Journal of Neurotrauma

This work describes a newly developed experimental mouse model reproducing features of blast-induced neurotrauma (BINT), induced in operationally relevant manner using a compressed air-driven shock tube. Mild BINT (smBINT) was induced by one exposure to a low-intensity blast (LIB), whereas subconcussive BINT (rscBINT) was caused by repeated exposures to LIB. To mimic an operational scenario when a soldier is standing when exposed to blast using a quadruped experimental animal (mouse), a whole-body holder was developed to position mice in a bipedal stance, face-on toward the pressure wave generated in a shock tube. This restraint avoids bobble head movement, thus prevents tertiary blast effects, and allows administration of fast-acting inhaled anesthetics via nose cone. Using this model, we established and validated paradigms for primary blast-induced mild and repetitive traumatic brain injuries Our results showed that a single exposure to 69 kPa (10 psi) was capable of inducing smBINT, whereas three-rounds of exposure to 41 kPa (6 psi) caused rscBINT. Mice recovered rapidly from both types of BINT without prolonged neurological dysfunction. Mild superficial pathology was found predominantly in the lungs 24h after injury, with equivalent pathology after smBINT or repetitive rscBINT. The Purkinje layer of the cerebellum exhibited neuronal damage persisting up to 7d. Similar to some other models as well as clinical findings, this model reproduces blast-induced cerebellar pathology. In conclusion, this model positioning mice in a bipedal stance and facing front-on toward the shockwave provides realistic representation of operational scenarios and reproduces militarily-relevant smBINT and rscBINT in the laboratory.

BackgroundPrognostication after moderate-to-severe traumatic brain injury (TBI) rarely captures long-term functional recovery, despite its importance to patients, families, and clinicians. Large trauma registries such as the Trauma Quality Improvement Program (TQIP) dataset contain detailed clinical data but lack systematic follow-up, limiting their ability to study longer-term functional outcomes. MethodsWe developed and externally validated a machine learning model to predict favorable six-month functional outcome (GOS "MD"/"GR" or GOSE [≥]5) using harmonized data from two randomized clinical trials: CRASH (training) and ROC-TBI (validation). Five candidate classifiers (random forest [RF], linear discriminant analysis, k-nearest neighbors, naive Bayes, and support vector machine) were trained using seven shared clinical predictors. Models were evaluated using ROC-AUC, calibration metrics, and performance at the Youden optimal threshold and a high-sensitivity secondary threshold. The final model was applied to patients with moderate-to-severe TBI in the national TQIP registry (2017-2022) to estimate population-level recovery patterns. ResultsThe RF model demonstrated the highest overall performance after recalibration, achieving strong discrimination (AUC internal and external, 0.887 and 0.784), good calibration, and high sensitivity (0.890) and negative predictive value (0.909). Applied to 63,289 patients from TQIP, the model estimated that 45% would achieve favorable six-month outcomes at the Youden optimal threshold and 57% at the high-sensitivity threshold, with predicted recovery aligning with established clinical correlates such as younger age, higher admission GCS, and lower rates of penetrating or brainstem injuries. ConclusionA machine learning model trained on high-quality trial data can generate clinically plausible estimates of long-term functional recovery when applied at scale to national trauma registries that lack systematic follow-up. This approach enables imputation of functional outcomes in datasets lacking follow-up, supports benchmarking and quality improvement across trauma systems, and provides a foundation for future models incorporating physiologic time-series, imaging, and biomarker data.

