Blast Wave Exposure Research Articles

Multifunctional redox modulator prevents blast-induced loss of cochlear and vestibular hair cells and auditory spiral ganglion neurons

Blast wave exposure, a leading cause of hearing loss and balance dysfunction among military personnel, arises primarily from direct mechanical damage to the mechanosensory hair cells and supporting structures or indirectly through excessive oxidative stress. We previously reported that HK-2, an orally active, multifunctional redox modulator (MFRM), was highly effective in reducing both hearing loss and hair cells loss in rats exposed to a moderate intensity workday noise that likely damages the cochlea primarily from oxidative stress versus direct mechanical trauma. To determine if HK-2 could also protect cochlear and vestibular cells from damage caused primarily from direct blast-induced mechanical trauma versus oxidative stress, we exposed rats to six blasts of 186 dB peak SPL. The rats were divided into four groups: (B) blast alone, (BEP) blast plus earplugs, (BHK-2) blast plus HK-2 and (BEPHK-2) blast plus earplugs plus HK-2. HK-2 was orally administered at 50 mg/kg/d from 7-days before to 30-day after the blast exposure. Cochlear and vestibular tissues were harvested 60-d post-exposure and evaluated for loss of outer hair cells (OHC), inner hair cells (IHC), auditory nerve fibers (ANF), spiral ganglion neurons (SGN) and vestibular hair cells in the saccule, utricle and semicircular canals. In the untreated blast-exposed group (B), massive losses occurred to OHC, IHC, ANF, SGN and only the vestibular hair cells in the striola region of the saccule. In contrast, rats treated with HK-2 (BHK-2) sustained significantly less OHC (67%) and IHC (57%) loss compared to the B group. OHC and IHC losses were smallest in the BEPHK-2 group, but not significantly different from the BEP group indicating lack of protective synergy between EP and HK-2. There was no loss of ANF, SGN or saccular hair cells in the BHK-2, BEP and BEPHK-2 groups. Thus, HK-2 not only significantly reduced OHC and IHC damage, but completely prevented loss of ANF, SGN and saccule hair cells. The powerful protective effects of this oral MFRM make HK-2 an extremely promising candidate for human clinical trials.

Fiscal Year 2018 National Defense Authorization Act, Section734, Weapon Systems Line ofInquiry: Overview andBlast Overpressure Tool-A Module forHuman Body Blast Wave Exposure forSafer Weapons Training.

Experiences by service members in recent conflicts and training environments illuminate concerns about the possible effects of blast overpressure (BOP) exposure on brain health. Section734 of the National Defense Authorization Act for Fiscal Year (FY) 2018 (Public Law 115-91) requires that the Secretary of Defense conducts a longitudinal medical study on blast pressure exposure of members of the Armed Forces during combat and training, and the Assistant Secretary of Defense for Health Affairs was assigned responsibility for fulfilling requirements. The study's goal is to improve DoD's understanding of the impact of BOP exposure from weapon systems on service members' brain health and inform policy for risk mitigation, unit readiness, and health care decisions. This article focuses on the activities of the Weapon Systems Line of Inquiry (LOI) and the development of a prototype BOP Tool. The DoD established the Section734 Workgroup, which developed a program structure with five LOIs. The Weapon Systems LOI coordinated, collated, and analyzed information on BOP resulting from heavy weapons and blast events to inform strategies, and accounted for emerging research on health effects and performance. Ongoing research was leveraged to develop a BOP Tool as a standalone module and for integration into the Range Managers Toolkit. The effort identified opportunities for the DoD to improve the clarity of communications about BOP exposure, risk, and safety; establish methods to leverage emerging research; and develop a prototype BOP Tool to predict exposure loads when firing heavy weapons in training. It is recommended that the DoD revises requirements and policy to improve and standardize safety guidance throughout research, development, testing, and evaluation; acquisition; and training. The validated BOP Tool allows users to generate a scenario to predict BOP exposure and allows service members to modify them during planning for safer training.

Soft-armor Vest Effectiveness and Intrathoracic Biomechanics in Rodents Exposed to Primary Blast.

