Chronic headaches after traumatic brain injury: Diagnostic complexity associated with increased cost.

BACKGROUND: Chronic headache after traumatic brain injury (TBI) is a common, yet disabling, disorder whose diverse clinical characteristics and treatment needs remain poorly defined. OBJECTIVE: To examine diagnostic coding patterns and cost among military Veterans with comorbid chronic headache and TBI. METHODS: We identified 141,125 post-9/11 era Veterans who served between 2001 and 2019 with a headache disorder diagnosed after TBI. We first identified patterns of Complex Headache Combinations (CHC) and then compared the patterns of healthcare costs in 2022-dollar values in the three years following the TBI diagnosis. RESULTS: Veterans had diverse individual headache and CHC diagnoses with uniformly high cost of care. Post-whiplash and post-TBI CHCs were common and consistently associated with higher costs after TBI than those with other types of headache and CHCs. Post-TBI migraine had the highest unadjusted mean inpatient ($27,698), outpatient ($61,417), and pharmacy ($4,231) costs, which persisted even after adjustment for confounders including demographic, military, and clinical characteristics. CONCLUSION: Headache diagnoses after TBI, particularly those diagnosed with post-traumatic headache, are complex, and associated with dual high cost and care burdens. More research is needed to examine whether this higher expenditure reflects more intensive treatment and better outcomes or refractory headache with worse outcomes.

Exposure to Adverse Childhood Experiences Predicts Increased Neurobehavioral Symptom Reporting in Adults with Mild Traumatic Brain Injury.

The objective of this study was to understand whether exposure to adverse childhood experiences (ACEs) before 18 years of age predicts increased neurobehavioral symptom reporting in adults presenting for treatment secondary to persistent symptoms after mild traumatic brain injury (mTBI). This cross-sectional study identified 78 individuals with mTBI from 2014 to 2018 presenting for treatment to an outpatient multidisciplinary rehabilitation clinic. Neurobehavioral symptom inventory (NSI-22) scores were collected on admission, and ACEs for each patient were abstracted by medical record review. A linear regression model was used to assess if an individual who experienced at least one ACE before age 18 resulted in significantly different neurobehavioral scores compared with those not reporting any history of an ACE before age 18. Participants who reported at least one ACE before age 18 had significantly increased NSI-22 scores on admission to the rehabilitation clinic compared with patients without history of ACEs (mean difference 10.1, p = 0.011), adjusted for age and gender. For individuals presenting for treatment after mTBI, a history of ACEs before age 18 was associated with increased neurobehavioral symptoms.

Examination of Congruity between Subjective and Objective Working Memory in Veterans with Mild TBI and Relation to Psychiatric Symptoms and Childhood Trauma.

OBJECTIVES: There is conflicting evidence regarding congruence between subjective cognitive decline and objective cognitive performance for individuals with a history of mild traumatic brain injury (mTBI). The current study investigated the congruity between subjective and objective cognition, particularly working memory, among veterans with an mTBI history, accounting for post-traumatic stress disorder (PTSD) and childhood trauma. METHODS: Participants included 35 veterans with a history of mTBI sustained during deployment. Participants completed measures of subjective [i.e., Behavioral Inventory Rating of Executive Functioning (BRIEF)] and objective working memory (i.e., WAIS-IV working memory index). Congruity between subjective and objective working memory was examined using linear regression. Bonferroni-corrected correlations were run to explore relationships among working memory, psychiatric symptoms, mTBI severity, and childhood trauma. RESULTS: Among Veterans with mTBI, subjective working memory and objective working memory performance were not significantly related (p > 0.05); however, the overall model was significant (p < 0.0001), and childhood trauma was a notable predictor (p = 0.02). Greater PTSD, depression, and sleep symptoms were significantly related to increased subjective working memory concerns, even after Bonferroni adjustments (ps < 0.0001). Better objective working memory was significantly related to a fewer number of childhood traumatic events; however, this did not sustain corrections. The majority of individuals (67%) endorsed significant working memory complaints, despite objectively performing within normal limits (within 1 SD and above). CONCLUSIONS: Subjective-objective working memory congruity among veterans with mTBI was limited. Subjective, but not objective, working memory concerns were associated with greater PTSD, depression, and sleep symptoms. Childhood trauma was a notable factor that contributed to both subjective and objective cognitive concerns. There remains clinical value in assessing subjective cognitive concerns given the strong relationships with psychiatric problems and, hence, a focus for intervention.