Traumatic spinal cord injury (tSCI) leads to an immediate loss of neurological function, with its recovery being difficult to predict in the acute phase. Here, we developed a contrast-enhanced ultrasound (CEUS) imaging biomarker to quantify the intraspinal vascular disruption after tSCI. In rodent thoracic tSCI, CEUS revealed a perfusion area deficit (PAD) which increased with injury severity (p = 0.001). The PAD size significantly correlated with hindlimb locomotor function at 8 weeks post injury (R2 = 0.82, p < 0.001). Additionally, we calculated a spinal perfusion index (SPI) comparing the amount of perfused tissue at the injury center to that in injury periphery. Our experiments demonstrated that SPI decreased in more severe injuries and correlated significantly with hindlimb locomotor function at 8 weeks post injury (R2 = 0.83, p < 0.001). Subsequently, we demonstrated the feasibility of intraoperative CEUS imaging in 20 patients with acute tSCI. A hyper-perfusion pattern was commonly seen in cervical motor-incomplete tSCI, while necrosis penumbra pattern was associated with motor-complete cervical or thoracic tSCI. We measured both PAD and SPI and detected statistically significant differences between motor-complete and motor-incomplete patients. In our patient cohort, SPI exhibited a strong predictive capacity for functional recovery at 6 months (R2 = 0.79, p < .001) compared to PAD. In conclusion, our study suggests that an intraoperative CEUS-derived biomarker holds promise for predicting injury severity and chronic functional outcome after tSCI. Larger clinical studies are needed to better assess the reliability of the proposed CEUS-derived biomarker and its prognostic capacity. One Sentence SummaryThis paper introduces a novel biomarker utilizing contrast-enhanced ultrasound in humans and rats that accurately predicts injury severity after traumatic spinal cord injury based on tissue perfusion.

Subconcussive impacts are highly prevalent in contact sports and are thought to increase concussion risk. However, the specific conditions under which these subconcussive impacts influence concussion outcomes are uncertain, limiting our understanding of the mechanisms behind repetitive head trauma. Given that subconcussive impacts elicit a microglial response, and microglial morphology offers insight into function, we examined how subconcussive preconditioning affects microglial morphology and cognitive outcome after concussion. To investigate this question, we developed and validated a scalable, closed-head controlled cortical impact model. Using this approach, we found that although concussion elicited features of hypersurveillant microglia at 1 day post-injury, they resolve by 9 days post-injury, and subconcussive impacts only produced microglial changes at 9 days post-injury. When subconcussive impacts preceded a concussive impact (i.e., preconditioned concussion) no changes in microglial morphology appeared at either 1 or 9 days after injury. Interestingly, subconcussive preconditioning eliminated concussion-associated cognitive deficits in novel object recognition and this cognitive protection was time dependent: preconditioning impacts were only protective if delivered within 2 minutes of concussion, and had no effect if delivered over a 48-hour window. These results suggest that some types of subconcussive impacts may offer protection against subsequent concussion and mitigate changes in microglial morphology. Understanding this timing window could inform strategies for minimizing cognitive impairments in athletes exposed to repetitive head trauma.

Spinal cord injury and traumatic brain injury are major causes of long-term disability and are often complicated by spasticity, a motor disorder characterized by increased muscle tone and exaggerated reflexes that significantly impair quality of life. Current diagnostic methods lack the sensitivity needed to accurately predict the severity of injury or the onset and progression of spasticity. Trauma-induced calcium dysregulation activates calpains, a family of proteases that cleave sodium channels, disrupting their inactivation and increasing persistent sodium currents. This cascade drives the overexcitability of motoneurons, contributing to the development of spasticity. Consequently, sodium channel fragments have emerged as promising biomarkers that link injury mechanisms to clinical outcomes. The present SpasT-SCI-T clinical trial protocol aims to evaluate sodium channel fragments as blood biomarkers for assessing the severity of spinal cord and traumatic brain injuries, as well as their potential to predict clinical outcomes, including the development of spasticity. This prospective, multicenter, case-control and cohort study involves 40 participants: 20 individuals with spinal cord injury, 10 individuals with traumatic brain injury, and 10 healthy controls. Blood samples are collected within six hours of injury and at follow-up points over six months. Clinical outcomes, including spasticity (assessed using the Modified Ashworth Scale), neurological recovery (measured by the American Spinal Injury Association Impairment Scale and Glasgow Coma Scale), and quality of life (evaluated using the Short Form-36 Health Survey), are analyzed in correlation with biomarker levels. We anticipate that calpain-mediated sodium channel fragments will transform the management of central nervous system injuries by enabling early diagnosis, improving prognostic accuracy, and guiding personalized therapeutic strategies. The clinical trial is registered on ClinicalTrials.gov (NCT06532760, January 10, 2024), with Assistance Publique-Hopitaux de Marseille as the sponsor.

