Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation

Individualized high-resolution analysis to categorize diverse learning and memory deficits in tau rTg4510 mice exposed to low-intensity blast

Mild traumatic brain injury (mTBI) resulting from low-intensity blast (LIB) exposure in military and civilian individuals is linked to enduring behavioral and cognitive abnormalities. These injuries can serve as confounding risk factors for the development of neurodegenerative disorders, including Alzheimer’s disease-related dementias (ADRD). Recent animal studies have demonstrated LIB-induced brain damage at the molecular and nanoscale levels. Nevertheless, the mechanisms linking these damages to cognitive abnormalities are unresolved. Challenges preventing the translation of preclinical studies into meaningful findings in “real-world clinics” encompass the heterogeneity observed between different species and strains, variable time durations of the tests, quantification of dosing effects and differing approaches to data analysis. Moreover, while behavioral tests in most pre-clinical studies are conducted at the group level, clinical tests are predominantly assessed on an individual basis. In this investigation, we advanced a high-resolution and sensitive method utilizing the CognitionWall test system and applying reversal learning data to the Boltzmann fitting curves. A flow chart was developed that enable categorizing individual mouse to different levels of learning deficits and patterns. In this study, rTg4510 mice, which represent a neuropathology model due to elevated levels of tau P301L, together with the non-carrier genotype were exposed to LIB. Results revealed distinct and intricate patterns of learning deficits and patterns within each group and in relation to blast exposure. With the current findings, it is possible to establish connections between mice with specific cognitive deficits to molecular changes. This approach can enhance the translational value of preclinical findings and also allow for future development of a precision clinical treatment plan for ameliorating neurologic damage of individuals with mTBI

Animal Models of Head Trauma

Summary: Animal models of traumatic brain injury (TBI) are used to elucidate primary and secondary sequelae underlying human head injury in an effort to identify potential neuroprotective therapies for developing and adult brains. The choice of experimental model depends upon both the research goal and underlying objectives. The intrinsic ability to study injury-induced changes in behavior, physiology, metabolism, the blood/tissue interface, the blood brain barrier, and/or inflammatory- and immune-mediated responses, makes in vivo TBI models essential for neurotrauma research. Whereas human TBI is a highly complex multifactorial disorder, animal trauma models tend to replicate only single factors involved in the pathobiology of head injury using genetically well-defined inbred animals of a single sex. Although such an experimental approach is helpful to delineate key injury mechanisms, the simplicity and hence inability of animal models to reflect the complexity of clinical head injury may underlie the discrepancy between preclinical and clinical trials of neuroprotective therapeutics. Thus, a search continues for new animal models, which would more closely mimic the highly heterogeneous nature of human TBI, and address key factors in treatment optimization

Creating a Distinct Medication-Use System for Children at the Point of Care: The Time is Now

Children need a distinct medicines-use system designed explicitly for them since their continued inclusion in a system of prescription processing developed for adults generates insoluble risk points and workarounds. The American Academy of Pediatrics (AAP), in its policy statement released by the AAP Committee on Drugs in early 2014 about off-label use in children, posits that federal legislation on increased drug testing in children has been effective, as “there have been over 500 pediatric-specific labeling changes.” However, the AAP’s position has not changed materially since the original 2002 policy statement. Indeed, other health professionals, their organizations, or affiliated practice-based research network (PBRNs) mechanisms continue to be excluded from consideration, collaboration, or even honorable mention. It is noteworthy that most of the 500 labeling changes made since 1997 have addressed the scientific validity of indications for medication use in pediatric population without regard to pharmacotherapy formulation or monitoring. Medication use in children continues to be associated with an unacceptably high rate of adverse events, morbidity, and death. Children should no longer be “shoehorned” into the adult medication-use system, which faces challenges in addressing even the adult population’s needs. The time is now to design a multi-phasic, systematic approach to the pharmacotherapy of children. This paper will argue for the establishment of a distinct medication use system for children, a trans-disciplinary system designed thoughtfully and intentionally, not by convention, consensus, or imitation

Blast-Induced Neurotrauma Results in Spatially Distinct Gray Matter Alteration Alongside Hormonal Alteration: A Preliminary Investigation

Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures to stress, BINT may negatively influence stress coping abilities. This study aimed to determine the effects of BINT on gray matter volume and hormonal alteration. Participants were Canadian Armed Forces personnel and veterans with a history of BINT (n = 12), and first responder controls (n = 8), recruited due to their characteristic occupational stress professions. Whole saliva was collected via passive drool on the morning of testing and analyzed for testosterone (pg/mL), cortisol (μg/dL), and testosterone/cortisol (T/C) ratio. Voxel-based morphometry was performed to compare gray matter (GM) volume, alongside measurement of cortical thickness and subcortical volumes. Saliva analyses revealed distinct alterations following BINT, with significantly elevated testosterone and T/C ratio. Widespread and largely symmetric loci of reduced GM were found specific to BINT, particularly in the temporal gyrus, precuneus, and thalamus. These findings suggest that BINT affects hypothalamic-pituitary-adrenal and -gonadal axis function, and causes anatomically-specific GM loss, which were not observed in a comparator group with similar occupational stressors. These findings support BINT as a unique injury with distinct structural and endocrine consequences