MCC950 Attenuates Microglial NLRP3-Mediated Chronic Neuroinflammation and Memory Impairment in a Rat Model of Repeated Low-Level Blast Exposure.

Blast-induced traumatic brain injury is typically regarded as a signature medical concern for military personnel who are exposed to explosive devices in active combat zones. However, soldiers as well as law enforcement personnel may be repeatedly exposed to low-level blasts during training sessions with heavy weaponries as part of combat readiness. Service personnel who sustain neurotrauma from repeated low-level blast (rLLB) exposure do not display overt pathological symptoms immediately but rather develop mild symptoms including cognitive impairments, attention deficits, mood changes, irritability, and sleep disturbances over time. Recently, we developed a rat model of rLLB by applying controlled low-level blast pressures (≤ 70 kPa) repeated five times successively to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also investigated the role of the NLRP3 inflammasome, a complex involved in chronic microglial activation and pro-inflammatory cytokine interleukin (IL)-1ß release, in rLLB-induced neuroinflammation. NLRP3 and caspase-1 protein expression, microglial activation, and IL-1ß release were examined as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic short-term memory impairments and chronic anxiety-like symptoms accompanied by increased microglial activation, NLRP3 expression, and IL-1ß release. Treatment with MCC950, an NLRP3 inflammasome complex inhibitor, suppressed microglial activation, reduced NLRP3 expression and IL-1ß release, and improved short-term memory deficits after rLLB exposure. Collectively, this study demonstrates that rLLB induces chronic neurobehavioral and neuropathological changes by increasing NLRP3 inflammasome protein expression followed by cytokine IL-1ß release.

Temporal Changes in Functional and Structural Neuronal Activities in Auditory System in Non-Severe Blast-Induced Tinnitus.

Background and Objectives: Epidemiological data indicate that blast exposure is the most common morbidity responsible for mild TBI among Service Members (SMs) during recent military operations. Blast-induced tinnitus is a comorbidity frequently reported by veterans, and despite its wide prevalence, it is also one of the least understood. Tinnitus arising from blast exposure is usually associated with direct structural damage that results in a conductive and sensorineural impairment in the auditory system. Tinnitus is also believed to be initiated by abnormal neuronal activities and temporal changes in neuroplasticity. Clinically, it is observed that tinnitus is frequently accompanied by sleep disruption as well as increased anxiety. In this study, we elucidated some of the mechanistic aspects of sensorineural injury caused by exposure to both shock waves and impulsive noise. The isolated conductive auditory damage hypothesis was minimized by employing an animal model wherein both ears were protected. Materials and Methods: After the exposure, the animals' hearing circuitry status was evaluated via acoustic startle response (ASR) to distinguish between hearing loss and tinnitus. We also compared the blast-induced tinnitus against the well-established sodium salicylate-induced tinnitus model as the positive control. The state of the sensorineural auditory system was evaluated by auditory brainstem response (ABR), and this test helped examine the neuronal circuits between the cochlea and inferior colliculus. We then further evaluated the role of the excitatory and inhibitory neurotransmitter receptors and neuronal synapses in the auditory cortex (AC) injury after blast exposure. Results: We observed sustained elevated ABR thresholds in animals exposed to blast shock waves, while only transient ABR threshold shifts were observed in the impulsive noise group solely at the acute time point. These changes were in concert with the increased expression of ribbon synapses, which is suggestive of neuroinflammation and cellular energy metabolic disorder. It was also found that the onset of tinnitus was accompanied by anxiety, depression-like symptoms, and altered sleep patterns. By comparing the effects of shock wave exposure and impulsive noise exposure, we unveiled that the shock wave exerted more significant effects on tinnitus induction and sensorineural impairments when compared to impulsive noise. Conclusions: In this study, we systematically studied the auditory system structural and functional changes after blast injury, providing more significant insights into the pathophysiology of blast-induced tinnitus.

Enhanced Targeted Delivery of Minocycline via Transferrin Conjugated Albumin Nanoparticle Improves Neuroprotection in a Blast Traumatic Brain Injury Model.