Mild traumatic brain injury (mTBI) affects millions of individuals annually primarily through falls, traffic collisions, or blunt trauma and can generate symptoms that persist for years. Closed-head rotational injury is the most common form of mTBI and is defined by a rapid change in acceleration within an intact skull. Injury kinematics - the mechanical descriptors of injury-inducing motion - explain movement of the head, energy transfer to the brain, and, therefore, determine injury severity. However, the relationship between closed-head rotational injury kinematics - such as angular velocity, angular acceleration, and injury duration - and outcome after mTBI is currently unknown. To address this gap in knowledge, we analyzed archived surgical records of 24 swine experiencing a diffuse closed-head rotational acceleration mTBI against 12 sham animals. Kinematics were contrasted against acute recovery outcomes, specifically apnea, extubation time, standing time, and recovery duration. Compared to controls, animals with mTBI were far more likely to have apnea (p<0.001) along with shorter time to extubation (p=0.023), and longer time from extubation to recovery (p=0.006). Using regression analyses with variable selection, we generated simplified linear models relating kinematics to apnea (R2=0.27), standing time (R2=0.39) and recovery duration (R2=0.42). Neuropathology was correlated with multiple kinematics, with maximum acceleration exhibiting the strongest correlation (R2=0.66). Together, these data suggest the interplay between multiple injury kinematics, including minimum velocity and middle to minimum acceleration time, best explain acute recovery parameters and neuropathology after mTBI in swine. Future experiments that independently manipulate individual kinematics could be instrumental in developing translational diagnostics for clinical mTBI.

PurposePrevious research has demonstrated effects of head impact exposure on cortical neurophysiology, which may help with understanding variability in clinical sequelae. In separate lines of research, neurochemical and gene transcription markers of vulnerability to traumatic brain injury (TBI) have been established. The purpose of this study was to examine whether these cortical neurochemical and gene transcription gradients are spatially aligned with neurophysiological effects. Methods and MaterialsMagnetoencephalography (MEG) data was collected at a total of 278 pre- and post-season timepoints from 91 high school football players across up to four seasons of play. Of the 91 football players, 10 experienced a concussion, and of the remaining 81 non-concussed players, 71 met the criteria for complete imaging and kinematic data, with post-season evaluations less than six weeks after the end of the season. Head impacts were tracked over the course of the season with helmet-mounted sensors. MEG data underwent source-imaging, frequency-transformation, spectral parameterization, and linear modeling to examine the effects of concussive and non-concussive head impact exposure on pre-to-post-season changes in rhythmic and arrhythmic neurophysiological activity. To determine clinical effects, parent reported Post-Concussive Symptom Inventory scores related to cognitive symptoms were correlated with cortical neurophysiological changes. Multi-atlas data of neurochemical system densities from neuromaps and gene expression from the Allen Human Brain Atlas were examined for alignment with head impact-related alterations in neurophysiology via nonparametric spin-tests with autocorrelation-preserving null models (5,000 Hungarian spins; pFDR <.05). ResultsConcussion-related reductions in cortical excitability (i.e., aperiodic exponent slowing) were aligned with atlas-based norepinephrine transporter (NET) and alpha-4 beta-2 nicotinic receptor (4{beta}2) densities, and with apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) expression levels. More severe cognitive symptoms associated with concussion-related slowing of aperiodic neurophysiology were also aligned with atlas-based NET and 4{beta}2 receptor densities. Similar changes in cortical excitability related to non-concussive head impact exposure were colocalized with serotonin receptor (5-HT1A) density maps and APOE and BDNF expression. Rhythmic alpha activity was reduced by concussion and colocalized with histamine (H3) and mu-opioid (MOR) receptors, among others, as well as with gene transcription atlases of APOE and C-C chemokine receptor 5 (CCR5). ConclusionsThese findings extend our previous work to show that the effects of head impact exposure on neurophysiology are strongest in cortical areas with specific neurochemical and genetic profiles that are known to signal vulnerability to traumatic brain injury, and that these spatial alignments are also associated with self-reported symptom severity. Clinical Relevance / ApplicationChange in cortical excitability, as measured here by MEG, has potential value as a clinical tool for concussion diagnosis and prognosis. We provide genetic and neurochemical contextualization for these changes that may extend their clinical applications, for example to concussion risk assessment and pharmacotherapies.

