Pathophysiology Of Traumatic Brain Injury Research Articles

Traumatic brain injury and sleep in military and veteran populations: A literature review

BACKGROUND: Traumatic brain injury (TBI) is a hallmark of wartime injury and is related to numerous sleep wake disorders (SWD), which persist long term in veterans. Current knowledge gaps in pathophysiology have hindered advances in diagnosis and treatment. OBJECTIVE: We reviewed TBI SWD pathophysiology, comorbidities, diagnosis and treatment that have emerged over the past two decades. METHODS: We conducted a literature review of English language publications evaluating sleep disorders (obstructive sleep apnea, insomnia, hypersomnia, parasomnias, restless legs syndrome and periodic limb movement disorder) and TBI published since 2000. We excluded studies that were not specifically evaluating TBI populations. RESULTS: Highlighted areas of interest and knowledge gaps were identified in TBI pathophysiology and mechanisms of sleep disruption, a comparison of TBI SWD and post-traumatic stress disorder SWD. The role of TBI and glymphatic biomarkers and management strategies for TBI SWD will also be discussed. CONCLUSION: Our understanding of the pathophysiologic underpinnings of TBI and sleep health, particularly at the basic science level, is limited. Developing an understanding of biomarkers, neuroimaging, and mixed-methods research in comorbid TBI SWD holds the greatest promise to advance our ability to diagnose and monitor response to therapy in this vulnerable population.

LncRNA H19 knockdown promotes neuropathologic and functional recovery via the Nrf2/HO-1 axis after traumatic brain injury.

Traumatic brain injury (TBI) stands as a significant concern in public health, frequently leading to enduring neurological deficits. Long non-coding RNA H19 (lncRNA H19) exerts a potential regulator role in the pathology of brain injury. This study investigates the effects of lncRNA H19 knockdown (H19-KD) on the pathophysiology of TBI and its potential neuroprotective mechanisms. Controlled cortical impact was employed to establish a stable TBI mouse model. The expression levels of various genes in perilesional cortex and striatum tissue after TBI was detected by RT-qPCR. AAV9-shRNA-H19 was injected into the lateral ventricle of mice to knockdown the expression of lncRNA H19. Various behavioral tests were performed to evaluate sensorimotor and cognitive functions after TBI. Immunofluorescence and Nissl staining were performed to assess brain tissue damage and neuroinflammation. The Nrf2 and HO-1 expression was performed by Western blot. After TBI, the expression of lncRNA H19 was elevated in perilesional tissue and gradually reverted to baseline. Behavioral tests demonstrated that H19-KD significantly promoted the recovery of sensorimotor and cognitive functions after TBI. Besides, H19-KD reduced brain tissue loss, preserved neuronal integrity, and ameliorated white matter damage at the histological level. In addition, H19-KD restrained the pro-inflammatory and facilitated anti-inflammatory phenotypes of microglia/macrophages, attenuating the neuroinflammatory response after TBI. Furthermore, H19-KD promoted activation of the Nrf2/HO-1 axis after TBI, while suppression of Nrf2 partially abolished the neuroprotective effect. H19-KD exerts neuroprotective effects after TBI in mice, partially mediated by the activation of the Nrf2/HO-1 axis.

Neuroprotection or Sex Bias: A Protective Response to Traumatic Brain Injury in the Females

Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and long-term outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.

The Role of Nanotechnology in Understanding the Pathophysiology of Traumatic Brain Injury.

Recently, traumatic brain injury (TBI) has been a growing disorder due to frequent brain dysfunction. The Glasgow Coma Scale expresses TBI as classified as having mild, moderate, or severe brain effects, according to the effects on the brain. Brain receptors undergo various modifications in their pathology through chemical synaptic pathways, leading to depression, Alzheimer's, and Parkinson's disease. These brain disorders can be controlled using central receptors such as dopamine, glutamate, and γ-aminobutyric acid, which are clearly explained in this review. Furthermore, there are many complications in TBI's clinical trials and diagnostics, leading to insignificant treatment, causing permanent neuro-damage, physical disability, and even death. Bio-screening and conventional molecular-based therapies are inappropriate due to poor preclinical testing and delayed recovery. Hence, modern nanotechnology utilizing nanopulsed laser therapy and advanced nanoparticle insertion will be suitable for TBI's diagnostics and treatment. In recent days, nanotechnology has an important role in TBI control and provides a higher success rate than conventional therapies. This review highlights the pathophysiology of TBI by comprising the drawbacks of conventional techniques and supports suitable modern alternates for treating TBI.