The biomechanics and efficacy of personal protective equipment in mitigating injuries from blast overpressure remain unclear. The objectives of this study were to define intrathoracic pressures in response to blast wave (BW) exposure and biomechanically evaluate a soft-armor vest (SA) at diminishing these perturbations. Male Sprague-Dawley rats were instrumented with pressure sensors in the thorax and were exposed laterally to multiple exposures ranging from 33 to 108kPa BW with SA and without SA. There were significant increases in rise time, peak negative pressure, and negative impulse in the thoracic cavity compared to the BW. Esophageal measurements were increased to a greater extent when compared to the carotid and the BW for all parameters (except positive impulse, which decreased). SA minimally altered the pressure parameters and energy content. This study establishes the relationship of external blast flow conditions and intra-body biomechanical responses in the thoracic cavity of rodents with and without SA.

Double Blast Wave Primary Effect on Synaptic, Glymphatic, Myelin, Neuronal and Neurovascular Markers

Explosive blasts are associated with neurological consequences as a result of blast waves impact on the brain. Yet, the neuropathologic and molecular consequences due to blast waves vs. blunt-TBI are not fully understood. An explosive-driven blast-generating system was used to reproduce blast wave exposure and examine pathological and molecular changes generated by primary wave effects of blast exposure. We assessed if pre- and post-synaptic (synaptophysin, PSD-95, spinophilin, GAP-43), neuronal (NF-L), glymphatic (LYVE1, podoplanin), myelin (MBP), neurovascular (AQP4, S100β, PDGF) and genomic (DNA polymerase-β, RNA polymerase II) markers could be altered across different brain regions of double blast vs. sham animals. Twelve male rats exposed to two consecutive blasts were compared to 12 control/sham rats. Western blot, ELISA, and immunofluorescence analyses were performed across the frontal cortex, hippocampus, cerebellum, and brainstem. The results showed altered levels of AQP4, S100β, DNA-polymerase-β, PDGF, synaptophysin and PSD-95 in double blast vs. sham animals in most of the examined regions. These data indicate that blast-generated changes are preferentially associated with neurovascular, glymphatic, and DNA repair markers, especially in the brainstem. Moreover, these changes were not accompanied by behavioral changes and corroborate the hypothesis for which an asymptomatic altered status is caused by repeated blast exposures.

The influence of tinnitus and hearing loss on the functional status of military Service members and Veterans

Objective This study evaluated the influence of tinnitus and hearing loss on the functional status of military Service members and Veterans. Design Participants completed audiologic testing and self-report instruments to assess tinnitus, hearing, and general functioning. We conducted multiple linear regression analyses using cross-sectional data with functional status as the dependent variable. The primary independent variables were tinnitus and average low-, high-, and extended high-frequency hearing thresholds. Secondary independent variables were subjective tinnitus severity and hearing difficulties. Each of the independent variables was modelled separately for Service members and Veterans; covariates for each multivariable model were identified a priori and, depending on the association being modelled, included age, gender, blast-wave exposure, and history of military traumatic brain injury. Study Sample Data were analysed from 283 Service members and 390 Veterans. Results After controlling for potential confounders, presence of tinnitus, tinnitus severity, average low-frequency hearing thresholds, and subjective hearing difficulties were significantly associated with functional status in Service members and Veterans. Conclusions These results suggest that tinnitus and poorer low-frequency hearing, and the perceived severity of tinnitus and hearing difficulties, may be associated with poorer functional status among Service members and Veterans.

An Experimental Model for the Study of Underwater Pressure Waves on the Central Nervous System in Rodents: A Feasibility Study