ImportanceBlast-related mild traumatic brain injuries (bTBI), the "signature injury" of post-9/11 conflicts, are associated with clinically-relevant long-term cognitive, psychological, and behavioral dysfunction and disability; however, the underlying neural mechanisms remain unclear. ObjectiveTo investigate associations between a history of remote bTBI and regional brain volume in a sample of United States (U.S.) Veterans and Active Duty Service Members (VADSM). DesignProspective case-control study of U.S. VADSM of participants from the Long-term Impact of Military-relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), which enrolled over 1,500 participants at five sites used in this analysis between 2014-2023. SettingParticipants were recruited from Veterans Affairs medical centers across the U.S. ParticipantsSeven hundred and seventy-four VADSM of the U.S. military met eligibility criteria for this analysis. ExposureAll participants had combat exposure, and 82% had one or more lifetime mild TBIs with variable injury mechanisms. Main Outcomes and MeasuresRegional brain volume was calculated using tensor-based morphometry on 3D T1-weighted magnetic resonance imaging scans. TBI history, including history of blast-related injury (bTBI), was assessed by structured clinical interview. Cognitive performance and psychiatric symptoms were assessed with a battery of validated instruments. We hypothesized that regional volume would be smaller in the bTBI group, and that this would be associated with cognitive performance. ResultsIndividuals with a history of bTBI had smaller brain volumes in several clusters, with the largest centered bilaterally in the superior corona radiata and globus pallidus. Greater volume deficits were associated with a larger number of lifetime bTBIs. Additionally, causal mediation analysis revealed that these volume differences significantly mediated the association between bTBI and performance on measures of working memory and processing speed. Conclusions and RelevanceOur results reveal robust volume differences associated with bTBI. Magnetic resonance elastography atlases reveal that the specific regions affected include the stiffest tissues in the brain, which may underlie their vulnerability to pressure waves from blast exposures. Furthermore, these volume differences significantly mediated the association between bTBI and cognitive function, indicating that this may be a helpful biomarker in tracking outcome after bTBI and suggesting potential treatment targets to prevent or limit chronic dysfunction.

ObjectiveTo compare the incremental prognostic value of pupillary reactivity as captured in the GCS-Pupils score (GCS-P) or added as separate variable to the Glasgow Coma Scale (GCS) in traumatic brain injury (TBI). MethodsWe analyzed patients enrolled between 2014 and 2018 in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, n=3521) and the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI, n=1439) cohorts. We used logistic regression to quantify the prognostic performances of GCS-P versus GCS according to Nagelkerkes R2. Endpoints were mortality and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-4) at 6 months after injury. We estimated 95% confidence intervals with bootstrap resampling to summarize the improvement in prognostic capability. ResultsGCS as a linear score had a R2 of 24% (95% confidence interval [CI] 17-30) and 30% (95%CI 17-43) for mortality and 29% (95%CI 25-34) and 38% (95%CI 29-47) for unfavorable outcome in CENTER-TBI and TRACK-TBI respectively. In the meta-analysis, pupillary reactivity as a separate variable improved the R2 by an absolute value of 6% and 2% for mortality and unfavorable outcome (95%CI 4.0-7.7 and 1.2-3.0, respectively), with half the improvement captured in the GCS-P score (3%, 95%CI 2.1-3.3 and 1%, 95%CI 1-1.7, respectively). ConclusionsGCS-P has a stronger association with outcome after TBI than the GCS alone. However, for prognostic models, inclusion of GCS and pupillary reactivity as separate scores is preferable.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Hemorrhagic shock (HS) aggravates tissue injury and complicates TBI recovery. We studied the combined insult of mild TBI and HS and investigated the impact of varying loss of blood volume on neurologic deficit and brain lesion volume. A novel positron emission tomography (PET) technique was employed to monitor tissue injury. Male Sprague Dawley rats received mTBI by controlled cortical impact (CCI) followed by withdrawal of 0%, 30-40%, 45%, or 50% of blood (mTBI, mTBI+HS[&le;]40%, mTBI+HS45%, and mTBI+HS50%, respectively). Neurological deficit (mNSS= 5.6, 7.6, and 12.3) and mortality (2/12, 2/6, and 7/12) were worse in mTBI+HS[&le;]40%, mTBI+HS45%, and mTBI+HS50%, respectively than in mTBI alone rats (no death; mNSS=3.3). Histologic lesion size increased 3.5-fold in mTBI+HS50% compared to mTBI alone and the infarct-avid PET agent 18F-fluorodeoxyglucaric acid (FGA) proportionately detected tissue necrosis in mTBI+HS50% rats. Based on these results, we conclude that HS aggravates mTBI-induced neurological deficits, tissue injury and mortality. PET/18F-FGA as an imaging marker can detect the extent of injury in a non-invasive manner.