Genetic Contributions to Recovery following Brain Trauma: A Narrative Review.

Traumatic brain injury (TBI) is a frequently encountered form of injury that can have lifelong implications. Despite advances in prevention, diagnosis, monitoring, and treatment, the degree of recovery can vary widely between patients. Much of this is explained by differences in severity of impact and patient-specific comorbidities; however, even among nearly identical patients, stark disparities can arise. Researchers have looked to genetics in recent years as a means of explaining this phenomenon. It has been hypothesized that individual genetic factors can influence initial inflammatory responses, recovery mechanisms, and overall prognoses. In this review, we focus on cytokine polymorphisms, mitochondrial DNA (mtDNA) haplotypes, immune cells, and gene therapy given their associated influx of novel research and magnitude of potential. This discussion is prefaced by a thorough background on TBI pathophysiology to better understand where each mechanism fits within the disease process. Cytokine polymorphisms causing unfavorable regulation of genes encoding IL-1β, IL-RA, and TNF-α have been linked to poor TBI outcomes like disability and death. mtDNA haplotype H has been correlated with deleterious effects on TBI recovery time, whereas haplotypes K, T, and J have been depicted as protective with faster recovery times. Immune cell genetics such as microglial differentially expressed genes (DEGs), monocyte receptor genes, and regulatory factors can be both detrimental and beneficial to TBI recovery. Gene therapy in the form of gene modification, inactivation, and editing show promise in improving post-TBI memory, cognition, and neuromotor function. Limitations of this study include a large proportion of cited literature being focused on pre-clinical murine models. Nevertheless, favorable evidence on the role of genetics in TBI recovery continues to grow. We aim for this work to inform interested parties on the current landscape of research, highlight promising targets for gene therapy, and galvanize translation of findings into clinical trials.

Context is key: glucocorticoid receptor and corticosteroid therapeutics in outcomes after traumatic brain injury.

Traumatic brain injury (TBI) is a global health burden, and survivors suffer functional and psychiatric consequences that can persist long after injury. TBI induces a physiological stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis, but the effects of injury on the stress response become more complex in the long term. Clinical and experimental evidence suggests long lasting dysfunction of the stress response after TBI. Additionally, pre- and post-injury stress both have negative impacts on outcome following TBI. This bidirectional relationship between stress and injury impedes recovery and exacerbates TBI-induced psychiatric and cognitive dysfunction. Previous clinical and experimental studies have explored the use of synthetic glucocorticoids as a therapeutic for stress-related TBI outcomes, but these have yielded mixed results. Furthermore, long-term steroid treatment is associated with multiple negative side effects. There is a pressing need for alternative approaches that improve stress functionality after TBI. Glucocorticoid receptor (GR) has been identified as a fundamental link between stress and immune responses, and preclinical evidence suggests GR plays an important role in microglia-mediated outcomes after TBI and other neuroinflammatory conditions. In this review, we will summarize GR-mediated stress dysfunction after TBI, highlighting the role of microglia. We will discuss recent studies which target microglial GR in the context of stress and injury, and we suggest that cell-specific GR interventions may be a promising strategy for long-term TBI pathophysiology.

Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury.