Underwater blast differs from blast in air. The increased density and viscosity of water relative to air cause injuries to occur almost exclusively as primary blast, and may cause disorientation in a diver, which may lead to inability to protect the airway and cause drowning. However, cognitive impairments from under water blast wave exposure have not been properly investigated, and no experimental model has been described. We established an experimental model (water shock tube) for simulating the effects of underwater blast pressure waves in rodents, and to investigate neurology in relation to organ injury. The model produced standardized pressure waves (duration of the primary peak 3.5 ms, duration of the entire complex waveform including all subsequent reflections 325 ms, mean impulse 141–281 kPa-ms, mean peak pressure 91–194 kPa). 31 rats were randomized to control (n = 6), exposure 90 kPa (n = 8), 152 kPa (n = 8), and 194 kPa (n = 9). There was a linear trend between the drop height of the water shock tube and electroencephalography (EEG) changes (p = 0.014), while no differences in oxygen saturation, heart rate, S100b or macroscopic bleedings were detected. Microscopic bleedings were detected in lung, intestines, and meninges. Underwater pressure waves caused changes in EEG, at pressures when mild hemorrhage occurred in organs, suggesting an impact on brain functions. The consistent injury profile enabled for the addition of future experimental interventions.

Cerebral Vasculature Influences Blast-Induced Biomechanical Responses of Human Brain Tissue.

Multiple finite-element (FE) models to predict the biomechanical responses in the human brain resulting from the interaction with blast waves have established the importance of including the brain-surface convolutions, the major cerebral veins, and using non-linear brain-tissue properties to improve model accuracy. We hypothesize that inclusion of a more detailed network of cerebral veins and arteries can further enhance the model-predicted biomechanical responses and help identify correlates of blast-induced brain injury. To more comprehensively capture the biomechanical responses of human brain tissues to blast-wave exposure, we coupled a three-dimensional (3-D) detailed-vasculature human-head FE model, previously validated for blunt impact, with a 3-D shock-tube FE model. Using the coupled model, we computed the biomechanical responses of a human head facing an incoming blast wave for blast overpressures (BOPs) equivalent to 68, 83, and 104 kPa. We validated our FE model, which includes the detailed network of cerebral veins and arteries, the gyri and the sulci, and hyper-viscoelastic brain-tissue properties, by comparing the model-predicted intracranial pressure (ICP) values with previously collected data from shock-tube experiments performed on cadaver heads. In addition, to quantify the influence of including a more comprehensive network of brain vessels, we compared the biomechanical responses of our detailed-vasculature model with those of a reduced-vasculature model and a no-vasculature model for the same blast-loading conditions. For the three BOPs, the predicted ICP values matched well with the experimental results in the frontal lobe, with peak-pressure differences of 4–11% and phase-shift differences of 9–13%. As expected, incorporating the detailed cerebral vasculature did not influence the ICP, however, it redistributed the peak brain-tissue strains by as much as 30% and yielded peak strain differences of up to 7%. When compared to existing reduced-vasculature FE models that only include the major cerebral veins, our high-fidelity model redistributed the brain-tissue strains in most of the brain, highlighting the importance of including a detailed cerebral vessel network in human-head FE models to more comprehensively account for the biomechanical responses induced by blast exposure.

Effects of intravitreal injection of siRNA against caspase-2 on retinal and optic nerve degeneration in air blast induced ocular trauma

Ocular repeated air blast injuries occur from low overpressure blast wave exposure, which are often repeated and in quick succession. We have shown that caspase-2 caused the death of retinal ganglion cells (RGC) after blunt ocular trauma. Here, we investigated if caspase-2 also mediates RGC apoptosis in a mouse model of air blast induced indirect traumatic optic neuropathy (b-ITON). C57BL/6 mice were exposed to repeated blasts of overpressure air (3 × 2 × 15 psi) and intravitreal injections of siRNA against caspase-2 (siCASP2) or against a control enhanced green fluorescent protein (siEGFP) at either 5 h after the first 2 × 15 psi (“post-blast”) or 48 h before the first blast exposure (“pre-blast”) and repeated every 7 days. RGC counts were unaffected by the b-ITON or intravitreal injections, despite increased degenerating ON axons, even in siCASP2 “post-blast” injection groups. Degenerating ON axons remained at sham levels after b-ITON and intravitreal siCASP2 “pre-blast” injections, but with less degenerating axons in siCASP2 compared to siEGFP-treated eyes. Intravitreal injections “post-blast” caused greater vitreous inflammation, potentiated by siCASP2, with less in “pre-blast” injected eyes, which was abrogated by siCASP2. We conclude that intravitreal injection timing after ocular trauma induced variable retinal and ON pathology, undermining our candidate neuroprotective therapy, siCASP2.

