Simultaneous High-Frame-Rate Acoustic Plane-Wave and Optical Imaging of Intracranial Cavitation in Polyacrylamide Brain Phantoms during Blunt Force Impact.

Blunt and blast impacts occur in civilian and military personnel, resulting in traumatic brain injuries necessitating a complete understanding of damage mechanisms and protective equipment design. However, the inability to monitor in vivo brain deformation and potential harmful cavitation events during collisions limits the investigation of injury mechanisms. To study the cavitation potential, we developed a full-scale human head phantom with features that allow a direct optical and acoustic observation at high frame rates during blunt impacts. The phantom consists of a transparent polyacrylamide material sealed with fluid in a 3D-printed skull where windows are integrated for data acquisition. The model has similar mechanical properties to brain tissue and includes simplified yet key anatomical features. Optical imaging indicated reproducible cavitation events above a threshold impact energy and localized cavitation to the fluid of the central sulcus, which appeared as high-intensity regions in acoustic images. An acoustic spectral analysis detected cavitation as harmonic and broadband signals that were mapped onto a reconstructed acoustic frame. Small bubbles trapped during phantom fabrication resulted in cavitation artifacts, which remain the largest challenge of the study. Ultimately, acoustic imaging demonstrated the potential to be a stand-alone tool, allowing observations at depth, where optical techniques are limited.

A Narrative Review of Existing and Developing Biomarkers in Acute Traumatic Brain Injury for Potential Military Deployed Use.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in both adult civilian and military populations. Currently, diagnostic and prognostic methods are limited to imaging and clinical findings. Biomarker measurements offer a potential method to assess head injuries and help predict outcomes, which has a potential benefit to the military, particularly in the deployed setting where imaging modalities are limited. We determine how biomarkers such as ubiquitin C-terminal hydrolase-L1 (UCH-L1), glial fibrillary acidic protein (GFAP), S100B, neurofilament light chain (NFL), and tau proteins can offer important information to guide the diagnosis, acute management, and prognosis of TBI, specifically in military personnel. MATERIALS AND METHODS: We performed a narrative review of peer-reviewed literature using online databases of Google Scholar and PubMed. We included articles published between 1988 and 2022. RESULTS: We screened a total of 73 sources finding a total of 39 original research studies that met inclusion for this review. We found five studies that focused on GFAP, four studies that focused on UCH-L1, eight studies that focused on tau proteins, six studies that focused on NFL, and eight studies that focused on S100B. The remainder of the studies included more than one of the biomarkers of interest. CONCLUSIONS: TBI occurs frequently in the military and civilian settings with limited methods to diagnose and prognosticate outcomes. We highlighted several promising biomarkers for these purposes including S100B, UCH-L1, NFL, GFAP, and tau proteins. S100B and UCH-L1 appear to have the strongest data to date, but further research is necessary. The robust data that explain the optimal timing and, more importantly, trending of these biomarker measurements are necessary before widespread application.

Mechanical characterization data of polyacrylamide hydrogel formulations and 3D printed PLA for application in human head phantoms.

To study human traumatic brain injury (TBI) mechanics, a realistic surrogate must be developed for testing in impact experiments. In this data brief, materials used to simulate brain tissue and skull are characterized for application in a full-scale human head phantom. Polyacrylamide hydrogels are implemented as tissue scaffolds and tissue mimics because they are bioinert and tunable. These properties make them ideal for use as brain tissue in studies that simulate head impacts. The objective is to modify hydrogel formulations to have minimal swelling and optical clarity while maintaining properties that mimic brain tissue, such as density, viscoelastic properties, and rheological properties. Secondly, polylactic acid (PLA) polymers are 3D printed to create biomimetic skulls to enclose the hydrogel brain tissue mimic or brain phantom. PLA samples are printed and tested to determine their mechanical strength with the intention of roughly matching human skull properties. Hydrogel data was obtained with an oscillatory rheometer, while PLA samples were tested using a mechanical tester with a 3-point bend setup. The present data brief highlights several hydrogel formulations and compares them to identify the benefits of each formula and reports mechanical values of 3D printed PLA samples with 100% grid infill patterns applied in a skull model.

Characterization of material properties and deformation in the ANGUS phantom during mild head impacts using MRI.

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.

Understanding Primary Blast Injury: High Frequency Pressure Acutely Disrupts Neuronal Network Dynamics in Cerebral Organoids.

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.

Sulcal Cavitation in Linear Head Acceleration: Possible Correlation With Chronic Traumatic Encephalopathy.