Traumatic brain injury (TBI) is a major source of death and disability worldwide as a result of motor vehicle accidents, falls, attacks and bomb explosions. Currently, there are no FDA-approved drugs to treat TBI patients predominantly because of a lack of appropriate methods to deliver drugs to the brain for therapeutic effect. Existing clinical and pre-clinical studies have shown that minocycline's neuroprotective effects either through high plasma protein binding or an increased dosage requirement have resulted in neurotoxicity. In this study, we focus on the formulation, characterization, in vivo biodistribution, behavioral improvements, neuroprotective effect and toxicity of transferrin receptor-targeted (tf) conjugated minocycline loaded albumin nanoparticles in a blast-induced TBI model. A novel tf conjugated minocycline encapsulated albumin nanoparticle was developed, characterized and quantified using a validated HPLC method as well as other various analytical methods. The results of the nanoformulation showed small, narrow hydrodynamic size distributions, with high entrapment, loading efficiencies and sustained release profiles. Furthermore, the nanoparticle administered at minimal doses in a rat model of blast TBI was able to cross the blood-brain barrier, enhanced nanoparticle accumulation in the brain, improved behavioral outcomes, neuroprotection, and reduced toxicity compared to free minocycline. Hence, tf conjugated minocycline loaded nanoparticle elicits a neuroprotective effect and can thus offer a potential therapeutic effect.

Effect of minocycline and its nano-formulation on central auditory system in blast-induced hearing loss rat model.

Blast injuries are common among the military service members and veterans. One of the devastating effects of blast wave induced TBI is either temporary or permanent hearing loss. Treating hearing loss using minocycline is restricted by optimal drug concentration, route of administration, and its half-life. Therefore, therapeutic approach using novel therapeutic delivery method is in great need. Among the different delivery methods, nanotechnology-based drug delivery is desirable, which can achieve longer systemic circulation, pass through some biological barriers and specifically targets desired sites. The current study aimed to examine therapeutic effect of minocycline and its nanoparticle formulation in moderate blast induced hearing loss rat model through central auditory system. The I.v. administered nanoparticle at reduced dose and frequency than regularly administered toxic dose. After moderate blast exposure, rats had hearing impairment as determined by ABR at 7- and 30-days post exposure. In chronic condition, free minocycline also showed the significant reduction in ABR threshold. In central auditory system, it is found in this study that minocycline nanoparticles ameliorate excitation in inferior colliculus; and astrocytes and microglia activation after the blast exposure is reduced by minocycline nanoparticles administration. The study demonstrated that in moderate blast induced hearing loss, minocycline and its nanoparticle formulation exhibited the optimal therapeutic effect on the recovery of the ABR impairment and a protective effect through central auditory system. In conclusion, targeted and non-targeted nanoparticle formulation have therapeutic effect on blast induced hearing loss.

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations. OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury. METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis. RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues. CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Animal model of repeated low-level blast traumatic brain injury displays acute and chronic neurobehavioral and neuropathological changes.

Blast-induced neurotrauma (BINT) is not only a signature injury to soldiers in combat field and training facilities but may also a growing concern in civilian population due to recent increases in the use of improvised explosives by insurgent groups. Unlike moderate or severe BINT, repeated low-level blast (rLLB) is different in its etiology as well as pathology. Due to the constant use of heavy weaponry as part of combat readiness, rLLB usually occurs in service members undergoing training as part of combat readiness. rLLB does not display overt pathological symptoms; however, earlier studies report chronic neurocognitive changes such as altered mood, irritability, and aggressive behavior, all of which may be caused by subtle neuropathological manifestations. Current animal models of rLLB for investigation of neurobehavioral and neuropathological alterations have not been adequate and do not sufficiently represent rLLB conditions. Here, we developed a rat model of rLLB by applying controlled low-level blast pressures (<10 psi) repeated successively five times to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also examined levels of superoxide-producing enzyme NADPH oxidase, microglial activation, and reactive astrocytosis as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic anxiety-like symptoms, motor and short-term memory impairments. These changes were paralleled by increased microglial activation and reactive astrocytosis. Conversely, animals exposed to a single low-level blast did not display significant changes. Collectively, this study demonstrates that, unlike a single low-level blast, rLLB exerts a cumulative impact on different brain regions and produces chronic neuropathological changes in so doing, may be responsible for neurobehavioral alterations.

Investigation of the direct and indirect mechanisms of primary blast insult to the brain.