Traumatic brain injury (TBI) is a public health burden affecting millions of people. Sustained neuroinflammation after TBI is often associated with poor outcome. As a result, increased attention has been placed on the role of immune cells in post-injury recovery. Microglia are highly dynamic after TBI and play a key role in the post-injury neuroinflammatory response. Therefore, microglia represent a malleable post-injury target that could substantially influence long-term outcome after TBI. This review highlights the cell specific role of microglia in TBI pathophysiology. Microglia have been manipulated via genetic deletion, drug inhibition, and pharmacological depletion in various pre-clinical TBI models. Notably, colony stimulating factor 1 (CSF1) and its receptor (CSF1R) have gained much traction in recent years as a pharmacological target on microglia. CSF1R is a transmembrane tyrosine kinase receptor that is essential for microglia proliferation, differentiation, and survival. Small molecule inhibitors targeting CSF1R result in a swift and effective depletion of microglia in rodents. Moreover, discontinuation of the inhibitors is sufficient for microglia repopulation. Attention is placed on summarizing studies that incorporate CSF1R inhibition of microglia. Indeed, microglia depletion affects multiple aspects of TBI pathophysiology, including neuroinflammation, oxidative stress, and functional recovery with measurable influence on astrocytes, peripheral immune cells, and neurons. Taken together, the data highlight an important role for microglia in sustaining neuroinflammation and increasing risk of oxidative stress, which lends to neuronal damage and behavioral deficits chronically after TBI. Ultimately, the insights gained from CSF1R depletion of microglia are critical for understanding the temporospatial role that microglia develop in mediating TBI pathophysiology and recovery.

ICAM-1 Deletion Using CRISPR/Cas9 Protects the Brain from Traumatic Brain Injury-Induced Inflammatory Leukocyte Adhesion and Transmigration Cascades by Attenuating the Paxillin/FAK-Dependent Rho GTPase Pathway.

Intercellular adhesion molecule-1 (ICAM-1) is identified as an initiator of neuroinflammatory responses that lead to neurodegeneration and cognitive and sensory-motor deficits in several pathophysiological conditions including traumatic brain injury (TBI). However, the underlying mechanisms of ICAM-1-mediated leukocyte adhesion and transmigration and its link with neuroinflammation and functional deficits following TBI remain elusive. Here, we hypothesize that blocking of ICAM-1 attenuates the transmigration of leukocytes to the brain and promotes functional recovery after TBI. The experimental TBI was induced in vivo by fluid percussion injury (25 psi) in male and female wild-type and ICAM-1-/- mice and in vitro by stretch injury (3 psi) in human brain microvascular endothelial cells (hBMVECs). We treated hBMVECs and animals with ICAM-1 CRISPR/Cas9 and conducted several biochemical analyses and demonstrated that CRISPR/Cas9-mediated ICAM-1 deletion mitigates blood-brain barrier (BBB) damage and leukocyte transmigration to the brain by attenuating the paxillin/focal adhesion kinase (FAK)-dependent Rho GTPase pathway. For analyzing functional outcomes, we used a cohort of behavioral tests that included sensorimotor functions, psychological stress analyses, and spatial memory and learning following TBI. In conclusion, this study could establish the significance of deletion or blocking of ICAM-1 in transforming into a novel preventive approach against the pathophysiology of TBI.

Acute brain injury and nanomedicine: sex as a biological variable

Sex as a biological variable has been recognized for decades to be a critical aspect of the drug development process, as differences in drug pharmacology and toxicity in female versus male subjects can drive the success or failure of new therapeutics. These concepts in development of traditional drug systems have only recently begun to be applied for advancing nanomedicine systems that are designed for drug delivery or imaging in the central nervous system (CNS). This review provides a comprehensive overview of the current state of two fields of research - nanomedicine and acute brain injury—centering on sex as a biological variable. We highlight areas of each field that provide foundational understanding of sex as a biological variable in nanomedicine, brain development, immune response, and pathophysiology of traumatic brain injury and stroke. We describe current knowledge on female versus male physiology as well as a growing number of empirical reports that directly address sex as a biological variable in these contexts. In sum, the data make clear two key observations. First, the manner in which sex affects nanomedicine distribution, toxicity, or efficacy is important, complex, and depends on the specific nanoparticle system under considerations; second, although field knowledge is accumulating to enable us to understand sex as a biological variable in the fields of nanomedicine and acute brain injury, there are critical gaps in knowledge that will need to be addressed. We anticipate that understanding sex as a biological variable in the development of nanomedicine systems to treat acute CNS injury will be an important determinant of their success.

Astroglial Cells: Emerging Therapeutic Targets in the Management of Traumatic Brain Injury.