Mild blast wave exposure produces intensity-dependent changes in MMP2 expression patches in rat brains – Findings from different blast severities

Matrix metalloproteinase 2 (MMP2) is a gelatinase with multiple functions at the neurovascular interface, including local modification of the glia limitans to facilitate access of immune cells into the brain and amyloid-beta degradation during responses to injury or disease. This study examines regional changes in immunoreactive MMP2 in the rat brain after a single mild (2.7–7.9 psi peak) or moderate (13–17.5 psi peak) blast overpressure (BOP) exposure. Immunopositive MMP2 expression was examined quantitatively in histological sections of decalcified rat heads as a marker at 2, 24, and 72 h after BOP. The MMP2 immunoreactivity was isolated to patchy deposits in brain parenchyma surrounding blood vessels. Separate analyses were conducted for the cerebellum, brain stem caudal to the thalamo-mesencephalic junction, and the cerebrum (including diencephalon). The deposits varied in number, size, staining homogeneity (standard deviation of immunopositive region), and a cumulative measure, the product of size, average intensity and number, as a function of blast intensity and time. The sequences of changes in MMP2 spots from sham control animals suggested that the mild BOP exposure differences normalized within 72 h. However, the responses to moderate exposure revealed a delayed response at 72 h in the subtentorial brain stem and the cerebrum, but not the cerebellum. Hence, local MMP2 responses may be a contextual biomarker for locally regulated responses to widely distributed brain injury foci.

Behavioral and Histopathological Impairments Caused by Topical Exposure of the Rat Brain to Mild-Impulse Laser-Induced Shock Waves: Impulse Dependency.

Although an enormous number of animal studies on blast-induced traumatic brain injury (bTBI) have been conducted, there still remain many uncertain issues in its neuropathology and mechanisms. This is partially due to the complex and hence difficult experimental environment settings, e.g., to minimize the effects of blast winds (tertiary mechanism) and to separate the effects of brain exposure and torso exposure. Since a laser-induced shock wave (LISW) is free from dynamic pressure and its energy is spatially well confined, the effects of pure shock wave exposure (primary mechanism) solely on the brain can be examined by using an LISW. In this study, we applied a set of four LISWs in the impulse range of 15–71 Pa·s to the rat brain through the intact scalp and skull; the interval between each exposure was ~5 s. For the rats, we conducted locomotor activity, elevated plus maze and forced swimming tests. Axonal injury in the brain was also examined by histological analysis using Bodian silver staining. Only the rats with exposure at higher impulses of 54 and 71 Pa·s showed significantly lower spontaneous movements at 1 and 2 days post-exposure by the locomotor activity test, but after 3 days post-exposure, they had recovered. At 7 days post-exposure, however, these rats (54 and 71 Pa·s) showed significantly higher levels of anxiety-related and depression-like behaviors by the elevated plus maze test and forced swimming test, respectively. To the best of the authors' knowledge, there have been few studies in which a rat model showed both anxiety-related and depression-like behaviors caused by blast or shock wave exposure. At that time point (7 days post-exposure), histological analysis showed significant decreases in axonal density in the cingulum bundle and corpus callosum in impulse-dependent manners; axons in the cingulum bundle were found to be more affected by a shock wave. Correlation analysis showed a statistically significant correlation between the depression like-behavior and axonal density reduction in the cingulum bundle. The results demonstrated the dependence of behavior deficits and axonal injury on the shock wave impulse loaded on the brain.

Animal Orientation Affects Brain Biomechanical Responses to Blast-Wave Exposure.