The interaction of explosion-induced blast waves with the head (i.e., a direct mechanism) or with the torso (i.e., an indirect mechanism) presumably causes traumatic brain injury. However, the understanding of the potential role of each mechanism in causing this injury is still limited. To address this knowledge gap, we characterized the changes in the brain tissue of rats resulting from the direct and indirect mechanisms at 24 h following blast exposure. To this end, we conducted separate blast-wave exposures on rats in a shock tube at an incident overpressure of 130 kPa, while using whole-body, head-only, and torso-only configurations to delineate each mechanism. Then, we performed histopathological (silver staining) and immunohistochemical (GFAP, Iba-1, and NeuN staining) analyses to evaluate brain-tissue changes resulting from each mechanism. Compared to controls, our results showed no significant changes in torso-only-exposed rats. In contrast, we observed significant changes in whole-body-exposed (GFAP and silver staining) and head-only-exposed rats (silver staining). In addition, our analyses showed that a head-only exposure causes changes similar to those observed for a whole-body exposure, provided the exposure conditions are similar. In conclusion, our results suggest that the direct mechanism is the major contributor to blast-induced changes in brain tissues.

Central and peripheral auditory abnormalities in chinchilla animal model of blast-injury.

Exposure to blast overpressure or high-intensity sound can cause injuries to the auditory system, which leads to hearing loss or tinnitus. In this study, we examined the involvement of peripheral auditory system (PAS), and central auditory system (CAS) changes after exposure to blast overpressure (15-25 psi) on Day 1 and additionally during 7 days of post blast time period in chinchillas. Auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and cochlear hair cell changes were measured or identified in post-blast period within 7 days to detect injuries in the PAS. In the CAS, changes in NMDAR1 (excitatory receptor) and GABAA (inhibitory receptor) as well as changes in serotonin (5-HT2A) and acetylcholine (AChR) receptors were examined in different brain regions: auditory cortex (AC), geniculate body (GB), inferior colliculus (IC) and amygdala by immunofluorescence staining. We observed the PAS abnormalities of increased ABR threshold and decreased DPOAE response in animals after blast exposure with hearing protection devices (e.g., earplug). Blast exposure also caused a reduction in both NMDAR1 and GABAA receptor levels in acute condition (post-blast or Day 1) in AC and IC, while serotonin and acetylcholine receptor levels displayed a biphasic response at Day 1 and Day 7 post-exposure. Results demonstrate that the earplug can protect the tympanic membrane and middle ear against structural damage, but the hearing level, cochlear outer hair cell, and the central auditory system (levels of excitatory and inhibitory neurotransmitter receptors) were only partially protected at the tested blast overpressure level. The findings in this study indicate that blast exposure can cause both peripheral and central auditory dysfunctions, and the central auditory response is independent of peripheral auditory damage. The CAS dysfunction is likely mediated by direct transmission of shockwaves in all the regions of central nervous system (CNS), including nerves and surrounding tissues along the auditory pathways. Hence, targeting central auditory neurotransmitter abnormalities may have a therapeutic benefit to attenuate blast-induced hearing loss and tinnitus.

Nanotechnology-based approaches for emerging and re-emerging viruses: Special emphasis on COVID-19.

In recent decades, the major concern of emerging and re-emerging viral diseases has become an increasingly important area of public health concern, and it is of significance to anticipate future pandemic that would inevitably threaten human lives. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged virus that causes mild to severe pneumonia. Coronavirus disease (COVID-19) became a very much concerned issue worldwide after its super-spread across the globe and emerging viral diseases have not got specific and reliable diagnostic and treatments. As the COVID-19 pandemic brings about a massive life-loss across the globe, there is an unmet need to discover a promising and typically effective diagnosis and treatment to prevent super-spreading and mortality from being decreased or even eliminated. This study was carried out to overview nanotechnology-based diagnostic and treatment approaches for emerging and re-emerging viruses with the current treatment of the disease and shed light on nanotechnology's remarkable potential to provide more effective treatment and prevention to a special focus on recently emerged coronavirus.

Variations in Constitutive Properties of the Fluid Elicit Divergent Vibrational and Pressure Response Under Shock Wave Loading.