Traumatic Brain Injury (TBI) is a significant public health and financial concern that is affecting tens of thousands of people in the United States annually. There were over a million hospital visits related to TBI in 2017. Along with immediate and short-term morbidity from TBI, chronic traumatic encephalopathy (CTE) can have life-altering, chronic morbidity, yet the direct linkage of how head impacts lead to this pathology remains unknown. A possible clue is that chronic traumatic encephalopathy appears to initiate in the depths of the sulci. The purpose of this study was to isolate the injury mechanism/s associated with blunt force impact events. To this end, drop tower experiments were performed on a human head phantom. Our phantom was fabricated into a three-dimensional extruded ellipsoid geometry made out of Polyacrylamide gelatin that incorporated gyri-sulci interaction. The phantom was assembled into a polylactic acid 3D-printed skull, surrounded with deionized water, and enclosed between two optical windows. The phantom received repetitive low-force impacts on the order of magnitude of an average boxing punch. Intracranial pressure profiles were recorded in conjunction with high-speed imaging, 25 k frames-per-second. Cavitation was observed in all trials. Cavitation is the spontaneous formation of vapor bubbles in the liquid phase resulting from a pressure drop that reaches the vapor pressure of the liquid. The observed cavitation was predominately located in the contrecoup during negative pressure phases of local intracranial pressure. To further investigate the cavitation interaction with the brain tissue phantom, a 2D plane strain computational model was built to simulate the deformation of gyrated tissue as a result from the initiation of cavitation bubbles seen in the phantom experiments. These computational experiments demonstrated a focusing of strain at the depths of the sulci from bubble expansion. Our results add further evidence that mechanical interactions could contribute to the development of chronic traumatic encephalopathy and also that fluid cavitation may play a role in this interaction.

Healthcare Avoidance in Aircraft Pilots Due to Concern for Aeromedical Certificate Loss: A Survey of 3765 Pilots.

OBJECTIVE: To study healthcare avoidance behavior in pilots related to fear of aeromedical certificate loss. METHODS: Voluntary participation in an anonymous survey distributed to U.S. pilots. RESULTS: A total of 3765 pilots were included in the analysis. There were 56.1% of pilots (n = 2111) who reported a history of healthcare avoidance behavior due fear for losing their aeromedical certificate. There were 45.7% who sought informal medical care (n = 1721) and 26.8% who misrepresented/withheld information on a written healthcare questionnaire for fear of aeromedical certificate loss (n = 994). CONCLUSIONS: Aircraft pilots may participate in healthcare avoidance behavior related to fear of losing their aeromedical certificate. Further work is necessary to address pilot healthcare avoidance.

Localizing Clinical Patterns of Blast Traumatic Brain Injury Through Computational Modeling and Simulation.

Blast traumatic brain injury is ubiquitous in modern military conflict with significant morbidity and mortality. Yet the mechanism by which blast overpressure waves cause specific intracranial injury in humans remains unclear. Reviewing of both the clinical experience of neurointensivists and neurosurgeons who treated service members exposed to blast have revealed a pattern of injury to cerebral blood vessels, manifested as subarachnoid hemorrhage, pseudoaneurysm, and early diffuse cerebral edema. Additionally, a seminal neuropathologic case series of victims of blast traumatic brain injury (TBI) showed unique astroglial scarring patterns at the following tissue interfaces: subpial glial plate, perivascular, periventricular, and cerebral gray-white interface. The uniting feature of both the clinical and neuropathologic findings in blast TBI is the co-location of injury to material interfaces, be it solid-fluid or solid-solid interface. This motivates the hypothesis that blast TBI is an injury at the intracranial mechanical interfaces. In order to investigate the intracranial interface dynamics, we performed a novel set of computational simulations using a model human head simplified but containing models of gyri, sulci, cerebrospinal fluid (CSF), ventricles, and vasculature with high spatial resolution of the mechanical interfaces. Simulations were performed within a hybrid Eulerian-Lagrangian simulation suite (CTH coupled via Zapotec to Sierra Mechanics). Because of the large computational meshes, simulations required high performance computing resources. Twenty simulations were performed across multiple exposure scenarios-overpressures of 150, 250, and 500 kPa with 1 ms overpressure durations-for multiple blast exposures (front blast, side blast, and wall blast) across large variations in material model parameters (brain shear properties, skull elastic moduli). All simulations predict fluid cavitation within CSF (where intracerebral vasculature reside) with cavitation occurring deep and diffusely into cerebral sulci. These cavitation events are adjacent to high interface strain rates at the subpial glial plate. Larger overpressure simulations (250 and 500kPa) demonstrated intraventricular cavitation-also associated with adjacent high periventricular strain rates. Additionally, models of embedded intraparenchymal vascular structures-with diameters as small as 0.6 mm-predicted intravascular cavitation with adjacent high perivascular strain rates. The co-location of local maxima of strain rates near several of the regions that appear to be preferentially damaged in blast TBI (vascular structures, subpial glial plate, perivascular regions, and periventricular regions) suggest that intracranial interface dynamics may be important in understanding how blast overpressures leads to intracranial injury.

