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Blast-induced traumatic brain injury (bTBI) has been widely accepted as a “signature” wound affecting service members in modern conflicts, yet the mechanisms that cause bTBI still remain poorly understood. One of the main reasons for such poor understanding is the technical challenge of reproducing under controlled laboratory conditions the typical time-varying loading cycles induced on brain tissue after a blast event. Blast events have a sub-millisecond onset of high pressure followed by complex dynamics resulting from interaction between the blast wave and the complex anatomical structure of the human head. To tackle these experimental challenges, our group developed a novel apparatus using a water-filled piston-cylinder assembly driven by a piezoelectric actuator to generate complex and fast-varying pressure profiles. The versatility of our apparatus in producing complex pressure profiles was demonstrated by generating a single pressure pulse with various pulse-widths and magnitudes, an approximate Friedlander waveform, and a multi-modal waveform. A feedforward controller was also designed for the apparatus enhancing its capabilities to generate custom, user-defined pressure profiles. The apparatus successfully generated pressures up to 450 kPa at frequencies up to 5 kHz. The designed apparatus is compact, easily portable, and highly controllable, making it well suited for biomedical applications. This apparatus can be used to conduct ex-vivo and in-vitro experiments involving animal brain tissue specimens, cell cultures, and organoids to explore their response to the complex pressure loadings observed during a bTBI event.

Blast exposure represents a common occupational risk capable of generating mild to severe traumatic brain injuries (TBI). During blast exposure, a pressure shockwave passes through the skull and exposes brain tissue to complex pressure waveforms. The primary neurophysiological response to blast-induced pressure waveforms remains poorly understood. Here, we use a computer-controlled table-top pressure chamber to expose human stem cell-derived cerebral organoids to varied frequency of pressure waves and characterize the neurophysiological response. Pressure waves that reach a maximum amplitude of 250 kPa were used to model a less severe TBI and 350 kPa for a more severe blast TBI event. With each amplitude, a frequency range of 500 Hz, 3000 Hz, and 5000 Hz was tested. Following the 250 kPa overpressure a multi-electrode array recorded organoid neural activity. We observed an acute suppression neuronal activity in single unit events, population events, and network oscillations that recovered within 24 h. Additionally, we observed a network desynchronization after exposure higher frequency waveforms. Conversely, organoids exposed to higher amplitude pressure (350k Pa) displayed drastic neurophysiological differences that failed to recover within 24 h. Further, lower amplitude "blast" (250 kPa) did not induce cellular damage whereas the higher amplitude "blast" (350 kPa) generated greater apoptosis throughout each organoid. Our data indicate that specific features of pressure waves found intracranially during blast TBI have varied effects on neurophysiological activity that can occur even without cellular damage.

Traumatic brain injury (TBI) is a major health concern affecting both military and civilian populations. Despite notable advances in TBI research in recent years, there remains a significant gap in linking the impulsive loadings from a blast or a blunt impact to the clinical injury patterns observed in TBI. Synthetic head models or phantoms can be used to establish this link as they can be constructed with geometry, anatomy, and material properties that match the human brain, and can be used as an alternative to animal models. This study presents one such phantom called the Anthropomorphic Neurologic Gyrencephalic Unified Standard (ANGUS) phantom, which is an idealized gyrencephalic brain phantom composed of polyacrylamide gel. Here we mechanically characterized the ANGUS phantom using tagged magnetic resonance imaging (MRI) and magnetic resonance elastography (MRE), and then compared the outcomes to data obtained in healthy volunteers. The direct comparison between the phantom’s response and the data from a cohort of in vivo human subjects demonstrate that the ANGUS phantom may be an appropriate model for bulk tissue response and gyral dynamics of the human brain under small amplitude linear impulses. However, the phantom’s response differs from that of the in vivo human brain under rotational impacts, suggesting avenues for future improvements to the phantom.