In this study, we investigated how animal orientation within a shock tube influences the biomechanical responses of the brain and cerebral vasculature of a rat when exposed to a blast wave. Using three-dimensional finite element (FE) models, we computed the biomechanical responses when the rat was exposed to the same blast-wave overpressure (100 kPa) in a prone (P), vertical (V), or head-only (HO) orientation. We validated our model by comparing the model-predicted and the experimentally measured brain pressures at the lateral ventricle. For all three orientations, the maximum difference between the predicted and measured pressures was 11%. Animal orientation markedly influenced the predicted peak pressure at the anterior position along the midsagittal plane of the brain (P = 187 kPa; V = 119 kPa; and HO = 142 kPa). However, the relative differences in the predicted peak pressure between the orientations decreased at the medial (21%) and posterior (7%) positions. In contrast to the pressure, the peak strain in the prone orientation relative to the other orientations at the anterior, medial, and posterior positions was 40-88% lower. Similarly, at these positions, the cerebral vasculature strain in the prone orientation was lower than the strain in the other orientations. These results show that animal orientation in a shock tube influences the biomechanical responses of the brain and the cerebral vasculature of the rat, strongly suggesting that a direct comparison of changes in brain tissue observed from animals exposed at different orientations can lead to incorrect conclusions.

The effect of low-pressure blast-wave exposure on middle aged rats

The objective of this study was to explore how age at the time of blast-exposure affects behavioral and cognitive responses.

Replicating landmine blast loading in cellular in vitro models

Trauma arising from landmines and improvised explosive devices promotes heterotopic ossification, the formation of extra-skeletal bone in non-osseous tissue. To date, experimental platforms that can replicate the loading parameter space relevant to improvised explosive device and landmine blast wave exposure have not been available to study the effects of such non-physiological mechanical loading on cells. Here, we present the design and calibration of three distinct in vitro experimental loading platforms that allow us to replicate the spectrum of loading conditions recorded in near-field blast wave exposure. We subjected cells in suspension or in a three-dimensional hydrogel to strain rates up to 6000 s−1 and pressure levels up to 45 MPa. Our results highlight that cellular activation is regulated in a non-linear fashion—not by a single mechanical parameter, it is the combined action of the applied mechanical pressure, rate of loading and loading impulse, along with the extracellular environment used to convey the pressure waves. Finally, our research indicates that PO MSCs are finely tuned to respond to mechanical stimuli that fall within defined ranges of loading.

An assessment of blast modelling techniques for injury biomechanics research.

Blast-induced traumatic brain injury (TBI) has been affecting combatants and civilians. The blast pressure wave is thought to have a significant contribution to blast-related TBI. Due to the limitations and difficulties of conducting blast tests on surrogates, computational modelling has been used as a key method for exploring this field. However, the blast wave modelling methods reported in current literature have drawbacks. They either cannot generate the desirable blast pressure wave history or they are unable to accurately simulate the blast wave/structure interaction. In addition, boundary conditions, which can have significant effects on model predictions, have not been described adequately. Here, we critically assess the commonly used methods for simulating blast wave propagation in air (open-field blast) and its interaction with the human body. We investigate the predicted blast wave time history, blast wave transmission, and the effects of various boundary conditions in three-dimensional (3D) models of blast prediction. We propose a suitable meshing topology, which enables accurate prediction of blast wave propagation and interaction with the human head and significantly decreases the computational cost in 3D simulations. Finally, we predict strain and strain rate in the human brain during blast wave exposure and show the influence of the blast wave modelling methods on the brain response. The findings presented here can serve as guidelines for accurately modelling blast wave generation and interaction with the human body for injury biomechanics studies and design of prevention systems.

Occupational Blast Wave Exposure During Multiday 0.50 Caliber Rifle Course.