Adverse Childhood Experience, Genes, and PTSD Risk in Soldiers: A Methylation Study.

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.

Materials Characterization of Cranial Simulants for Blast-Induced Traumatic Brain Injury.

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.

Transport of extremely low birth weight neonates for persistent ductus arteriosus closure in the catheterization lab.

OBJECTIVE: The objective of this article is to describe the elements involved with transporting extremely low birth weight (ELBW) infants from referring centers to our center's neonatal intensive care unit (NICU) and then from the NICU to the catheterization lab for transcatheter closure of patent ductus arteriosus (PDA). SETTING: Several referring centers are over 300 miles away. ELBW infants are transferred in to our NICU safely for the procedure and transferred back following the procedure. A multidisciplinary team approach is necessary in order to achieve a safe transport of these fragile patients. PATIENTS: To date, we have over 12 centers referring patients that weigh <1000 g for transcatheter PDA closure (TCPC). Three of these centers are over 300 miles away. Five other centers are between 100 and 300 miles from the hospital in which we perform TCPC. INTERVENTIONS: Fixed-wing aircrafts are necessary for long-distance transfers. Various modes of mechanical ventilators including transport oscillators are built into temperature- and humidity-controlled incubators in which these infants are transported. Ambulances are used to take the patient between the airport and the hospital. Shorter distance transports are accomplished via helicopters or ambulances. Transfer from the NICU to the catheterization lab to perform TCPC is a relatively easier endeavor. OUTCOME MEASURES: Patients' body temperature, fluid balance, and hemodynamics have to be maintained throughout the transport and the procedure for best outcomes. RESULTS: There has been 100% procedural success of performing TCPC in ELBW infants with no hemodynamic compromise during transport. CONCLUSIONS: TCPC has shown promise in improving overall patient outcomes that the potential hazards associated with complex transport measures are worth it. Successful transfer to and from referring centers and to and from the catheterization lab can be accomplished safely with increasing institutional experience.

Open-loop organization of thalamic reticular nucleus and dorsal thalamus: a computational model.

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.

Lower neurocognitive function in U-2 pilots: Relationship to white matter hyperintensities.

OBJECTIVE: Determine whether United States Air Force (USAF) U-2 pilots (U2Ps) with occupational exposure to repeated hypobaria had lower neurocognitive performance compared to pilots without repeated hypobaric exposure and whether U2P neurocognitive performance correlated with white matter hyperintensity (WMH) burden. METHODS: We collected Multidimensional Aptitude Battery-II (MAB-II) and MicroCog: Assessment of Cognitive Functioning (MicroCog) neurocognitive data on USAF U2Ps with a history of repeated occupational exposure to hypobaria and compared these with control data collected from USAF pilots (AFPs) without repeated hypobaric exposure (U2Ps/AFPs MAB-II 87/83; MicroCog 93/80). Additional comparisons were performed between U2Ps with high vs low WMH burden. RESULTS: U2Ps with repeated hypobaric exposure had significantly lower scores than control pilots on reasoning/calculation (U2Ps/AFPs 99.4/106.5), memory (105.5/110.9), information processing accuracy (102.1/105.8), and general cognitive functioning (103.5/108.5). In addition, U2Ps with high whole-brain WMH count showed significantly lower scores on reasoning/calculation (high/low 96.8/104.1), memory (102.9/110.2), general cognitive functioning (101.5/107.2), and general cognitive proficiency (103.6/108.8) than U2Ps with low WMH burden (high/low WMH mean volume 0.213/0.003 cm(3) and mean count 14.2/0.4). CONCLUSION: In these otherwise healthy, highly functioning individuals, pilots with occupational exposure to repeated hypobaria demonstrated lower neurocognitive performance, albeit demonstrable on only some tests, than pilots without repeated exposure. Furthermore, within the U2P population, higher WMH burden was associated with lower neurocognitive test performance. Hypobaric exposure may be a risk factor for subtle changes in neurocognition.