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Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.

Wearable inertial sensors measure human head impact kinematics important to the on-going development and validation of head injury criteria. However, sensor specifications have not been scientifically justified in the context of the anticipated field impact dynamics. The objective of our study is to determine the minimum bandwidth and sample rate required to capture the impact frequency response relevant to injury. We used high-bandwidth head impact data as ground-truth measurements, and investigated the attenuation of various injury criteria at lower bandwidths. Given a 10% attenuation threshold, we determined the minimum bandwidths required to study injury criteria based on skull kinematics and brain deformation in three different model systems: helmeted cadaver (no neck), unhelmeted cadaver (no neck), and helmeted dummy impacts (with neck). We found that higher bandwidths are required for unhelmeted impacts in general and for studying strain rate injury criteria. Minimum gyroscope bandwidths of 300 Hz in helmeted sports and 500 Hz in unhelmeted sports are necessary to study strain rate based injury criteria. A minimum accelerometer bandwidth of 500 Hz in unhelmeted sports is necessary to study most injury criteria. Current devices typically sample at 1000 Hz, with gyroscope bandwidths below 200 Hz, which are not always sufficient according to these requirements. With hard contact test conditions, the identified requirements may be higher than most soft contacts on the field, but should be satisfied to capture the worst contact, and often higher risk, scenarios relative to the specific sport or activity. Our findings will help establish standard guidelines for sensor choice and design in traumatic brain injury research., QC 20161129

Underwater blasts propagate further and injure more readily than equivalent air blasts. Development of effective personal protection and countermeasures, however, requires knowledge of the currently unknown human tolerance to underwater blast. Current guidelines for prevention of underwater blast injury are not based on any organized injury risk assessment, human data or experimental data. The goal of this study was to derive injury risk assessments for underwater blast using well-characterized human underwater blast exposures in the open literature. The human injury dataset was compiled using 34 case reports on underwater blast exposure to 475 personnel, dating as early as 1916. Using severity ratings, computational reconstructions of the blasts, and survival information from a final set of 262 human exposures, injury risk models were developed for both injury severity and risk of fatality as functions of blast impulse and blast peak overpressure. Based on this human data, we found that the 50% risk of fatality from underwater blast occurred at 600 170 kPa-ms impulse. This risk value is the first impulse-based fatality risk calculated from human data. The gross inconsistency between the exposures in the case reports and the previously available guidelines further underscored the need for this new guideline based on injury data., Presented at the Personal Armour Systems Symposium on 8 Sep 2014. Prepared in collaboration with Pratt School of Engineering, Duke University, Durham, NC, Durham Veterans Administration Medical Center, Durham, NC, and William Beaumont Hospital, Royal Oak, MI.

Military service members are often exposed to at least one explosive event, and many blast-exposed veterans present with symptoms of traumatic brain injury. However, there is little information on the intensity and duration of blast necessary to cause brain injury. Varying intensity shock tube blasts were focused on the head of anesthetized ferrets, whose thorax and abdomen were protected. Injury evaluations included physiologic consequences, gross necropsy, and histologic diagnosis. The resulting apnea, meningeal bleeding, and fatality were analyzed using logistic regressions to determine injury risk functions. Increasing severity of blast exposure demonstrated increasing apnea immediately after the blast. Gross necropsy revealed hemorrhages, frequently near the brain stem, at the highest blast intensities. Apnea, bleeding, and fatality risk functions from blast exposure to the head were determined for peak overpressure and positive-phase duration. The 50% risk of apnea and moderate hemorrhage were similar, whereas the 50% risk of mild hemorrhage was independent of duration and required lower overpressures (144 kPa). Another fatality risk function was determined with existing data for scaled positive-phase durations from 1 millisecond to 20 milliseconds. The first primary blast brain injury risk assessments for mild and moderate/severe injuries in a gyrencephalic animal model were determined. The blast level needed to cause a mild/moderate brain injury may be similar to or less than that needed for pulmonary injury. The risk functions can be used in future research for blast brain injury by providing realistic injury risks to guide the design of protection or evaluate injury., Published in the Journal of Trauma and Acute Care Surgery, v73 n4 p895-901, 24 Jul 2012.