We performed a characterization of the shock wave loading on the response of the specimen representing a simplified head model. A polycarbonate cylinder (2-in. outer diameter, wall thickness: 0.06 or 0.12 in.) was filled with two fluids: pure de-ionized water and 40% glycerol in water, which differ only slightly in their constitutive material properties. These two fluids were selected to represent the cerebrospinal fluid and cerebral blood, using their high strain rate viscosity as a primary selection criterion. The model specimen was exposed to a single shock wave with two nominal intensities: 70 and 130 kPa overpressure. The response of the model was measured using three strain gauges and three pressure sensors, one mounted on the front face of the cylinder and two embedded in the cylinder to measure the pressure inside of the fluid. We noted several discriminant characteristics in the collected data, which indicate that the type of fluid is strongly influencing the response. The vibrations of the cylinder walls are strongly correlated with the fluid kind. The similarity analysis via the Pearson coefficient indicated that the pressure waveforms in the fluid are only moderately correlated, and these results were further corroborated by Euclidean distance analysis. Continuous wavelet transform of pressure waveforms revealed that the frequency response is strongly correlated with the properties of the fluid. The observed differences in strain and pressure modalities stem from relatively small differences in the properties of the fluids used in this study.

Behavioral Deficits in Animal Models of Blast Traumatic Brain Injury.

Blast exposure has been identified to be the most common cause for traumatic brain injury (TBI) in soldiers. Over the years, rodent models to mimic blast exposures and the behavioral outcomes observed in veterans have been developed extensively. However, blast tube design and varying experimental parameters lead to inconsistencies in the behavioral outcomes reported across research laboratories. This review aims to curate the behavioral outcomes reported in rodent models of blast TBI using shockwave tubes or open field detonations between the years 2008-2019 and highlight the important experimental parameters that affect behavioral outcome. Further, we discuss the role of various design parameters of the blast tube that can affect the nature of blast exposure experienced by the rodents. Finally, we assess the most common behavioral tests done to measure cognitive, motor, anxiety, auditory, and fear conditioning deficits in blast TBI (bTBI) and discuss the advantages and disadvantages of these tests.

Sensor orientation and other factors which increase the blast overpressure reporting errors.

This study compared the response of the wearable sensors tested against the industry-standard pressure transducers at blast overpressure (BOP) levels typically experienced in training. We systematically evaluated the effects of the sensor orientation with respect to the direction of the incident shock wave and demonstrated how the averaging methods affect the reported pressure values. The evaluated methods included averaging peak overpressure and impulse of all four sensors mounted on a helmet, taking the average of the three sensors, or isolating the incident pressure equivalent using two sensors. The experimental procedures were conducted in controlled laboratory conditions using the shock tube, and some of the findings were verified in field conditions with live fire charges during explosive breaching training. We used four different orientations (0°, 90°, 180°, and 270°) of the headform retrofitted with commonly fielded helmets (ACH, ECH, Ops-Core) with four B3 Blast Gauge sensors. We determined that averaging the peak overpressure values overestimates the actual dosage experienced by operators, which is caused by the reflected pressure contribution. This conclusion is valid despite the identified limitation of the B3 gauges that consistently underreport the peak reflected overpressure, compared to the industry-standard sensors. We also noted consistent overestimation of the impulse. These findings demonstrate that extreme caution should be exercised when interpreting occupational blast exposure results without knowing the orientation of the sensors. Pure numerical values without the geometrical, training-regime specific information such as the position of the sensors, the distance and orientation of the trainee to the source of the blast wave, and weapon system used will inevitably lead to erroneous estimation of the individual and cumulative blast overpressure (BOP) dosages. Considering that the 4 psi (~28 kPa) incident BOP is currently accepted as the threshold exposure safety value, a misinterpretation of exposure level may lead to an inaccurate estimation of BOP at the minimum standoff distance (MSD), or exclusion criteria.

Blast exposure predisposes the brain to increased neurological deficits in a model of blast plus blunt traumatic brain injury.

Soldiers are often exposed to more than one traumatic brain injury (TBI) over the course of their service. In recent years, more attention has been drawn to the increased risk of neurological deficits caused by the 'blast plus' polytrauma, which typically is a blast trauma combined with other forms of TBI. In this study, we investigated the behavioral and neuronal deficits resulting from a blast plus injury involving a mild-moderate blast followed by a mild blunt trauma using the fluid percussion injury model. We identified that the blast injury predisposed the brain to increased cognitive deficits, chronic ventricular enlargement, increased neurodegeneration at acute time points and chronic neuronal loss. Interestingly, a single blast and single blunt injury differed in their onset and manifestation of cognitive and regional neuronal loss. We also identified the presence of cleaved RIP1 from caspase 8 mediated apoptosis in the blunt injury while the blast injury did not activate immediate apoptosis but led to decreased hilar neuronal survival over time.