Neuropathological mRNA Expression Changes after Single Mild Traumatic Brain Injury in Pigs.

Traumatic brain injury (TBI) is a public health concern, with an estimated 42 million cases globally every year. The majority of TBIs are mild TBIs, also known as concussion, and result from the application of mechanical forces on the head. Most patients make a complete recovery and mortality is rare; therefore, studies investigating cellular changes after mild TBI in a clinical setting are limited. To address this constraint, our group utilized a pig model of closed-head rotational acceleration-induced TBI, which recreated the biomechanical loading parameters associated with concussion on a large gyrencephalic brain similar to humans. While our previous research has focused on immunohistochemical characterization of neuropathology, the current study utilized transcriptomic assays to evaluate an array of TBI-induced neurodegenerative analytes. Pigs subjected to mild TBI were survived for 3 days post-injury (DPI) (n = 3), 30 DPI (n = 3), or 1 year post-injury (YPI) (n = 3) and compared to animals undergoing a sham procedure (n = 8). RNA was isolated from whole coronal sections of fixed tissue and multiplexed on a Nanostring neuropathology panel. Differential expression analysis revealed 11 differentially expressed genes at 3 DPI versus sham, including downregulation of the synaptotagmin calcium sensor gene (SYT1), upregulation of the neurofibromin gene (NF1), and upregulation of the Alzheimer's disease-associated receptor gene (SORL1). There were no differentially expressed genes at 30 DPI or 1 YPI compared to shams. Additionally, high-magnitude undirected global significance scores (GSS) were detected at 3 DPI for chromatin modification and autophagy gene sets, and at 30 DPI for cytokine gene sets, while many dysregulated gene sets were highlighted by directed GSSs out to 1 YPI. This study adds to a growing body of literature on transcriptomic changes in a clinically relevant large animal model of closed-head TBI, which highlights potential therapeutic targets following mild TBI.

Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries in mice.

Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific symptoms and risk factors. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following TBIs. Repetitive mild TBIs (rmTBI) compound these issues, resulting in cumulative and long-term brain damage in the brain. In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI by employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI). Our hypothesis is that the effects of rmTBI are worsened in aged animals, with this group showing more pronounced alterations in brain connectivity and white matter structure. Utilizing the closed-head impact model of engineered rotational acceleration (CHIMERA) model, we conducted rmTBIs or sham (control) procedures on young (2.5-3-months-old) and aged (22-months-old) male and female mice to model high-risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposhigh-risking effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Neuroinflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in injured aged animals compared to sham aged. These findings offer insight into the interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBI.

Adverse impact of female reproductive signaling on age-dependent neurodegeneration after mild head trauma in Drosophila.

Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Increasing age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify sex peptide signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights a reduction in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration.

Symptomatic Recovery from Concussion in Military Service Members with and Without Associated Bodily Injuries.

Research has found that service members (SMs) with mild traumatic brain injury (mTBI) and co-occurring bodily injuries endorse lower chronic postconcussive symptom severity than SMs with mTBI and no bodily injuries. Investigations were conducted with primarily post-9/11 war-era SMs with blast injuries. The current study explores these findings in a cohort of more heterogeneous and recently evaluated military SM. Possible reasons suggested for the earlier findings include SMs with bodily injuries report fewer postconcussive symptoms due to (1) focusing attention on extra-cranial injuries and associated pain; (2) receiving more interpersonal and medical support, lowering distress; (3) using analgesics such as morphine or opioids; or (4) experiencing delayed postconcussive symptoms. The current investigation evaluates each of these hypothesized reasons for the earlier findings and the generalizability of the findings to a more recent sample. Data were extracted from 165 SMs in a TBI repository at a U.S. military medical center. All participants reported a history of an mTBI, confirmed by a clinical interview to meet Veterans Affairs and Department of Defense criteria. Other bodily injuries received at the time of the mTBI were documented with the Abbreviated Injury Scale (AIS). Multiple regression models evaluated the ability of the four hypothesized mechanisms to predict postconcussive symptom severity, measured by the Neurobehavioral Symptom Inventory. SMs with bodily injuries (n = 48) reported nonsignificantly lower postconcussive symptoms than SMs with no bodily injuries (n = 117). The level of subjective pain was a determinant of postconcussive symptom severity among SMs with a history of mTBI, with or without associated bodily injuries. Social support was a weaker negative predictor of postconcussive symptoms among SMs with no associated bodily injuries.