Research on blast overpressure (BOP) experienced by military personnel in operations like breaching, identifies transient, measurable effects on operator readiness. Specifically, blast seems to be associated with suppressed response speed and cognitive function. This work evaluates 50 caliber weapon systems to ascertain BOP effects from the weapon usage. Marksmen were a collection of professionals who use 0.50 caliber weapon systems as part of their daily activities, and the environment measured was during a training course. The 20 human subjects were equipped with B3 blast gauges and occupational BOP exposure monitored over the course of 3 day training period with measurements taken from 500+ shots. We noted a considerable variation in total cumulative peak pressure (50–350 psi) and impulse (25–180 psi·ms) values. The frequency analysis (number of shots fired by the trainee) revealed that the number of exposures per day varied between 4 and 27 per day (peak at 7: 14.3% of the data), and 2 to 17 per hour (peak at 8: 18% of the data). The cumulative number of exposures was 24–50 per trainee. The neurocognitive performance was evaluated using Defense Automated Neurobehavioral Assessment (DANA) Rapid: Simple Reaction Time (SRT), Procedural Reaction Time (PRT) and Go/No-Go (GNG). The results recorded before the training were a baseline for each training day and compared with the results recorded after and at the end of the day. Only PRT and GNG tests revealed a cumulative increase in proportion of subjects with slowed reaction times over the progression of course with concomitant dispersion increase at the end of the day. Noticeably, on average 2/3rd of the trainees performed faster, while 1/3rd of trainees performed these tasks slower, but there was no correlation with the cumulative pressure dosage. The fatigue appears as an aggravating factor affecting the neurocognitive performance, and a more sophisticated evaluation regimen is necessary to discern potential neurological effects. Additional investigation is needed to understand the increasing dispersion of results between subjects and future works should be mindful of such continued trends. Future work should seek to determine the recovery period and longitudinal effects of heavy usage of these weapon systems.

A zebrafish model for hearing loss and regeneration induced by blast wave

Abstract Zebrafish have the potential to regrow injured organs and tissues, but their use as a model for hearing regeneration following blast injury has never been reported. In this study, zebrafish were exposed to a blast wave produced by an underwater blast wave generator. The first peak sound pressures produced by this generator were up to 224 dB and 160kPa, measured at 25 cm away from the machine. Zebrafish hearing sensitivity was examined by analyzing auditory evoked potentials from 1 to 35 days post blast wave exposure. Cell death and cell proliferation in inner ear organs, including the saccule, lagena, and utricle, were investigated using a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and cell proliferation assay using 5-ethynyl-2′-deoxyuridine, respectively. Significant differences in auditory evoked potential thresholds were observed between exposed and control groups, demonstrating both blast wave-induced hearing loss and recovery of hearing sensitivity. An apoptosis assay revealed significantly increased numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells in the inner ear sensory epithelia of exposed groups compared with the control group. However, numbers of 5-ethynyl-2′-deoxyuridine-positive cells in the inner ear of exposed groups recovered to a normal level within 10 post blast wave exposure. Furthermore, blast wave exposure caused brain injury with increased cell apoptosis and decreased neurogenesis. Compared with drug or noise-induced zebrafish models, our blast wave-induced model elicited more serious hearing loss phenotypes, which required more time to return to a normal level. Overall, this zebrafish model can provide a reliable animal model for both hearing loss and regeneration research. The study was approved by the Shanghai 6th Hospital Animal Care and Use Committee, China (approval No. 2017-0196) on February 28, 2017.

A 3-D Rat Brain Model for Blast-Wave Exposure: Effects of Brain Vasculature and Material Properties

Exposure to blast waves is suspected to cause primary traumatic brain injury. However, existing finite-element (FE) models of the rat head lack the necessary fidelity to characterize the biomechanical responses in the brain due to blast exposure. They neglect to represent the cerebral vasculature, which increases brain stiffness, and lack the appropriate brain material properties characteristic of high strain rates observed in blast exposures. To address these limitations, we developed a high-fidelity three-dimensional FE model of a rat head. We explicitly represented the rat’s cerebral vasculature and used high-strain-rate material properties of the rat brain. For a range of blast overpressures (100 to 230 kPa) the brain-pressure predictions matched experimental results and largely overlapped with and tracked the incident pressure–time profile. Incorporating the vasculature decreased the average peak strain in the cerebrum, cerebellum, and brainstem by 17, 33, and 18%, respectively. When compared with our model based on rat-brain properties, the use of human-brain properties in the FE model led to a three-fold reduction in the strain predictions. For simulations of blast exposure in rats, our findings suggest that representing cerebral vasculature and species-specific brain properties has a considerable influence in the resulting brain strain but not the pressure predictions.

