controls. Specifically, 47.6% of head-injured SMs displayed hypofunction in at least one of five hormones at 3 years post-injury. Anxiety disorders were the most common MHD observed in concussed SMs with hypopituitarism, while there was also a trend for SMs with chronic pituitary dysfunction to have MHD diagnoses. Findings indicate blast-related mTBI may be associated with long-term health outcomes following a period of incubation. Neuroendocrine screenings may increase treatment opportunities, inform rehabilitation strategies, and improve overall quality of life for patients.

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aβ) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aβ42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aβ 42 levels and Aβ oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Exposure to blast overpressure may result in cerebrovascular impairment, including cerebral vasospasm. The mechanisms contributing to this vascular response are unclear. The aim of this study was to evaluate the relationship between blast and functional alterations of the cerebral microcirculation and to investigate potential underlying changes in vascular microstructure. Cerebrovascular responses were assessed in sham- and blast-exposed male rats at multiple time points from 2 h through 28 days after a single 130-kPa (18.9-psi) exposure. Pial microcirculation was assessed through a cranial window created in the parietal bone of anesthetized rats. Pial arteriolar reactivity was evaluated in vivo using hypercapnia, barium chloride, and serotonin. We found that exposure to blast leads to impairment of arteriolar reactivity >24 h after blast exposure, suggesting delayed injury mechanisms that are not simply attributed to direct mechanical deformation. Observed vascular impairment included a reduction in hypercapnia-induced vasodilation, increase in barium-induced constriction, and reversal of the serotonin effect from constriction to dilation. A reduction in vascular smooth muscle contractile proteins consistent with vascular wall proliferation was observed, as well as delayed reduction in nitric oxide synthase and increase in endothelin-1 B receptors, mainly in astrocytes. Collectively, the data show that exposure to blast results in delayed and prolonged alterations in cerebrovascular reactivity that are associated with changes in the microarchitecture of the vessel wall and astrocytes. These changes may contribute to long-term pathologies involving dysfunction of the neurovascular unit, including cerebral vasospasm.

To evaluate how blast exposure impacts peripheral biomarkers.in military personnel enrolled in 10-day blast training.On day 7, 21 military personnel experienced peak overpressure2 pounds per square inch (psi); while 29 military personnel experienced peak overpressure ≥5 psi. Blood samples were collected each day to measure changes in amyloid beta (Aβ), neurofilament light chain (NFL), and tau concentrations.Within 24 hours following exposure ≥5 psi, the ≥5 psi group had lower Aβ42 (These findings provide an initial report of acute alterations in biomarker concentrations following blast exposure.

At present, there are no set guidelines establishing cumulative limits for blast exposure numbers and intensities in military personnel, in combat or training operations. The objective of the current study was to define lung injury, pathology, and associated behavioral changes from primary repeated blast lung injury under appropriate exposure conditions and combinations (i.e. blast overpressure (BOP) intensity and exposure frequency) using an advanced blast simulator. Male Sprague Dawley rats were exposed to BOP frontally and laterally at a pressure range of ~ 8.5–19 psi, for up to 30 daily exposures. The extent of lung injury was identified at 24 h following BOP by assessing the extent of surface hemorrhage/contusion, Hematoxylin and Eosin staining, and behavioral deficits with open field activity. Lung injury was mathematically modeled to define the military standard 1% lung injury threshold. Significant levels of histiocytosis and inflammation were observed in pressures ≥ 10 psi and orientation effects were observed at pressures ≥ 13 psi. Experimental data demonstrated ~ 8.5 psi is the threshold for hemorrhage/contusion, up to 30 exposures. Modeling the data predicted injury risk up to 50 exposures with intensity thresholds at 8 psi for front exposure and 6psi for side exposures, which needs to be validated further.