Traumatic Brain Injury (TBI) represents a significant health concern, necessitating advanced therapeutic interventions. This detailed review explores the critical roles of astrocytes, key cellular constituents of the central nervous system (CNS), in both the pathophysiology and possible rehabilitation of TBI. Following injury, astrocytes exhibit reactive transformations, differentiating into pro-inflammatory (A1) and neuroprotective (A2) phenotypes. This paper elucidates the interactions of astrocytes with neurons, their role in neuroinflammation, and the potential for their therapeutic exploitation. Emphasized strategies encompass the utilization of endocannabinoid and calcium signaling pathways, hormone-based treatments like 17β-estradiol, biological therapies employing anti-HBGB1 monoclonal antibodies, gene therapy targeting Connexin 43, and the innovative technique of astrocyte transplantation as a means to repair damaged neural tissues.

The neuroprotective potential of phytochemicals in traumatic brain injury: mechanistic insights and pharmacological implications.

Traumatic brain injury (TBI) leads to brain damage, comprising both immediate primary damage and a subsequent cascade of secondary injury mechanisms. The primary injury results in localized brain damage, while the secondary damage initiates inflammatory responses, followed by the disruption of the blood-brain barrier, infiltration of peripheral blood cells, brain edema, and the release of various immune mediators, including chemotactic factors and interleukins. TBI disrupts molecular signaling, cell structures, and functions. In addition to physical tissue damage, such as axonal injuries, contusions, and haemorrhages, TBI interferes with brain functioning, impacting cognition, decision-making, memory, attention, and speech capabilities. Despite a deep understanding of the pathophysiology of TBI, an intensive effort to evaluate the underlying mechanisms with effective therapeutic interventions is imperative to manage the repercussions of TBI. Studies have commenced to explore the potential of employing natural compounds as therapeutic interventions for TBI. These compounds are characterized by their low toxicity and limited interactions with conventional drugs. Moreover, many natural compounds demonstrate the capacity to target various aspects of the secondary injury process. While our understanding of the pathophysiology of TBI, there is an urgent need for effective therapeutic interventions to mitigate its consequences. Here, we aimed to summarize the mechanism of action and the role of phytochemicals against TBI progression. This review discusses the therapeutic implications of various phytonutrients and addresses primary and secondary consequences of TBI. In addition, we highlighted the roles of emerging phytochemicals as promising candidates for therapeutic intervention of TBI. The review highlights the neuroprotective roles of phytochemicals against TBI and the mechanistic approach. Furthermore, our efforts focused on the underlying mechanisms, providing a better understanding of the therapeutic potential of phytochemicals in TBI therapeutics.

Is age or cardiovascular comorbidity the main predictor of reduced cerebrovascular pressure reactivity in older patients with traumatic brain injury?

IntroductionThe Pressure Reactivity index (PRx) has been proposed as a surrogate measure for cerebrovascular autoregulation (CA) and it has been described that older age is associated with worse PRx. The etiology for this reduced capacity remains unknown. Research questionTo investigate the relation between age and PRx in a cohort of patients with traumatic brain injury (TBI) while correcting for cardiovascular comorbidities. Material and methodsThis is a retrospective analysis on prospectively collected data in 151 consecutive TBI patients between 2013 and 2023. PRx was averaged over 5 monitoring days and correlated with demographic, patient and injury data. A multiple regression analysis was performed with PRx as dependent variable and cardiovascular comorbidities, age, Glasgow motor score and pupillary reaction as independent variables. A similar model was constructed without age and compared. ResultsAge, sex, thromboembolic history, arterial hypertension, Glasgow motor score and pupillary reaction significantly correlated with PRx in univariate analysis. In multivariate analysis, age had a significant worsening effect on PRx (p = 0.01), while the cardiovascular risk factors and injury severity had no impact. The comparison of the models with and without age yielded a significant difference (p = 0.01), underpinning the independent effect of age. Discussion and conclusionIn the present cohort study in TBI patients it was found that older age independently impaired cerebrovascular pressure reactivity regardless of cardiovascular comorbidity. Pathophysiology of TBI and physiology of ageing seem to line up to synergistically produce a negative effect on brain perfusion.

