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.

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.

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.

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.

Synergistic Role of Oxidative Stress and Blood-Brain Barrier Permeability as Injury Mechanisms in the Acute Pathophysiology of Blast-induced Neurotrauma.

Blast-induced traumatic brain injury (bTBI) has been recognized as the common mode of neurotrauma amongst military and civilian personnel due to an increased insurgent activity domestically and abroad. Previous studies from our laboratory have identified enhanced blood-brain barrier (BBB) permeability as a significant, sub-acute (four hours post-blast) pathological change in bTBI. We also found that NADPH oxidase (NOX)-mediated oxidative stress occurs at the same time post-blast when the BBB permeability changes. We therefore hypothesized that oxidative stress is a major causative factor in the BBB breakdown in the sub-acute stages. This work therefore examined the role of NOX1 and its downstream effects on BBB permeability in the frontal cortex (a region previously shown to be the most vulnerable) immediately and four hours post-blast exposure. Rats were injured by primary blast waves in a compressed gas-driven shock tube at 180 kPa and the BBB integrity was assessed by extravasation of Evans blue and changes in tight junction proteins (TJPs) as well as translocation of macromolecules from blood to brain and vice versa. NOX1 abundance was also assessed in neurovascular endothelial cells. Blast injury resulted in increased extravasation and reduced levels of TJPs in tissues consistent with our previous observations. NOX1 levels were significantly increased in endothelial cells followed by increased superoxide production within 4 hours of blast. Blast injury also increased the levels/activation of matrix metalloproteinase 3 and 9. To test the role of oxidative stress, rats were administered apocynin, which is known to inhibit the assembly of NOX subunits and arrests its function. We found apocynin completely inhibited dye extravasation as well as restored TJP levels to that of controls and reduced matrix metalloproteinase activation in the sub-acute stages following blast. Together these data strongly suggest that NOX-mediated oxidative stress contributes to enhanced BBB permeability in bTBI through a pathway involving increased matrix metalloproteinase activation.

Effect of Tissue Material Properties in Blast Loading: Coupled Experimentation and Finite Element Simulation.

Computational models of blast-induced traumatic brain injury (bTBI) require a robust definition of the material models of the brain. The mechanical constitutive models of these tissues are difficult to characterize, leading to a wide range of values reported in literature. Therefore, the sensitivity of the intracranial pressure (ICP) and maximum principal strain to variations in the material model of the brain was investigated through a combined computational and experimental approach. A finite element model of a rat was created to simulate a shock wave exposure, guided by the experimental measurements of rats subjected to shock loading conditions corresponding to that of mild traumatic brain injury in a field-validated shock tube. In the numerical model, the properties of the brain were parametrically varied. A comparison of the ICP measured at two locations revealed that experimental and simulated ICP were higher in the cerebellum (p < 0.0001), highlighting the significance of pressure sensor locations within the cranium. The ICP and strain were correlated with the long-term bulk (p < 0.0001) and shear moduli (p < 0.0001), with an 80 MPa effective bulk modulus value matching best with experimental measurements. In bTBI, the solution is sensitive to the brain material model, necessitating robust validation methods.

Effective testing of personal protective equipment in blast loading conditions in shock tube: Comparison of three different testing locations.

We exposed a headform instrumented with 10 pressure sensors mounted flush with the surface to a shock wave with three nominal intensities: 70, 140 and 210 kPa. The headform was mounted on a Hybrid III neck, in a rigid configuration to eliminate motion and associated pressure variations. We evaluated the effect of the test location by placing the headform inside, at the end and outside of the shock tube. The shock wave intensity gradually decreases the further it travels in the shock tube and the end effect degrades shock wave characteristics, which makes comparison of the results obtained at three locations a difficult task. To resolve these issues, we developed a simple strategy of data reduction: the respective pressure parameters recorded by headform sensors were divided by their equivalents associated with the incident shock wave. As a result, we obtained a comprehensive set of non-dimensional parameters. These non-dimensional parameters (or amplification factors) allow for direct comparison of pressure waveform characteristic parameters generated by a range of incident shock waves differing in intensity and for the headform located in different locations. Using this approach, we found a correlation function which allows prediction of the peak pressure on the headform that depends only on the peak pressure of the incident shock wave (for specific sensor location on the headform), and itis independent on the headform location. We also found a similar relationship for the rise time. However, for the duration and impulse, comparable correlation functions do not exist. These findings using a headform with simplified geometry are baseline values and address a need for the development of standardized parameters for the evaluation of personal protective equipment (PPE) under shock wave loading.