Introduction Epigenetics can serve as a marker of susceptibility to many known psychiatric diseases. DNA methylation patterns of multiple genes have been studied in both civilian populations and military personnel with post-traumatic stress disorder (PTSD). Many of these genes serve various functions that span the hypothalamic-pituitary-adrenal axis, immune system, and central nervous system (CNS) growth factors and neurotransmission. It is thought that the methylation levels of such genes may be able to identify individuals who are at higher risk of developing PTSD. Our study seeks to establish whether previously reported PTSD genes possess a particular methylation pattern that is predictive of PTSD in active duty military members with combat exposure. Materials and Methods This is an institutional review board (IRB)-approved, cross-sectional, case control, gene-environment interaction study. About 170 active military members with and without PTSD were recruited. Patients with a history of structural brain damage, traumatic brain injury (TBI) resulting in loss of consciousness, predeployment diagnosis of PTSD or anxiety disorder, and predeployment prescription of an antidepressant or psychoactive medication were excluded. Validated measures of childhood trauma and adversity (adverse childhood experience [ACE] score), PTSD symptoms (PTSD check-list military version [PCL-M]), and combat exposure scales (CES) were measured via validated questionnaires for all subjects. After extracting DNA from peripheral blood provided by the 170 subjects, we determined methylation percentages, via pyrosequencing assays, for nine target areas within the following seven genes: BDNF, NR3C1, MAN2C1, TLR8, SLC6A4, IL-18, and SKA2. These genes are commonly reported in the literature as being highly correlated with PTSD and early-life traumatic experiences. Methylation levels were measured as a percentage at specific sites within the previously mentioned genes. Data were examined with SPSS v 22.0 Statistics and JMP v13.1 software using a general linear model for methylation × trauma (CES scores) split by diagnosis of PTSD or not, methylation versus childhood trauma (ACE scores), and methylation versus PTSD severity (PCL-M score). Two-way ANOVA was performed to control for antidepressant use. A two-tailed Student t-test was performed for PTSD analyses and was correlated with PTSD diagnosis, demographic information as well as ACE score, PCL-M score, and CES scores. Results Differentially methylated sites that were highly associated with PTSD diagnosis were found in three of seven candidate genes: BDNF, NR3C1, and MAN2C1. When compared to controls, patients with PTSD diagnosis had significantly lower levels of methylation, even after controlling for antidepressant use. PCL-M, ACE, and CES scores were significantly associated with PTSD diagnosis. Conclusion Our study suggests that methylation of key genes involved in synaptic plasticity and the hypothalamic-pituitary-adrenal axis is associated with lower levels of methylation in military PTSD subjects exposed to combat when compared to their non-PTSD counterparts. Strengths of this study include controlling for antidepressant use and excluding TBI patients. Similar studies in an active duty population of this size are scarce. What is not clear is whether methylation changes are driving PTSD symptomology or whether they are merely a marker of disease. Future areas of research include prospective studies that measure methylation pre- and postcombat exposure in the same individual.

This study shows the basic design and experimental characterization of the Advanced Blast Chamber at Michigan State University. This facility is a large cross-section explosively-driven blast chamber. The cross-section of the facility is 2.03 m × 2.03 m, and the length of its tunnel is 5.5 m. This relatively short length was made possible by introducing a new driver design shaped like a pair of logarithmic spirals with a coincident focus. The experimental characterization of the facility demonstrates that this driver design produces blast fronts with very low curvature, and overpressure durations as short as 1.2 ms. Since this was the initial characterization of the facility, the maximum overpressure considered was 144 kPa. This facility was conceived to perform studies of blast-induced TBI based on full-size models of the human body or large animal models. Its large cross section ensures that area blockage is within permissible values, and its driver design ensures short overpressure durations typical of battle field blast events.

Introduction The mechanical response of brain tissue to high-speed forces in the blast and blunt traumatic brain injury is poorly understood. Object-to-object variation and interspecies differences are current limitations in animal and cadaver studies conducted to study damage mechanisms. Biofidelic and transparent tissue simulants allow the use of high-speed optical diagnostics during a blast event, making it possible to observe deformations and damage patterns for comparison to observed injuries seen post-mortem in traumatic brain injury victims. Methods Material properties of several tissue simulants were quantified using standard mechanical characterization techniques, that is, shear rheometric, tensile, and compressive testing. Results Polyacrylamide simulants exhibited the best optical and mechanical property matching with the fewest trade-offs in the design of a cranial test object. Polyacrylamide gels yielded densities of ~1.04 g/cc and shear moduli ranging 1.3–14.55 kPa, allowing gray and white matter simulant tuning to a 30–35% difference in shear for biofidelity. Conclusions These materials are intended for use as layered cranial phantoms in a shock tube and open field blasts, with focus on observing phenomena occurring at the interfaces of adjacent tissue simulant types or material-fluid boundaries. Mechanistic findings from these studies may be used to inform the design of protective gear to mitigate blast injuries.