Derivation of the Quebec Brain Injury Categories for complicated mild traumatic brain injuries.

OBJECTIVE: Approximately 10% of patients with mild traumatic brain injury (TBI) present with intracranial bleeding, and only 3.5% eventually require neurosurgical intervention, which often necessitates interhospital transfer. Better guidelines and recommendations are needed to manage complicated mild TBI in the emergency department (ED). The main objective of this study was to derive a clinical decision rule, the Quebec Brain Injury Categories (QueBIC), to predict the risk of adverse outcomes for complicated mild TBI in the ED. The secondary objective was to compare the QueBIC's performance with those of other existing guidelines. METHODS: The authors conducted a retrospective multicenter cohort study in 3 level I trauma centers. Consecutive patients with complicated mild TBI (Glasgow Coma Scale [GCS] score 13-15) who were aged ≥ 16 years were included. The primary outcome was a combination of neurosurgical intervention, mild TBI-related death, and clinical deterioration. Statistical analyses included set covering machine analyses. RESULTS: In total, 477 patients were included in the study. The mean age was 62.9 years, and 68.1% were male. The algorithm classified patients into three risk categories (low, moderate, and high risk). The high-risk group (128 patients) (subdural hemorrhage [SDH] width > 7 mm or any midline shift) presented a sensitivity of 84% (95% CI 71%-93%) and a specificity of 80% (95% CI 76%-84%) to detect neurosurgical intervention and mild TBI-related death, leaving 8 undetected cases. Patients in the moderate-risk group (169 patients) had at least 1 variable: SDH width > 4 mm, initial GCS score ≤ 14, > 1 intraparenchymal hemorrhage, or intraparenchymal hemorrhage width > 4 mm. The combined QueBIC high- and moderate-risk category had a sensitivity of 100% (95% CI 63%-100%) and a specificity of 53% (95% CI 47%-58%) to detect mild TBI-related death or neurosurgical intervention. The sensitivity and specificity values for clinical deterioration when no death or neurosurgical intervention occurred were 81% (95% CI 64%-93%) and 44% (95% CI 39%-49%), respectively. The remaining 180 patients (37.7%) did not meet any high-risk or moderate-risk criteria and were considered low risk. None had neurosurgical intervention or mild TBI-related death. Only 6 (3.3%) low-risk patients showed clinical deterioration. CONCLUSIONS: QueBIC is a safe and effective tool to guide the management of patients presenting to the ED with complicated mild TBI. It accurately identifies patients at low risk for specialized neurotrauma or neurosurgical care. Further validation is required before its use in EDs.

Effects of hours of sleep on ImPACT concussion testing: comparing baseline with postinjury scores.

OBJECTIVE: The influence of sleep on baseline and postconcussion neurocognitive performance prior to Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is poorly understood. Since ImPACT is widely used in youth sport to assess neurocognitive performance before and after head injury, it is important to delineate factors that affect testing performance. While some have reported correlations between fewer hours of sleep and lower scores on baseline tests, others have not observed any such associations. Therefore, the authors sought to compare the relationship between sleep and neurocognitive performance on ImPACT at both baseline and postinjury. METHODS: The authors queried a database of 25,815 ImPACT tests taken from 2009 to 2019 by athletes aged 12-22 years. There were 11,564 baseline concussion tests and 7446 postinjury concussion ImPACT tests used in the analysis. Linear regression was used to model the effect of sleep on baseline and postconcussion ImPACT scores adjusting for sex, age, learning disability, attention-deficit/hyperactivity disorder, number of prior concussions, number of games missed, and strenuous exercise before testing. RESULTS: Mean composite scores expectedly were all significantly lower in the post-head injury group compared with the baseline group. In the multivariable analysis, at baseline, hours of sleep significantly affected symptom scores (ß = -1.050, 95% CI -1.187 to -0.9138; p < 0.0001). In the postinjury multivariable analysis, verbal memory (ß = 0.4595, 95% CI 0.2080-0.7110; p = 0.0003), visual memory (ß = 0.3111, 95% CI 0.04463-0.5777; p = 0.0221), impulse control (ß = -0.2321, 95% CI -0.3581 to -0.1062; p = 0.0003), and symptom scores (ß = -0.9168, 95% CI -1.259 to -0.5750; p < 0.0001) were all affected by hours of sleep. CONCLUSIONS: Hours of sleep did not alter neurocognitive metrics at baseline but did have an impact on post-head injury metrics. These findings suggest that individuals may be able to compensate for lack of sleep at baseline but not immediately after concussion. Concussions may reduce cognitive reserve or detract from the brain's resources, making sleep even more important for proper neurocognitive functioning postconcussion. Future work will analyze the effects of sleep on postconcussion test performance.