Chemokine signaling mediated monocyte infiltration affects anxiety-like behavior following blast injury.

The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2RFP/+: CX3CR1GFP/+ mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4 h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1ß were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1ß leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.

Oxidative stress contributes to cerebral metabolomic profile changes in animal model of blast-induced traumatic brain injury.

INTRODUCTION: Blast-induced neurotrauma (BINT) has been recognized as the common mode of traumatic brain injury amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from this laboratory have identified three major pathological events following BINT which include blood brain barrier disruption the earliest event, followed by oxidative stress and neuroinflammation as secondary events occurring a few hours following blast. OBJECTIVES: Our recent studies have also identified an increase in oxidative stress mediated by the activation of superoxide producing enzyme NADPH oxidase (NOX) in different brain regions at varying levels with neurons displaying higher oxidative stress (NOX activation) compared to any other neural cell. Since neurons have higher energy demands in brain and are more prone to oxidative damage, this study evaluated the effect of oxidative stress on blast-blast induced changes in metabolomics profiles in different brain regions. METHODS: Animals were exposed to mild/moderate blast injury (180 kPa) and examined the metabolites of energy metabolism, amino acid metabolism as well as the profiles of plasma membrane metabolites in different brain regions at different time points (24 h, 3 day and 7 day) after blast using 1H NMR spectroscopy. Effect of apocynin, an inhibitor of superoxide producing enzyme NADPH oxidase on cerebral metabalomics profiles was also examined. RESULTS: Several metabolomic profile changes were observed in frontal cortex and hippocampus with concomitant decrease in energy metabolism. In addition, glutamate/glutamine and other amino acid metabolism as well as metabolites involved in plasma membrane integrity were also altered. Hippocampus appears metabolically more vulnerable than the frontal cortex. A post-treatment of animals with apocynin, an inhibitor of NOX activation significantly prevented the changes in metabolite profiles. CONCLUSION: Together these studies indicate that blast injury reduces both cerebral energy and neurotransmitter amino acid metabolism and that oxidative stress contributes to these processes. Thus, strategies aimed at reducing oxidative stress can have a therapeutic benefit in mitigating metabolic changes following BINT.

The evolution of secondary flow phenomena and their effect on primary shock conditions in shock tubes: Experimentation and numerical model.

Compressed gas-driven shock tubes are widely used for laboratory simulation of primary blasts by accurately replicating pressure profiles measured in live-fire explosions. These investigations require sound characterization of the primary blast wave, including the temporal and spatial evolution of the static and dynamic components of the blast wave. The goal of this work is to characterize the propagation of shock waves in and around the exit of a shock tube via analysis of the primary shock flow, including shock wave propagation and decay of the shock front, and secondary flow phenomena. To this end, a nine-inch shock tube and a cylindrical sensing apparatus were used to determine incident and total pressures outside of the shock tube, highlighting the presence of additional flow phenomena. Blast overpressure, impulse, shock wave arrival times, positive phase duration, and shock wave planarity were examined using a finite element model of the system. The shock wave remained planar inside of the shock tube and lost its planarity upon exiting. The peak overpressure and pressure impulse decayed rapidly upon exit from the shock tube, reducing by 92-95%. The primary flow phenomenon, or the planar shock front, is observed within the shock tube, while two distinct flow phenomena are a result of the shock wave exiting the confines of the shock tube. A vortex ring is formed as the shock wave exited the shock tube into the still, ambient air, which induces a large increase in the total pressure impulse. Additionally, a rarefaction wave was formed following shock front expansion, which traveled upstream into the shock tube, reducing the total and incident pressure impulses for approximately half of the simulated region.

Does Blast Exposure to the Torso Cause a Blood Surge to the Brain?