Introduction: A growing number of clinicians and scientists acknowledge that there exists some level of primary blast exposure that can disrupt or damage neuronal tissue resulting in traumatic brain injury. This injury may be associated with persistent and progressive sequelae. While the groundwork for identifying the brain s tolerance to primary blast has been created using animal and computational models, the mode (volumetric or deviatoric) and threshold of tissue-level deformation associated with brain tissue injury remains unknown. We report here a new test methodology to apply overpressure conditions to brain tissue preparations in vitro similar to those created from blast. We hypothesize this method would replicate the physical characteristics of blast, allowing measurements of tissue mechanical response and ultimately cell and tissue injury response. Materials and Methods: Blast waves were generated by a helium-driven shock tube (76 mm diameter tube with a 25 mm driver and a 1220 mm driven section). The blast wave impacts a fluid-filled apparatus that contains living brain tissue, creating a single overpressure pulse that propagates through the suspended tissue. Downstream, the apparatus was designed to mitigate returning shock reflections. An axisymmetric numerical model of the apparatus and tissue was developed in LS-DYNA to assess the response of the tissue that could not be measured experimentally. Experimental and modeled results were compared. Results and Discussion: The apparatus was able to generate blast overpressure waves at the tissue culture that were characteristic of Friedlander blast waves with minimal amount of reflected overpressure, but with slightly longer rise times (Figure 1A). Peak reflected overpressures generated using the shock tube ranged from 500 to 1500 kPa with durations from 0.5 to 1.0 ms., The original document contains color images. Prepared in collaboration with the Departments of Biomedical Engineering and Psychiatry and Behavioral Sciences, Duke University, Durham, NC, the Department of Biomedical Engineering, Columbia University, New York, NY, and the Department of Bioengineering, University of Pennsylvania, Philadelphia, PA.

Objectives: Blast-induced traumatic brain injury (bTBI) has risen to a new level of importance and is recognized to be a major cause of injuries to the brain. A simplified, free field blast-injury model would facilitate studies to correlate biological outcomes with blast-injury mechanics to generate novel tolerance criteria for bTBI. Methods: Organotypic hippocampal slice cultures (OHSC) were cultured as previously described. OHSC were plated onto porous membranes in supplemented Neurobasal medium. Culture medium was changed to conditioned full-serum medium starting 3-5 days following plating. OHSC were cultured under standard conditions (37 C, 5% CO2) for 10-14 days. A 76 mm diameter shock-tube pressurized with helium was used to produce blast overpressures. A custom designed, water-filled receiver was maintained at 37 C. Cultures were placed into sealed bags with warmed culture medium and placed in the receiver. Pressure transducers at the shock-tube exit and adjacent to the sample characterized loading of the sample. Control OHSC were secured in the receiver but were not exposed to blast. To test the neuroprotective potential of hypothermia, a group of cultures were injured with the temperature of the water in the receiver at 25 C. All cultures were immediately returned to fresh culture medium and incubated. Propidium iodide (PI) fluorescence was used to measure tissue health prior to and at 1, 6, and 24 hours following injury. Cell death was determined for all OHSC regions as the percent area staining above an intensity threshold. Results: This in vitro blast-injury model was capable of producing 175 kPa overspressures, which elicited diffuse cell death in OHSC that increased over 24 hours following blast. Control cultures experienced minimal cell death. Hypothermia was significantly neuroprotective and prevented cell death in cultures exposed to 175 kPa or 325 kPa overpressures.