Accurate quantification of locomotor recovery is essential for evaluating therapeutic outcomes in spinal cord injury (SCI) models. Manual scoring systems remain observer-dependent, and commercial gait-analysis platforms are costly and proprietary. Markerless pose-estimation tools such as DeepLabCut generate accurate body-part coordinates, but converting these coordinates into biologically meaningful locomotor parameters typically requires custom programming and multiple external tools. We developed KiMA (Kinematic Motion Analysis), an open-source, browser-based suite for integrated analysis of rodent gait and hindlimb kinematics. KiMA accepts DeepLabCut coordinate files and performs automated coordinate parsing, stick-figure reconstruction, frame-by-frame movement inspection, and single- and multi-sample analysis, with dedicated workflows for ladder and rung analysis, footfall detection, and CatWalk gait analysis. The platform quantifies joint angles (metatarsophalangeal, ankle, knee, hip, and pelvic), stride length, stride width, cadence, stance and swing durations, paw-contact events, swing clearance, and locomotor symmetry, and supports cohort-level comparisons, correlation analysis, principal component analysis, and export of processed datasets and publication-quality figures. Because KiMA runs entirely within a standard web browser, it requires no software installation or local programming environment, supporting cross-platform accessibility and data privacy. By unifying gait quantification, visualization, and multivariate analysis in a single interface, KiMA lowers the computational barrier to markerless locomotor analysis and helps researchers detect subtle functional recovery after SCI.

Study designSystematic review ObjectivesTo examine the prevalence, diagnostic challenges, and functional impact of concomitant traumatic brain injury (TBI) in individuals with traumatic spinal cord injury (SCI). MethodsPubMed, Embase and Scopus databases were searched with a search strategy containing key search terms for TBI, SCI and concomitant injury. Original research articles reporting on prevalence and/or functional outcomes following a TBI at the time of SCI in adult populations were included. ResultsForty studies met the inclusion criteria, with 32 reporting prevalence and 18 information on functional outcomes. Reported prevalence rates of concomitant TBI varied widely (10-75%) across studies, largely due to inconsistent diagnostic criteria, retrospective data collection, and reliance on incomplete medical records or ICD coding. The identification of mild TBI (mTBI) was particularly problematic, with differing diagnostic criteria employed.. Moderate-severe TBI at the time of SCI significantly increased in-hospital mortality and complications like pneumonia, sepsis, but had minimal effects on rehabilitation trajectory. Functional outcomes, particularly motor and sensory recovery, were generally unaffected by concomitant injury, though subtle cognitive deficits were observed in moderate to severe TBI cases during rehabilitation. Few studies examined outcomes beyond one year post injury. ConclusionOverall, current evidence suggests that concomitant TBI is common in people presenting with an SCI, but its long term functional and cognitive impact remains underexplored. Future research should employ standardised diagnostic criteria, prospective data collection, and long term follow up to clarify the role of concomitant TBI not only in the acute recovery phase, but also chronically.