Mild traumatic brain injury (mTBI) is a risk for military personnel due to blast overpressures, which may result from a variety of sources, including artillery and improvised explosive devices. Much research has gone into the search for a biomarker to identify patients with a TBI. The FDA recently identified two proteins, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), as biomarkers to evaluate suspected brain injury. Our group previously observed changes in UCH-L1 in a military population exposed to repeated blast. In our current study we assessed GFAP protein levels in a military population exposed to repeated blast during a 2-week training protocol. We observed GFAP levels were reduced in the moderate blast cases on days 6 and 7 during the training. Specifically, moderate blast cases showed a 24.07% reduction from baseline on day 6 and a 29.61% reduction on day 7. Further, GFAP levels were negatively correlated with cumulative blast experienced during training and with duration of military service. We observed that repeated blast exposure at low levels may impact acute changes in GFAP. Additionally subacute cumulative blast exposure or duration of service was also a factor in influencing GFAP levels.

Recent evidence linking repeated low-level blast overpressure exposure in operational and training environments with neurocognitive decline, neuroinflammation, and neurodegenerative processes has prompted concern over the cumulative deleterious effects of repeated blast exposure on the brains of service members. Repetitive exposure to low-level primary blast may cause symptoms (subclinical) similar to those seen in mild traumatic brain injury (TBI), with progressive vascular and cellular changes, which could contribute to neurodegeneration. At the cellular level, the mechanical force associated with blast exposure can cause cellular perturbations in the brain, leading to secondary injury. To examine the cumulative effects of repetitive blast on the brain, an advanced blast simulator (ABS) was used to closely mimic “free-field” blast. Rats were exposed to 1–4 daily blasts (one blast per day, separated by 24 h) at 13, 16, or 19 psi peak incident pressures with a positive duration of 4–5 ms, either in a transverse or longitudinal orientation. Blood-brain barrier (BBB) markers (vascular endothelial growth factor (VEGF), occludin, and claudin-5), transactive response DNA binding protein (TDP-43), and the mechanosensitive channel Piezo2 were measured following blast exposure. Changes in expression of VEGF, occludin, and claudin-5 after repeated blast exposure indicate alterations in the BBB, which has been shown to be disrupted following TBI. TDP-43 is very tightly regulated in the brain and altered expression of TDP-43 is found in clinically-diagnosed TBI patients. TDP-43 levels were differentially affected by the number and magnitude of blast exposures, decreasing after 2 exposures, but increasing following a greater number of exposures at various intensities. Lastly, Piezo2 has been shown to be dysregulated following blast exposure and was here observed to increase after multiple blasts of moderate magnitude, indicating that blast may cause a change in sensitivity to mechanical stimuli in the brain and may contribute to cellular injury. These findings reveal that cumulative effects of repeated exposures to blast can lead to pathophysiological changes in the brain, demonstrating a possible link between blast injury and neurodegenerative disease, which is an important first step in understanding how to prevent these diseases in soldiers exposed to blast.

Mild traumatic brain injury is a common outcome of blast exposure, and current literature indicates high rates of comorbid posttraumatic stress disorder (PTSD) in military personnel. Blast-exposed rats display PTSD-like behavior, suggesting relationships may exist between PTSD and blast exposure. Other studies demonstrate the roles of stathmin and corticosterone associated with fear- and anxiety-like behaviors in rodent models. Furthermore, studies have observed ranges of responses to both physical and psychological trauma in animal populations (Elder 2012, Ritov 2016). This study exposed rodents to repeated blast overpressure (BOP) and analyzed behavioral responses and molecular variables at 3 weeks and 6 months after exposure. We applied a modified version of a previously reported behavioral profiling approach that separates "affected" and "unaffected" rats based on the presence of anxiety-like behaviors (Ritov, 2016). We report that "affected" 3 week animals showed higher plasma corticosterone and amygdalar stathmin levels, while "affected" 6 month animals had lower prefrontal cortex stathmin. Higher corticosterone also paralleled anxiety behavior in "affected" 3 week animals, which was not observed in 6 month animals, indicating possible negative feedback loop mechanisms. Elevated levels of amygdalar stathmin correlated with anxiety behaviors in "affected" 3 week and 6 month animals, indicating sustained molecular changes. We conclude that this unique analysis may provide more information about response to blast. This type of analysis should also be considered when treating clinical populations, since individual differences may affect behavioral and long-term outcomes. Future studies should elucidate relationships of stress and fear responses in the context of BOP.