The interaction of explosion-induced blast waves with the torso is suspected to contribute to brain injury. In this indirect mechanism, the wave-torso interaction is assumed to generate a blood surge, which ultimately reaches and damages the brain. However, this hypothesis has not been comprehensively and systematically investigated, and the potential role, if any, of the indirect mechanism in causing brain injury remains unclear. In this interdisciplinary study, we performed experiments and developed mathematical models to address this knowledge gap. First, we conducted blast-wave exposures of Sprague-Dawley rats in a shock tube at incident overpressures of 70 and 130 kPa, where we measured carotid-artery and brain pressures while limiting exposure to the torso. Then, we developed three-dimensional (3-D) fluid-structure interaction (FSI) models of the neck and cerebral vasculature and, using the measured carotid-artery pressures, performed simulations to predict mass flow rates and wall shear stresses in the cerebral vasculature. Finally, we developed a 3-D finite element (FE) model of the brain and used the FSI-computed vasculature pressures to drive the FE model to quantify the blast-exposure effects in the brain tissue. The measurements from the torso-only exposure experiments revealed marginal increases in the peak carotid-artery overpressures (from 13.1 to 28.9 kPa). Yet, relative to the blast-free, normotensive condition, the FSI simulations for the blast exposures predicted increases in the peak mass flow rate of up to 255% at the base of the brain and increases in the wall shear stress of up to 289% on the cerebral vasculature. In contrast, our simulations suggest that the effect of the indirect mechanism on the brain-tissue-strain response is negligible (<1%). In summary, our analyses show that the indirect mechanism causes a sudden and abundant stream of blood to rapidly propagate from the torso through the neck to the cerebral vasculature. This blood surge causes a considerable increase in the wall shear stresses in the brain vasculature network, which may lead to functional and structural effects on the cerebral veins and arteries, ultimately leading to vascular pathology. In contrast, our findings do not support the notion of strain-induced brain-tissue damage due to the indirect mechanism.

A Comprehensive Review of Experimental Rodent Models of Repeated Blast TBI.

We reviewed the relevant literature delineating advances in the development of the experimental models of repeated blast TBI (rbTBI). It appears this subject is a relatively unexplored area considering the first work published in 2007 and the bulk of peer-reviewed papers was published post-2011. There are merely 34 papers published to date utilizing rodent rbTBI models. We performed an analysis and extracted basic parameters to capture the characteristics of the exposure conditions (the blast intensity, inter-exposure interval and the number of exposures), the age and weight of the animal models most commonly used in the studies, and their endpoints. Our analysis revealed three strains of rodents are predominantly used: Sprague Dawley and Long Evans rats and wild type (C57BL/6J) mice, and young adult animals 8 to 12-week-old are a preferred choice. Typical exposure conditions are the following: (1) peak overpressure in the 27-145 kPa (4-21 psi) range, (2) number of exposures: 2 (13.9%), 3 (63.9%), 5 (16.7%), or 12 (5.6%) with a single exposure used for a baseline comparison in 41.24% of the studies. Two inter-exposure interval durations were used: (1) short (1-30 min.) and (2) extended (24 h) between consecutive shock wave exposures. The experiments included characterization of repeated blast exposure effects on auditory, ocular and neurological function, with a focus on brain etiology in most of the published work. We present an overview of major histopathological findings, which are supplemented by studies implementing MRI (DTI) and behavioral changes after rbTBI in the acute (1-7 days post-injury), subacute (7-14 days), and chronic (>14 days) phases post-injury.

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.

Characterization of a controlled shock wave delivered by a pneumatic table-top gas driven shock tube.

Blast simulators facilitate the creation of shock waves and measurement of pressure morphology in a controlled laboratory setting and are currently a vital model for replicating blast-induced neurotrauma. Due to the maintenance and operation cost of conventional blast simulators, we developed a pneumatic, table-top, gas-driven shock tube to test an alternative method of shock wave generation using a membrane-less driver section. Its unique operational mechanism based on air gun technology does not rely on a plastic membrane rupture for the generation of pressure pulses, allowing the simulator to be quickly reset and thus decreasing the experimental turnaround time. The focus of this study is to demonstrate that this proof-of-concept device can generate shock waves with diverse characteristics based on the selection of driver gas, driver pressurization, and driven section material. Pressure waves were generated using compressed nitrogen or helium at 15 psig and 80 psig and were analyzed based on their velocity and profile shape characteristics. At 15 psig, independent of the type of driver gas, driver pressurization, and driven section material, pressure pulses travelled at sonic velocities. At 80 psig, generation of shock waves was observed in all conditions. The choice of the driver gas affected the velocities of the resulting pressure waves and the shape of pressure waveforms, particularly the peak overpressure and rise time values. Our results demonstrate that depending on the selection of driver gas and magnitude of driver pressurization, the shock wave signatures can be controlled and altered using a piston-based driver section.