Traumatic brain injury heterogeneity affects cell death and autophagy.

Traumatic brain injury (TBI) mechanism and severity are heterogenous clinically, resulting in a multitude of physical, cognitive, and behavioral deficits. Impact variability influences the origin, spread, and classification of molecular dysfunction which limits strategies for comprehensive clinical intervention. Indeed, there are currently no clinically approved therapeutics for treating the secondary consequences associated with TBI. Thus, examining pathophysiological changes from heterogeneous impacts is imperative for improving clinical translation and evaluating the efficacy of potential therapeutic strategies. Here we utilized TBI models that varied in both injury mechanism and severity including severe traditional controlled cortical impact (CCI), modified mild CCI (MTBI), and multiple severities of closed-head diffuse TBI (DTBI), and assessed pathophysiological changes. Severe CCI induced cortical lesions and necrosis, while both MTBI and DTBI lacked lesions or significant necrotic damage. Autophagy was activated in the ipsilateral cortex following CCI, but acutely impaired in the ipsilateral hippocampus. Additionally, autophagy was activated in the cortex following DTBI, and autophagic impairment was observed in either the cortex or hippocampus following impact from each DTBI severity. Thus, we provide evidence that autophagy is a therapeutic target for both mild and severe TBI. However, dramatic increases in necrosis following CCI may negatively impact the clinical translatability of therapeutics designed to treat acute dysfunction in TBI. Overall, these results provide evidence that injury sequalae affiliated with TBI heterogeneity is linked through autophagy activation and/or impaired autophagic flux. Thus, therapeutic strategies designed to intervene in autophagy may alleviate pathophysiological consequences, in addition to the cognitive and behavioral deficits observed in TBI.

Defining Mild Traumatic Brain Injury: From Research Definition to Clinical Practice.

INTRODUCTION: Approximately 75% of traumatic brain injuries (TBIs) qualify as mild. However, there exists no universally agreed upon definition for mild TBI (mTBI). Consequently, treatment guidelines for this group are lacking. The Center for Disease Control (CDC), American College of Rehabilitation Medicine (ACRM), Veterans Affairs and Department of Defense (VA/DoD), Eastern Association for the Surgery of Trauma (EAST), and the University of Arizona's Brain Injury Guidelines (BIG) have each published differing definitions for mTBI. The aim of this study was to compare the ability of these definitions to correctly classify mTBI patients in the acute care setting. METHODS: A single-center, retrospective cohort study comparing the performance of the varying definitions of mTBI was performed at a Level I trauma center from August 2015 to December 2018. Definitions were compared by sensitivity, specificity, positive predictive value, negative predictive value, as well as overtriage and undertriage rates. Finally, a cost-savings analysis was performed. RESULTS: We identified 596 patients suffering blunt TBI with Glasgow Coma Scale 13-15. The CDC/ACRM definitions demonstrated 100% sensitivity but 0% specificity along with the highest rate of undertriage and TBI-related mortality. BIG 1 included nearly twice as many patients than EAST and VA/DoD while achieving a superior positive predictive value and undertriage rate. CONCLUSIONS: The BIG definition identified a larger number of patients compared to the VA/DoD and EAST definitions while having an acceptable and more accurate overtriage and undertriage rate compared to the CDC and ACRM. By eliminating undertriage and minimizing overtriage rates, the BIG maintains patient safety while enhancing the efficiency of healthcare systems. Using the BIG definition, a cost savings of $395,288.95-$401,263.95 per year could be obtained at our level 1 trauma facility without additional mortality.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Longitudinal Biochemical and Behavioral Alterations in a Gyrencephalic Model of Blast-Related Mild Traumatic Brain Injury.

Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N-acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure.

Evaluating the Utility of Repeat Computed Tomography Scans in Patients with Isolated Mild Traumatic Subarachnoid Hemorrhage.

BACKGROUND: Traumatic subarachnoid hemorrhage (tSAH) is a common consequence of head trauma. Treatment of patients with tSAH commonly involves serial computed tomography (CT) scans to assess for expansile hemorrhage. However, growing evidence suggests that these patients rarely deteriorate or require neurosurgical intervention. We assessed the utility of repeat CT scans in adult patients with isolated tSAH and an intact initial neurological examination. METHODS: Patients presenting to Mass General Brigham hospitals with tSAH between 2000 and 2021 were eligible for inclusion in this retrospective cohort study. Patients were excluded if subarachnoid hemorrhage was nontraumatic, they experienced another form of intracerebral hemorrhage, or they had a documented Glasgow Coma Scale score of ≤12 and/or poor presenting neurological examination. Univariate and multivariate regression models were used for statistical analysis. RESULTS: Overall, 405 patients were included (191 male). The most common mechanism of trauma was fall from standing (58%). The mean number of total CT scans for all patients was 2.3, with 329 patients (80%) receiving ≥2 scans. In 309 patients, no significant neurological symptoms were present. No patients developed acute neurological deterioration or required neurosurgical intervention related to their bleed, although 5 patients had mild hemorrhagic expansion on follow-up imaging. CONCLUSIONS: In this study, repeat imaging rarely demonstrated meaningful hemorrhagic expansion in this cohort of neurologically intact patients with isolated tSAH. In these patients with mild traumatic brain injury, excessive CT scans are perhaps unlikely to affect patient management and may present unnecessary burden to patients and hospital systems.

The game changer: UCH-L1 and GFAP-based blood test as the first marketed in vitro diagnostic test for mild traumatic brain injury.

INTRODUCTION: Major organ-based in vitro diagnostic (IVD) tests like ALT/AST for the liver and cardiac troponins for the heart are established, but an approved IVD blood test for the brain has been missing, highlighting a gap in medical diagnostics. AREAS COVERED: In response to this need, Abbott Diagnostics secured FDA clearance in 2021 for the i-STAT Alinity™, a point-of-care plasma blood test for mild traumatic brain injury (TBI). BioMerieux VIDAS, also approved in Europe, utilizes two brain-derived protein biomarkers: neuronal ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP). These biomarkers, which are typically present in minimal amounts in healthy individuals, are instrumental in diagnosing mild TBI with potential brain lesions. The study explores how UCH-L1 and GFAP levels increase significantly in the bloodstream following traumatic brain injury, aiding in early and accurate diagnosis. EXPERT OPINION: The introduction of the i-STAT Alinity™ and the Biomerieux VIDAS TBI blood tests mark a groundbreaking development in TBI diagnosis. It paves the way for the integration of TBI biomarker tools into clinical practice and therapeutic trials, enhancing the precision medicine approach by generating valuable data. This advancement is a critical step in addressing the long-standing gap in brain-related diagnostics and promises to revolutionize the management and treatment of mild TBI.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

Subjective cognitive complaints and objective cognitive functioning in combat veterans: Effects of PTSD and deployment mild TBI.

OBJECTIVES: (1) Examine the relationship between subjective cognitive complaints and objective cognitive functioning in combat veterans; and (2) evaluate conditional effects of posttraumatic stress disorder (PTSD) and deployment-related mild traumatic brain injury (TBI) within that relationship. METHOD: Combat veterans (N = 225, 86.22% male) completed a lifetime TBI interview, a structured interview assessing PTSD symptoms, a neuropsychological assessment battery, and a self-report measure of cognitive symptoms. RESULTS: All correlations between subjective cognitive complaints and objective cognitive measures were not statistically significant. Hierarchical linear regression indicated that cognitive performance was not significantly related to cognitive complaints, but both PTSD diagnosis and history of deployment mild TBI explained a significant amount of unique variance in self-reported cognitive symptoms. Interactions between the studied variables were not significant. CONCLUSIONS: PTSD and history of deployment mild TBI were uniquely related to cognitive complaints, but cognitive test performance was not. No confounding effects of PTSD or deployment mild TBI were observed in the relationship between cognitive performance and cognitive complaints. This provides support that symptom distress may be a better explanatory factor for perception of lower cognitive functioning than actual cognitive performance.