A Single Primary Blast-Induced Traumatic Brain Injury in a Rodent Model Causes Cell-Type Dependent Increase in Nicotinamide Adenine Dinucleotide Phosphate Oxidase Isoforms in Vulnerable Brain Regions.

Blast-induced traumatic brain injury (bTBI) is a leading cause of morbidity in soldiers on the battlefield and in training sites with long-term neurological and psychological pathologies. Previous studies from our laboratory demonstrated activation of oxidative stress pathways after blast injury, but their distribution among different brain regions and their impact on the pathogenesis of bTBI have not been explored. The present study examined the protein expression of two isoforms: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 and 2 (NOX1, NOX2), corresponding superoxide production, a downstream event of NOX activation, and the extent of lipid peroxidation adducts of 4-hydroxynonenal (4HNE) to a range of proteins. Brain injury was evaluated 4 h after the shock-wave exposure, and immunofluorescence signal quantification was performed in different brain regions. Expression of NOX isoforms displayed a differential increase in various brain regions: in hippocampus and thalamus, there was the highest increase of NOX1, whereas in the frontal cortex, there was the highest increase of NOX2 expression. Cell-specific analysis of changes in NOX expression with respect to corresponding controls revealed that blast resulted in a higher increase of NOX1 and NOX 2 levels in neurons compared with astrocytes and microglia. Blast exposure also resulted in increased superoxide levels in different brain regions, and such changes were reflected in 4HNE protein adduct formation. Collectively, this study demonstrates that primary blast TBI induces upregulation of NADPH oxidase isoforms in different regions of the brain parenchyma and that neurons appear to be at higher risk for oxidative damage compared with other neural cells.

On the Accurate Determination of Shock Wave Time-Pressure Profile in the Experimental Models of Blast-Induced Neurotrauma.

Measurement issues leading to the acquisition of artifact-free shock wave pressure-time profiles are discussed. We address the importance of in-house sensor calibration and data acquisition sampling rate. Sensor calibration takes into account possible differences between calibration methodology in a manufacturing facility, and those used in the specific laboratory. We found in-house calibration factors of brand new sensors differ by less than 10% from their manufacturer supplied data. Larger differences were noticeable for sensors that have been used for hundreds of experiments and were as high as 30% for sensors close to the end of their useful lifetime. These observations were despite the fact that typical overpressures in our experiments do not exceed 50 psi for sensors that are rated at 1,000 psi maximum pressure. We demonstrate that sampling rate of 1,000 kHz is necessary to capture the correct rise time values, but there were no statistically significant differences between peak overpressure and impulse values for low-intensity shock waves (Mach number <2) at lower rates. We discuss two sources of experimental errors originating from mechanical vibration and electromagnetic interference on the quality of a waveform recorded using state-of-the-art high-frequency pressure sensors. The implementation of preventive measures, pressure acquisition artifacts, and data interpretation with examples, are provided in this paper that will help the community at large to avoid these mistakes. In order to facilitate inter-laboratory data comparison, common reporting standards should be developed by the blast TBI research community. We noticed the majority of published literature on the subject limits reporting to peak overpressure; with much less attention directed toward other important parameters, i.e., duration, impulse, and dynamic pressure. These parameters should be included as a mandatory requirement in publications so the results can be properly compared with others.