The split Hopkinson pressure bar (SHPB) technique is used to characterize the mechanical response of a material during impact loading when a single stress wave pulse passes through that material [1]. The SHPB setup consists of two long bars: an incident bar and a transmission bar. The specimen, which needs to be characterized, is placed between these two bars. A striker propelled from a gas gun hits the incident bar generating a stress wave that propagates through the incident bar. A part of this wave is transmitted to the specimen and the transmission bar while the remaining part of the wave reflects back into the incident bar. By measuring the incident, transmitted, and reflected waves, the mechanical properties of the specimen are determined for high-strain-rate deformations.

The thalamic reticular nucleus (TRN) is a shell of GABAergic neurons that surrounds the dorsal thalamus. Previous work has shown that TRN neurons send GABAergic projections to thalamocortical (TC) cells to form reciprocal, closed-loop circuits. This has led to the hypothesis that the TRN is responsible for oscillatory phenomena, such as sleep spindles and absence seizures. However, there is emerging evidence that open-loop circuits are also found between TRN and TC cells. The implications of open-loop configurations are not yet known, particularly when they include time-dependent nonlinearities in TC cells such as low-threshold bursting. We hypothesized that low-threshold bursting in an open-loop circuit could be a mechanism by which the TRN could paradoxically enhance TC activation, and that enhancement would depend on the relative timing of TRN vs. TC cell stimulation. To test this, we modeled small circuits containing TC neurons, TRN neurons, and layer 4 thalamorecipient cells in both open- and closed-loop configurations. We found that open-loop TRN stimulation, rather than universally depressing TC activation, increased cortical output across a broad parameter space, modified the filter properties of TC neurons, and altered the mutual information between input and output in a frequency-dependent and T-type calcium channel-dependent manner. Therefore, an open-loop model of TRN-TC interactions, rather than suppressing transmission through the thalamus, creates a tunable filter whose properties may be modified by outside influences onto the TRN. These simulations make experimentally testable predictions about the potential role for the TRN for flexible enhancement of cortical activation.

It has been suggested that stochastic thermal fluctuations directly affect the dynamics and stability of thin liquid films. We investigate this by comparing atomistic simulations of spreading drops with predictions from stochastically forced lubrication equations. Initially the drops spread according to Tanner’s law, l ∼ t1/7 , but then accelerate as predicted for cases where fluctuating thermal stresses govern the process.Copyright © 2007 by ASME

Atomistic simulations are used to investigate the relaxation dynamics of thermal capillary waves on thin flat liquid films. Short Lennard-Jones polymers (n=2, 4, and 8) model the liquid in films of thickness 6σ to 96σ, where σ is the Lennard-Jones atomic length-scale parameter. Assuming no-slip boundary conditions on the solid wall and constant surface tension and viscosity, the standard continuum model predicts that capillary waves decay with rates ω that scale with wavenumber q as ω∼q4 for long wavelengths and ω∼q for short wavelengths. The atomistic simulations do indeed show these scalings for ranges of q, and, of course, this model must fail for large q as wavelengths approach atomic scales. However, before a complete breakdown of the continuum description, an unexpected intermediate regime is found. Here the decay rates follow an apparent ω∼q2 power law. The behavior in this range collapses for all the cases simulated when q is scaled with the radius of gyration of the polymers, indicating that a mo...

The lubrication equation that governs the dynamics of thin liquid films can be augmented to account for stochastic stresses associated with the thermal fluctuations of the fluid. It has been suggested that under certain conditions the spreading rate of a liquid drop on a surface will be increased by these stochastic stresses. Here, an atomistic simulation of a spreading drop is designed to examine such a regime and provide a quantitative assessment of the stochastic lubrication equation for spreading. It is found that the atomistic drop does indeed spread faster than the standard lubrication equations would suggest and that the stochastic lubrication equation of Grün et al (2006 J. Stat. Phys. 122 1261-91) predicts the spread rate.