BACKGROUND Apache pilots needing refractive correction are issued modified HGU-4/P aviator spectacles. However, a recently published survey found field of view (FOV) dissatisfaction with the current spectacles when sighting in with a Helmet Display Unit (HDU). A current Air Force flight frame was modified in-lab and the purpose of this study was to evaluate the FOV with the current Apache flight frame vs. the modified flight frame. METHODS Recruited were 21 Apache pilots to assess FOV under three conditions: 1) wearing the current Apache frame; 2) wearing the modified Apache frame; and 3) wearing no frame. The main outcome measure was total FOV of four quadrants tested: superior left (45°); superior right (135°); inferior right (225°); and inferior left (315°). RESULTS No significant differences in FOV were seen between the two frames tested while wearing the current Apache helmet (P = 0.33) and the new Apache helmet (P = 0.64). However, there were significant differences in FOV between the no frame condition and the two frame conditions tested with both helmets (P < 0.001). DISCUSSION No significant differences in FOV were seen between the two frames tested while wearing either Apache helmet. However, with both helmets there were significant differences in FOV between the no frame condition and the two frame conditions tested. This suggests that wearing no eyewear is still optimal in integrating the HDU device. With advances in contact lens technology, future research can study the viability of the latest generation of multifocal contact lenses with Apache aviators. Walsh DV, Jurek GM, McLean WE, Statz JK, Allen RL, Riggs DW. Assessment of a prototype Apache flight eyewear. Aerosp Med Hum Perform. 2016; 87(9):800-805.

Finite difference equations can be used to study the responses of biochemical chain reactions at any step of the chain to an external stimulus. In this study, we developed mathematical models for two hypothetical chain reactions involving loops to study the responses in the chain as the length of the chain gets longer, so called transient and steady state responses. The first model is for a chain with a negative feedforward loop, and the second one is for a chain that has a negative feedback loop. Although both of the models have the same steady state equations and values, we showed that the chain with negative feedforward and negative feedback loops can produce significantly different behaviors. The former can bring the chain into oscillations with various periods and eventually chaos when the feedback is strong enough as the length of the reaction chain increases, whereas the latter is not capable of producing oscillations and more complicated dynamics.

Project Manager (PM) Apache Block III contacted the U.S. Army Aeromedical Research Laboratory (USAARL), Fort Rucker, Alabama, requesting assistance to evaluate and find solutions to a government-developed Helmet Display Unit (HDU) device called the Mock HDU for helmet alignment of the Apache Advanced Integrated Helmet (AAIH). The AAIH is a modified Head Gear Unit No. 56 for Personnel (HGU-56/P) to replace the current Integrated Helmet and Sighting System (IHADSS). The current flashlight-based HDU simulator for helmet/HDU alignment was no longer in production or available. Proper helmet/HDU alignment is critical to position the right eye in the small HDU eye box to obtain image alignment and full field of view (FOV). The initial approach of the PM to developing a helmet/HDU fitting device (Mock HDU) was to duplicate the optical characteristics of the current tactical HDU using less complex optics. However, the results produced questionable alignment, FOV, and distortion issues, with cost and development time overruns. After evaluating the Mock HDU, USAARL proposed a cost effective, less complex optical design called the Helmet/HDU Alignment Tool (HAT). This paper will show the development, components, and evaluations of the HAT compared to the current flashlight HDU simulator device. The laboratory evaluations included FOV measurements and alignment accuracies compared to tactical HDUs. The Apache helmet fitter technicians and Apache pilots compared the HAT to the current flashlight based HDU and ranked the HAT superior.