The mechanical behavior of brain surrogates manufactured from silicone elastomers

The ongoing conflict against terrorism has resulted in an escalation of blast-induced traumatic brain injuries (bTBI) caused by improvised explosive devices (IEDs). The destructive IEDs create a blast wave that travels through the atmosphere. Blast-induced traumatic brain injuries, attributed to the blast wave, can cause life-threatening injuries and fatalities. This study aims to find a surrogate brain material for assessing the effectiveness of head protection systems designed to mitigate bTBI. Polydimethylsiloxane (PDMS) is considered as the surrogate brain material. The stiffness of PDMS (Sylgard 184, Dow Corning Corp.) can be controlled by varying the ratio of base and curing agent. Cylindrical PDMS specimen with ratios of 1:10, 1:70, and 1:80 were subjected to unconfined compression experiments at linear rates of 5 mm/min, 50 mm/min, and 500 mm/min. A ramp-hold strain profile was used to simulate a stress relaxation experiment. The fractional Zener viscoelastic model was used to describe the stress relaxation response, after optimization of the material constants for the brain surrogate and shock wave exposure brain tissue. The results show that the low cost PDMS can be used as a surrogate brain material to study the dynamic brain response to blast wave exposure.

Caffeine attenuates brain injury but increases mortality induced by high-intensity blast wave exposure

Caffeine is a substance that is consumed worldwide, and it may exert neuroprotective effects against various cerebral insults, including neurotrauma, which is the most prevalent injury among military personnel. To investigate the effects of caffeine on high-intensity blast wave-induced severe blast injury in mice, three different paradigms of caffeine were applied to male C57BL/6 mice with severe whole body blast injury (WBBI). The results demonstrated that chronic caffeine treatment alleviated blast-induced traumatic brain injury (bTBI); however, both chronic and acute caffeine treatments exacerbated blast-induced lung injuries and, more importantly, increased both the cumulative and time-segmented mortalities postinjury. Interestingly, withdrawing caffeine intake preinjury resulted in favorable outcomes in mortality and lung injury, similar to the findings in water-treated mice, and had the trend to attenuate brain injury. These findings demonstrated that although drinking coffee or caffeine preparations attenuated blast-induced brain trauma, these beverages may place personnel in the battlefield at high risk of casualties, which will help us re-evaluate the therapeutic strategy of caffeine application, particularly in multiple-organ-trauma settings. Furthermore, these findings provided possible strategies for reducing the risk of casualties with caffeine consumption, which may help to change the coffee-drinking habits of military personnel.

Role of Endogenous and Exogenous Corticosterone on Behavioral and Cognitive Responses to Low-Pressure Blast Wave Exposure.

The complex interactions and overlapping symptoms of comorbid post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) induced by an explosive blast wave have become a focus of attention in recent years, making clinical distinction and effective intervention difficult. Because dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to underlie trauma-related (psycho)pathology, we evaluated both the endogenous corticosterone response and the efficacy of exogenous hydrocortisone treatment provided shortly after blast exposure. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast wave produced by exploding a thin copper wire. Endogenous corticosterone concentrations were evaluated at different time points (before, and 3 h, 5 h and 17 days) after blast exposure. Subsequently, the efficacy of exogenous hydrocortisone (25 mg/kg-1 or 125 mg/kg-1) injected intraperitoneally 1 h after exposure was compared with that of a similarly timed saline injection. Validated cognitive and behavioral tests were used to assess both PTSD and mTBI phenotypes on days 7-14 following the blast. Retrospective analysis revealed that animals demonstrating the PTSD phenotype exhibited a significantly blunted endogenous corticosterone response to the blast compared with all other groups. Moreover, a single 125 mg/kg-1 dose of hydrocortisone administered 1 h after exposure significantly reduced the occurrence of the PTSD phenotype. Hydrocortisone treatment did not have a similar effect on the mTBI phenotype. Results of this study indicate that an inadequate corticosteroid response following blast exposure increases risk for PTSD phenotype, and corticosteroid treatment is a potential clinical intervention for attenuating PTSD. The differences in patterns of physiological and therapeutic response between PTSD and mTBI phenotypes lend credence to the retrospective behavioral and cognitive classification criteria we designed, and is in keeping with the assumption that mTBI and PTSD phenotypes may reflect distinct underlying biological and clinical profiles.