Cross-spectral analysis of cerebral autoregulation after mild traumatic brain injury.

Severe traumatic brain injury (TBI) disrupts cerebral autoregulation (CAR), which may increase the risk of secondary neuronal damage in victims with large fluctuations in blood pressure (BP). CAR is also impaired in mild TBI. Given that mild TBI accounts for up to 70% of cases, this issue needs to be addressed. Physiological and non-invasive methods are now required to study CAR without the sharp fluctuations in blood pressure that underlie CAR tests. The cross-spectral analysis of fluctuations between cerebral blood flow and blood pressure discussed in the article is truly non-invasive and physiological. Forty-eight victims with mild traumatic brain injury were studied. CAR was assessed using two methods. The cuff test was used as a control method to assess autoregulation (RoR). Non-invasive cross-spectral analysis with phase shift (PS) detection was performed. The RoR values were normal, but there were cases within the group with varying severity of symptoms of the acute period of mild TBI. For example, the RoR was significantly higher (p < 0.001) in 32 patients with regression of symptoms than in 16 with persistence of symptoms. Their RoR and PS indicated a violation of the CAR, which required correction of the treatment. It was found that in 1/3 of the patients with mild TBI, a different state of CAR required individual tactics. RoR and PS correlated well.

Whole-Blood Metabolomics of a Rat Model of Repetitive Concussion.

Mild traumatic brain injury (mTBI) and repetitive mTBI (RmTBI) are silent epidemics, and so far, there is no objective diagnosis. The severity of the injury is solely based on the Glasgow Coma Score (GCS) scale. Most patients suffer from one or more behavioral abnormalities, such as headache, amnesia, cognitive decline, disturbed sleep pattern, anxiety, depression, and vision abnormalities. Additionally, most neuroimaging modalities are insensitive to capture structural and functional alterations in the brain, leading to inefficient patient management. Metabolomics is one of the established omics technologies to identify metabolic alterations, mostly in biofluids. NMR-based metabolomics provides quantitative metabolic information with non-destructive and minimal sample preparation. We employed whole-blood NMR analysis to identify metabolic markers using a high-field NMR spectrometer (800 MHz). Our approach involves chemical-free sample pretreatment and minimal sample preparation to obtain a robust whole-blood metabolic profile from a rat model of concussion. A single head injury was given to the mTBI group, and three head injuries to the RmTBI group. We found significant alterations in blood metabolites in both mTBI and RmTBI groups compared with the control, such as alanine, branched amino acid (BAA), adenosine diphosphate/adenosine try phosphate (ADP/ATP), creatine, glucose, pyruvate, and glycerphosphocholine (GPC). Choline was significantly altered only in the mTBI group and formate in the RmTBI group compared with the control. These metabolites corroborate previous findings in clinical and preclinical cohorts. Comprehensive whole-blood metabolomics can provide a robust metabolic marker for more accurate diagnosis and treatment intervention for a disease population.

Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military APOE ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.

Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD. Lipid extracts of plasma from active-duty soldiers deployed to the Iraq/Afghanistan wars (control = 52, mTBI = 21, PTSD = 34, and TBI + PTSD = 13) were subjected to liquid chromatography/mass spectrometry analysis to examine oxylipins and ethanolamides. Linear regression analyses followed by post hoc comparisons were performed to assess the association of these lipids with diagnostic classifications. Significant differences were found in oxylipins derived from arachidonic acid (AA) between controls and mTBI, PTSD, and mTBI + PTSD groups. Levels of AA-derived oxylipins through the cytochrome P450 pathways and anandamide were significantly elevated among mTBI + PTSD patients who were carriers of the apolipoprotein E E4 allele. These studies demonstrate that AA-derived oxylipins and anandamide may be unique blood biomarkers of PTSD and mTBI + PTSD. Further, these AA metabolites may be indicative of an underlying inflammatory process that warrants further investigation. Future validation studies in larger cohorts are required to determine a potential application of this approach in providing a differential diagnosis of mTBI and PTSD in a clinical setting.