Transcriptional and Translational Regulation of Differentially Expressed Genes in Yucatan Miniswine Brain Tissues following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity, disability, and mortality worldwide. Motor and cognitive deficits and emotional disturbances are long-term consequences of TBI. A lack of effective treatment for TBI-induced neural damage, functional impairments, and cognitive deficits makes it challenging in the recovery following TBI. One of the reasons may be the lack of knowledge underlying the complex pathophysiology of TBI and the regulatory factors involved in the cellular and molecular mechanisms of inflammation, neural regeneration, and injury repair. These mechanisms involve a change in the expression of various proteins encoded by genes whose expression is regulated by transcription factors (TFs) at the transcriptional level and microRNA (miRs) at the mRNA level. In this pilot study, we performed the RNA sequencing of injured tissues and non-injured tissues from the brain of Yucatan miniswine and analyzed the sequencing data for differentially expressed genes (DEGs) and the TFs and miRs regulating the expression of DEGs using in-silico analysis. We also compared the effect of the electromagnetic field (EMF) applied to the injured miniswine on the expression profile of various DEGs. The results of this pilot study revealed a few DEGs that were significantly upregulated in the injured brain tissue and the EMF stimulation showed effect on their expression profile.

Lateral fluid percussion injury: A rat model of experimental traumatic brain injury.

Traumatic brain injury (TBI) represents one of the leading causes of disability and death worldwide. The annual economic impact of TBI-including direct and indirect costs-is high, particularly impacting low- and middle-income countries. Despite extensive research, a comprehensive understanding of the primary and secondary TBI pathophysiology, followed by the development of promising therapeutic approaches, remains limited. These fundamental caveats in knowledge have motivated the development of various experimental models to explore the molecular mechanisms underpinning the pathogenesis of TBI. In this context, the Lateral Fluid Percussion Injury (LFPI) model produces a brain injury that mimics most of the neurological and systemic aspects observed in human TBI. Moreover, its high reproducibility makes the LFPI model one of the most widely used rodent-based TBI models. In this chapter, we provide a detailed surgical protocol of the LFPI model used to induce TBI in adult Wistar rats. We further highlight the neuroscore test as a valuable tool for the evaluation of TBI-induced sensorimotor consequences and their severity in rats. Lastly, we briefly summarize the current knowledge on the pathological aspects and functional outcomes observed in the LFPI-induced TBI model in rodents.

A role for decorin in improving motor deficits after traumatic brain injury

Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn−/− mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI.

The Role of Substance P and NK1 Receptors in Mild to Severe Traumatic Brain Injury: From CTE to ICP

Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention.

Prevalence andRisk Factors ofSelf-reported Dizziness inPost-9/11 Service Members andVeterans.

Dizziness is prevalent in the general population, but little is known about its prevalence in the U.S. military population. Dizziness is commonly associated with blast exposure and traumatic brain injury (TBI), but the potential independent contributions of blast and TBI have yet to be evaluated. This study's goal was to estimate the prevalence of dizziness among post-9/11 service members and Veterans and to examine independent and joint associations between military TBI history, blast exposure, and self-reported dizziness. The study sample consisted of service members (n = 424) and recently separated (< ∼2.5 years) Veterans (n = 492) enrolled in the Noise Outcomes in Service members Epidemiology (NOISE) Study. We examined associations between self-reported history of probable TBI and blast exposure and recent dizziness using logistic regression. Models were stratified by service member versus Veteran status and adjusted to account for potentially confounding demographic and military characteristics. Overall, 22% of service members and 31% of Veterans self-reported dizziness. Compared to those with neither TBI nor blast exposure history, both service members and Veterans with TBI (with or without blast) were three to four times more likely to self-report dizziness. Those with blast exposure but no TBI history were not more likely to self-report dizziness. There was no evidence of an interaction effect between blast exposure and a history of TBI on the occurrence of dizziness. Self-reported dizziness was prevalent in this sample of service members and Veterans. Probable TBI history, with or without blast exposure, was associated with dizziness, but blast exposure without TBI history was not. This suggests that treatment guidelines for TBI-related dizziness may not need to be tailored to the injury mechanism. However, future efforts should be directed toward the understanding of the pathophysiology of TBI on self-reported dizziness, which is fundamental to the design of treatment strategies.

Characterization of Traumatic Brain Injury in a Gyrencephalic Ferret Model Using the Novel Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA).