ImportanceIn patients with traumatic brain injury (TBI), baseline pupillary assessment is common. However, the incidence and frequency of pupil abnormalities within the first several days remain poorly characterized. ObjectivesOur aim was to test the association between pupil abnormality frequency over the first 72 hours of admission and clinical outcomes. DesignWe conducted a retrospective observational study of patients with a primary diagnosis of TBI with at least three quantitative pupillometry measurements within 72 hours at a single-center ICU from 2018 to 2022. Outcomes and MeasuresNeurological Pupil index (NPi), a quantitative composite metric for pupil reactivity, was obtained at each clinical neurologic assessment over 72 hours. Pupil measurements were defined as abnormal if they had a NPi of <3 in either eye, NPi asymmetry [&ge;]0.7, or pupil size asymmetry [&ge;]1mm. We tested the association of increased frequency of pupil abnormalities over 72 hours and unfavorable discharge disposition (death, hospice, or long-term care) using multivariable logistic regression, adjusting for confounders. We then compared whether the IMPACT model was improved by the frequency of pupil abnormalities using goodness-of-fit. ResultsOf 131 patients, median age was 59 years, and 30% were women. Thirty-five percent had unfavorable discharge disposition. Pupil abnormalities occurred in 62%, 61%, and 88% of mild, moderate, and severe TBI patients, respectively. Odds ratio of unfavorable discharge for every 1% increase in pupil abnormality frequency was 1.03 (95% Cl, 1.01-1.05), equivalent to one additional abnormal pupil measurement within a 72-hour period. The adjusted IMPACT TBI models goodness-of-fit improved with pupil abnormality frequency (X2=5.67, p=0.02). Conclusions and RelevancePupil abnormalities occur commonly in TBI and have the highest frequency in severe TBI. Increased pupil abnormality frequency is associated with unfavorable discharge disposition and improves performance of prognostic TBI models. Key PointsThe goal of this study was to test the association between pupil abnormality frequency over the first 72 hours of admission and unfavorable discharge disposition and whether it improved the IMPACT model. In this retrospective observational study of 131 TBI patients at a single-center, we found that an increased frequency of pupil abnormalities across 72-hours significantly correlated with unfavorable discharge in patients and improved the IMPACT models goodness-of-fit. These findings highlight the potential of long-term pupillary metrics and their role as not only a prognostic indicator in patients but also a tool that improves the performance of prognostic TBI models.

Pain sensitivity varies widely among individuals and is influenced by a complex interplay of multi-omics factors, including genetic variations, gene expression, and brain morphology. While previous studies have identified associations between pain sensitivity and brain morphology, the exact mechanisms by which genetic profiles interact with brain structure to influence individual pain sensitivity remain unclear. In this study, we used aggregated datasets, including magnetic resonance imaging (MRI) and single nucleotide polymorphism (SNP) genotypes from 432 healthy participants, along with gene expression data from the Allen Human Brain Atlas (AHBA), to explore this multi-omics interplay. We first measured individual pain thresholds using laser stimuli and discovered structural brain differences between high and low pain sensitivity groups. We then identified two key gene sets with polarized expression patterns linked to brain morphology variations, enriched in functions related to ion channels and transmembrane transporter activities. Further statistical and mediation analyses revealed specific SNPs from ECM1, SLC24A2, and SCN9A genes that influence pain sensitivity, mediated through brain morphological changes in multiple basal ganglia regions. Our findings suggested that these SNPs not only affect brain structure but also modulate how individuals pain perception. Finally, we proposed an interpretation model integrating genomic, transcriptomic, and neuroimaging data, providing a detailed framework that illustrates the multi-omics contributions to individual difference in pain sensitivity. This study advances our understanding of how genetic and brain structural factors combine to shape pain perception, offering potential targets for personalized pain management strategies.