Blast-related traumatic brain injury is the most prevalent injury for combat personnel seen in the current conflicts in Iraq and Afghanistan, yet as a research community, we still do not fully understand the detailed etiology and pathology of this injury. Finite element (FE) modeling is well suited for studying the mechanical response of the head and brain to blast loading. This paper details the development of a FE head and brain model for blast simulation by examining both the dilatational and deviatoric response of the brain as potential injury mechanisms. The levels of blast exposure simulated ranged from 50 to 1000 kPa peak incident overpressure and 1 8 ms in positive-phase duration, and were comparable to real-world blast events. The frontal portion of the brain had the highest pressures corresponding to the location of initial impact, and peak pressure attenuated by 40 60% as the wave propagated from the frontal to the occipital lobe. Predicted brain pressures were primarily dependent on the peak overpressure of the impinging blast wave, and the highest predicted brain pressures were 30% less than the reflected pressure at the surface of blast impact. Predicted shear strain was highest at the interface between the brain and the CSF. Strain magnitude was largely dependent on the impulse of the blast, and primarily caused by the radial coupling between the brain and deforming skull.The largest predicted strains were generally less than 10%, and occurred after the shock wave passed through the head. For blasts with high impulses, CSF cavitation had a large role in increasing strain levels in the cerebral cortex and periventricular tissues by decoupling the brain from the skull. Relating the results of this study with recent experimental blast testing suggest that a rate-dependent strain-based tissue injury mechanism is the source primary blast TBI., The original document contains color images. Published in Annals of Biomedical Engineering, 2 Feb 2012. Prepared in collaboration with the University of Pennsylvania, Philadelphia and the Departments of Biomedical Engineering and Psychiatry and Behavioral Sciences, Duke University, Durham, NC.

Recent studies have shown an increase in the frequency of traumatic brain injuries related to blast exposure. However, the mechanisms that cause blast neurotrauma are unknown. Blast neurotrauma research using computational models has been one method to elucidate that response of the brain in blast, and to identify possible mechanical correlates of injury. However, model validation against experimental data is required to ensure that the model output is representative of in vivo biomechanical response. This study exposes porcine subjects to primary blast overpressures generated using a compressed-gas shock tube. Shock tube blasts were directed to the unprotected head of each animal while the lungs and thorax were protected using ballistic protective vests similar to those employed in theater. The test conditions ranged from 110 to 740 kPa peak incident overpressure with scaled durations from 1.3 to 6.9 ms and correspond approximately with a 50% injury risk for brain bleeding and apnea in a ferret model scaled to porcine exposure. Instrumentation was placed on the porcine head to measure bulk acceleration, pressure at the surface of the head, and pressure inside the cranial cavity. Immediately after the blast, 5 of the 20 animals tested were apneic. Three subjects recovered without intervention within 30 s and the remaining two recovered within 8 min following respiratory assistance and administration of the respiratory stimulant doxapram. Gross examination of the brain revealed no indication of bleeding. Intracranial pressures ranged from 80 to 390 kPa as a result of the blast and were notably lower than the shock tube reflected pressures of 300–2830 kPa, indicating pressure attenuation by the skull up to a factor of 8.4. Peak head accelerations were measured from 385 to 3845 G’s and were well correlated with peak incident overpressure (R[superscript 2] = 0.90). One SD corridors for the surface pressure, intracranial pressure (ICP), and head acceleration are presente, United States. Multidisciplinary University Research Initiative (W911MF-10-1-526), Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies

See also ADM002313. Department of Defense Explosives Safety Board Seminar (34th) held in Portland, Oregon on 13-15 July 2010. The original document contains color images.

Mild traumatic brain injury may affect as many as 400,000 soldiers returning from recent wars in Afghanistan and Iraq. To determine how shockwaves directly affect neurons, we used a biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in vitro, and after a 24-48 hour period of incubation following shockwave exposure, immunocytochemical labeling showed a significant reduction in synaptic densities in shockwave-exposed cultures compared to control cultures. While the molecular mechanism responsible for this phenomenon is not known, these results suggest that shockwaves emanating from explosive devices may specifically affect synaptic plasticity in the brain., The original document contains color images. Prepared in cooperation with Dept. of Aeronautics and Astronautics, Massachusetts of Technology, MA and Duke Univ., Durham, NC.