Traumatic brain injury (TBI) results from mechanical force to the brain and leads to a series of biochemical responses that further damage neurons and supporting cells. Clinically, most TBIs result from an impact to the intact skull, making closed head TBI pre-clinical models highly relevant. However, most of these closed head TBI models use lissencephalic rodents, which may not transduce biomechanical load in the same manner as gyrencephalic humans. To address this translational gap, this study aimed to characterize acute axonal injury and microglial responses in ferrets-the smallest gyrencephalic mammal. Injury was induced in male ferrets (Mustela furo; 1.20-1.51 kg; 6-9 months old) with the novel Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) model. Animals were randomly allocated to either sham (n = 4), a 22J (joules) impact (n = 4), or a 27J impact (n = 4). Axonal injury was examined histologically with amyloid precursor protein (APP), neurofilament M (RMO 14.9) (RMO-14), and phosphorylated tau (AT180) and the microglial response with ionized calcium-binding adaptor molecule 1 at 24 h post-injury in gray and white matter regions. Graded axonal injury was observed with modest increases in APP and RMO-14 immunoreactivity in the 22J TBI group, mostly within the corpus callosum and fornix and more extensive diffuse axonal injury encompassing gray matter structures like the thalamus and hypothalamus in the 27J group. Accompanying microglial activation was only observed in the 27J group, most prominently within the white matter tracts in response to the larger amounts of axonal injury. The 27J, but not the 22J, group showed an increase in AT180 within the base of the sulci post-injury. This could suggest that the strain may be highest in this region, demonstrating the different responses in gyrencephalic compared to lissencephalic brains. The CHIMERA model in ferrets mimic many of the histopathological features of human closed head TBI acutely and provides a promising model to investigate the pathophysiology of TBI.

Updates on Improving Imaging Modalities for Traumatic Brain Injury.

The Center for Disease Control and Prevention reports that traumatic brain injury (TBI) was related to over 64,000 deaths in the United States in 2020, equating to more than 611 TBI-related hospitalizations and 176 TBI-related deaths per day. There are both long- and short-term sequelae involved with the pathophysiology of TBI that can range from mild to severe. Recently, more effort has been devoted to understanding the long-term consequences of TBI and how early detection of these injuries can prevent late clinical manifestations. Obtaining proper, detailed imaging is key to guiding the direction of intervention, but there is a gap in the understanding of how TBI imaging can be used to predict and prevent the long-term morbidities seen with even mild forms of TBI. There have been significant strides in the advancement of TBI imaging that allows for quicker, more affordable, and more effective imaging of intracranial bleeds, axonal injury, tissue damage, and more. Despite this, there is still room for improved standardization and more data supporting the justification of using certain imaging modalities. This review aims to outline recent advancements in TBI imaging and areas that require further investigation to improve patient outcomes and minimize the acute and chronic comorbidities associated with TBI.

Neurobehavioral and inflammatory responses following traumatic brain injury in male and female mice

Traumatic brain injury (TBI) is a leading cause of mortality and is associated with a high rate of functional comorbidities, including motor, cognitive, anxiety, depression, and emotional disorders. TBI pathophysiology and recovery are complicated and involve several mechanistic pathways that control neurobehavioral outcomes. In this study, male and female C57Bl/6 J mice were subjected to a controlled cortical impact model of TBI or sham injury and evaluated for different neurobehavioral and inflammatory outcomes over a month. We demonstrate that TBI mice have increased motor dysfunction at early and late time points following the injury as compared to the sham group. Anxiety-like symptoms were time- and task-dependent, with both sexes having increased anxiety-like behavior 2 weeks post-injury. Cognitive functions measured by T-maze presented greater deficits in TBI mice, while there was no sex or injury-related difference in depressive-like behaviors. Notably, a significant effect of sex was found in empathy-like behavior, with females showing more allogrooming and freezing behavior in the consoling and fear observational tests, respectively. Evaluating the impact of the injury-induced brain damage demonstrated a greater injury volume and neuronal degeneration in males compared to females one month after TBI. Moreover, male mice showed higher peripheral inflammatory responses, as represented by elevated serum levels of peripheral leukocytes and inflammatory markers. These results will have significant implications for understanding TBI's long-term consequences on neurobehavioral and inflammatory responses, which are sex-specific and can be considered for individualized therapeutic strategies in treating TBI.