Importance: Outcomes following traumatic brain injury (TBI) vary substantially, with a subset of individuals experiencing neuropsychiatric morbidity and worse prognosis. Exposure to psychosocial and environmental stressors may be an important, yet understudied, modifier of TBI trajectory. Allostatic load (AL) represents the cumulative physiological burden of chronic stress and provides a useful framework for evaluating pre-injury vulnerability. Objective: To assess the relationship between pre-injury AL burden and risk of mortality and incident neuropsychiatric diagnosis following TBI. Design, Setting, and Participants: This cohort study leveraged electronic health record, survey, and laboratory data from the All of Us Research Program, version 8. Participants aged 18 years or older enrolled between May 6, 2018, and October 1, 2023, were queried for TBI diagnosis using clinical diagnostic codes. Data were analyzed between November 11, 2024, and January 7, 2026. Exposure: The physiological burden of pre-injury chronic stress exposure was estimated using an AL index (pALI) derived from anthropometric and laboratory biomarkers collected before index TBI. Main Outcomes and Measures: Post-TBI mortality and incident neuropsychiatric diagnosis clusters. Mortality risk was assessed using Cox proportional hazards models (hazard ratio [HR] with 95% CI), and risk of incident neuropsychiatric diagnosis was modeled using competing-risk regression with death as a competing event (sub-distribution HR with 95% CI). Results: The primary cohort included 4,552 individuals with an established TBI diagnosis and sufficient biomarker data to estimate pALI. The pALI measure differed across sociodemographic groups and was positively correlated with perceived stress (r=.08, p=.002). Higher pALI was associated with increased post-TBI mortality risk (adjusted HR=1.71; 95%CI, 1.36-2.14). Elevated pALI was also associated with greater risk of incident post-traumatic stress disorder (PTSD; adjusted HR=1.28; 95%CI, 1.10-1.50) and sleep disorder (adjusted HR=1.42 95%CI, 1.29-1.57) diagnoses. Conclusions and Relevance: Higher pre-injury ALI was associated with increased risk of mortality and select neuropsychiatric outcomes following TBI, suggesting that AL burden may shape post-injury trajectories. Pre-injury chronic stress exposure and underlying stress biology may represent underrecognized determinants of vulnerability and resilience in brain injury recovery.

Mild Traumatic Brain Injury (mTBI) caused by sports-related incidents in children and youth can lead to prolonged cognitive impairments, underscoring the importance of improved diagnosis and comprehension of its enduring impacts on neuropathology. A pig model was chosen for its similarities to the human brain in terms of gyrencephalic structure, size, and regional proportions, and a closed-head mTBI was induced in adolescent pigs. In this study, 12 (n=4 male and n=8 female) 16-weeks old Yucatan pigs were tested; n=6 received mTBI and n=6 received a Sham procedure. This study utilized T1-weighted imaging to assess volumetric alterations in different regions of the brain and diffusion tensor imaging (DTI) to examine microstructural damage in white matter. The pigs were imaged at one and three months post-injury. Our volumetric analysis of key white and gray matter regions showed significant longitudinal changes in pigs with mTBI compared to sham controls. The observed volume increases may be attributed to swelling, neuroinflammation, or hyperactivity. Fractional anisotropy (FA) values derived from DTI images demonstrated an increase in corpus callosum from 1 month to 3 months only in mTBI pigs. Additionally, comparisons of the left and right internal capsules revealed a decrease in FA in the right internal capsule for mTBI pigs, likely due to the impact being slightly localized to the right side of the brain, which may indicate demyelination. Thus, the injury has disrupted the maturation of white and gray matter of the developing brain. This signifies the need for longitudinal investigations after mTBI to comprehensively assess its long-term effects and contribute to the clinical management of concussion in youth.

ObjectiveDetermine whether acute behavioral, electroencephalography (EEG), and functional MRI (fMRI) biomarkers of consciousness are associated with outcome after severe traumatic brain injury (TBI). MethodsPatients with acute severe TBI admitted consecutively to the intensive care unit (ICU) participated in a multimodal battery assessing behavioral level of consciousness (Coma Recovery Scale-Revised [CRS-R]), cognitive motor dissociation (CMD; task-based EEG and fMRI), covert cortical processing (CCP; stimulus-based EEG and fMRI), and default mode network connectivity (DMN; resting-state fMRI). The primary outcome was 6-month Disability Rating Scale (DRS) total scores. ResultsWe enrolled 55 patients with acute severe TBI. Six-month outcome was available in 45 (45.2{+/-}20.7 years old, 70% male), of whom 10 died, all due to withdrawal of life-sustaining treatment (WLST). Behavioral level of consciousness and presence of command-following in the ICU were each associated with lower (i.e., better) DRS scores (p=0.003, p=0.011). EEG and fMRI biomarkers did not strengthen this relationship, but higher DMN connectivity was associated with better recovery on multiple secondary outcome measures. In a subsample of participants without command-following on the CRS-R, CMD (EEG:18%; fMRI:33%) and CCP (EEG:91%; fMRI:79%) were not associated with outcome, an unexpected result that may reflect the high rate of WLST. However, higher DMN connectivity was associated with lower DRS scores ({rho}[95%CI]=-0.41[-0.707, -0.027]; p=0.046) in this group. InterpretationStandardized behavioral assessment in the ICU may improve prediction of recovery from severe TBI. Further research is required to determine whether integrating behavioral, EEG, and fMRI biomarkers of consciousness is more predictive than behavioral assessment alone.

Traumatic Brain Injury (TBI) patients may suffer from a number of long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here we investigate the effect of exercise on pain outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies employed the administration of noradrenergic (NA) and serotoninergic receptor blockers. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of the acute phase of pain from [~]5 weeks to 2-3 weeks in female and male TBI rats respectively, gains that could be reversed using the 1-adrenoceptor (1AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT7 receptor antagonist, SB-267790, the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Therefore, the transition from a noradrenergic to a serotonergic inhibitory pain pathway that we typically see in male TBI rats, was blocked by exercise. Assessment of neuropathology, acutely after TBI, reveals that both the astrocyte and microglial response to injury is significantly greater in male TBI compared to female TBI, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. In contrast, exercise significantly decreased the amount of axonal loss in the corpus callosum in both male and female TBI rats compared to sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups respectively. These results demonstrate that exercise is a promising treatment for chronic pain after TBI in both male and females. It also highlights that dysfunction of the endogenous pain modulatory pathways observed in male rats after TBI can be prevented by exercise, possibly by reducing axonal loss.

The absence of effective pharmacological interventions in acute traumatic spinal cord injury is a major problem in its management. A critical barrier in identifying such interventions lies in the vast heterogeneity of recovery profiles, which masks the potential efficacy of treatments in clinical trials. To determine the impact of temporal recovery profiles on long-term functional independence, we used EMSCI (European Multicenter Study about Spinal Cord Injury) data. Total motor scores from the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) and the Spinal Cord Independence Measure (SCIM) were used to assess neurological and functional outcomes, respectively. We developed a classification method consisting of thresholding and unsupervised machine learning clustering and applied it to the total motor score profiles. Comparing SCIM scores between classes revealed that functional independence is significantly higher among patients displaying advanced neurological recovery profile. Our study suggests that the evaluation of temporal recovery profiles can provide novel insights in spinal cord injury clinical trials.

BackgroundConcussion is a public health crisis, but mounting evidence indicates that repetitive subconcussive head impacts can also lead to lasting structural and functional brain changes. Subconcussive exposures are common in military environments where personnel are routinely subjected to occupational blast overpressure. While functional consequences of blast exposure are increasingly recognized, corresponding structural alterations remain less consistently reported. Here, we investigated how cumulative subconcussive exposure relates to cortical and subcortical brain structure in a military cohort. MethodsUsing FreeSurfer, we analyzed high-resolution T1-weighted images from 80 participants (n = 41 high blast, n = 39 low blast; 4 and 8 females, respectively), grouped by lifetime blast exposure history using the generalized blast exposure value. Vertex-wise general linear models tested for cortical differences in cortical volume, thickness, surface area, and curvature, adjusting for age, trauma exposure, and diagnosed concussion count. ANCOVAs evaluated subcortical volume differences. ResultsCompared to the low blast group, individuals with high blast exposure demonstrated widespread cortical alterations. Across metrics, higher values were predominantly observed in frontal and central regions, including the precentral and superior frontal gyri, whereas lower metrics mainly appeared in temporal, parietal, and occipital cortices. Specifically, high blast participants showed greater cortical volume, thickness, and surface area in precentral and superior frontal regions, higher curvature in frontoparietal and temporal areas, and reduced volume, surface area, and thickness in lateral temporal, parietal, and occipital cortices (e.g., supramarginal, inferior parietal, and lingual gyri) and the entorhinal cortex. Subcortically, high blast participants showed no volumetric differences from the low blast group. ConclusionThese findings provide evidence that repetitive subconcussive blast exposure alters cortical morphometry, independent of concussion history, suggesting complex, spatially heterogenous structural changes and highlighting the need for proactive monitoring and mitigation strategies in operational populations.