Journal of Neurotrauma

Importance There is an urgent need for objective blood tests to guide triage of suspected traumatic brain injury (TBI) in far-forward combat environments, where blast exposure is common and neuroimaging is frequently unavailable. Blood-based glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) are transforming triage of suspected TBI due to their 99% negative predictive value for ruling out acute intracranial trauma in civilian impact TBI. However, accuracy in military blast-dominant TBI is unclear. Objective To determine accuracy of day-of-injury serum or plasma GFAP and UCH-L1 levels for ruling-out acute intracranial trauma in a sequential real-world cohort of combat casualties. Design Retrospective cohort study leveraging existing data from a clinical laboratory validation protocol that processed and stored leftover day-of-injury clinical samples from evacuated combat casualties between January 1, 2024, and February 6, 2025 for subsequent analysis for GFAP and UCH-L1 using FDA-cleared assay thresholds. Setting Single-center, tertiary referral trauma center. Participants Day-of-injury plasma or serum GFAP and UCH-L1 levels were available for 137 combat casualties. The cohort was 99.3% male with a median age of 21.8 years; 75.2% sustained blast-related injuries. Most (92.7%) had blood collected within 6 hours of injury. Exposure Serum or plasma GFAP and UCH-L1 measured with Abbott Alinity-i or i-STAT TBI assays. Elevation was defined as GFAP [≥]35 pg/mL or UCH-L1 [≥]400 pg/mL on Alinity-i, and GFAP [≥]30 pg/mL or UCH-L1 [≥]360 pg/mL on i-STAT. Main Outcomes and Measures Accuracy of biomarker elevation for ruling-out intracranial trauma on head CT, including sensitivity, specificity, and negative predictive value (NPV). Results Among 137 casualties, 83 (60.6%) were biomarker-elevated. Sixteen participants (11.7%) had CT-confirmed intracranial trauma, of whom 15 were biomarker-elevated, yielding 93.8% sensitivity and 98.2% NPV, and 43.8% specificity. Twenty-three participants (16.8%) had intracranial trauma and/or head/face/c-spine fracture; 21 were biomarker-elevated, corresponding to 91.3% sensitivity, 96.3% NPV, and 45.6% specificity. Conclusions and Relevance In this real-world cohort of blast-dominant combat casualties, day-of-injury GFAP and UCH-L1 demonstrated high NPV and sensitivity for intracranial trauma, with modest specificity. These findings support the utility of GFAP and UCH-L1 to aid early triage and decision-making in blast-dominant military TBI.

Collision and contact sport athletes are repeatedly exposed to subconcussive head impacts or subclinical head acceleration events (HAEs), which are impacts that do not result in a clinical diagnosis of mild traumatic brain injury but may induce subtle neurological alterations. These effects may include structural, functional, and metabolic changes within the brain. Various exposure quantification techniques have been developed to characterise HAE exposure, while diffusion MRI enables assessment of brain microstructural organisation, with changes in diffusion-derived metrics associated with pathophysiological processes. This systematic review was conducted in accordance with PRISMA guidelines to evaluate the use of various HAE exposure quantification techniques, exposure weighting approaches, and diffusion MRI in characterising the relationship between HAE exposure and brain microstructure in athletes. Across studies, longitudinal findings for fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) were inconsistent, and substantial heterogeneity in exposure quantification methods and analyses was observed. However, quantitative analysis demonstrated a significant negative association between total subclinical HAE count across the season and FA, and a positive association with MD, suggesting cumulative microstructural alteration. Exposure metrics, including risk-weighted, time-weighted, and finite-element-derived strain measures, showed stronger associations with diffusion MRI alterations than simple impact counts or peak acceleration measures. However, HAE exposure risk models are sport-specific and require broader validation for applicability across sporting cohorts. Future studies should reduce methodological heterogeneity, control for confounding variables, and refine exposure quantification and weighting approaches to better understand the relationship between repetitive subclinical HAE exposure and WM microstructural integrity.

Rehabilitation is the cornerstone of clinical care following spinal cord injury (SCI) and is frequently incorporated into preclinical studies to evaluate emerging therapies. However, the variables that influence the effectiveness of rehabilitation interventions in rodent models remain poorly characterized, limiting the translational value of preclinical research. Here, we performed a meta-analysis of 150 preclinical studies comprising more than 3000 rodents and 292 effect sizes to identify such factors associated with successful rehabilitation after SCI. Rehabilitation improved functional outcomes across multiple behavioral domains, with larger effects observed in thoracic than cervical injury models. Meta-regression identified environmental enrichment as the most effective strategy, particularly when combined with task-specific training. Longer rehabilitation duration was associated with improved recovery, whereas greater daily exposure to forced rehabilitation was associated with smaller gains. In contrast, prolonged access to voluntary rehabilitation did not show this relationship. Rehabilitation improved outcomes when initiated at all time points after injury, with greater benefits when initiated during the late subacute and intermediate phases. Rehabilitation approaches associated with higher stress burden produced reduced benefits, suggesting that stress may limit rehabilitation-induced recovery. Collectively, these findings identify rehabilitation type, duration, and delivery context as important determinants of recovery after SCI and support a broad therapeutic window for intervention. Our results favor low-stress, voluntary rehabilitation strategies that promote sustained engagement and provide principles for designing effective and biologically appropriate rehabilitation strategies, potentially improving translational success for emerging SCI therapies. One Sentence SummarySustained voluntary rehabilitation promotes functional recovery across stages of experimental spinal cord injury, whereas prolonged forced training may reduce its benefits.

BACKGROUND Traditional organ dysfunction classifications after severe trauma rely on binary categories (e.g., chronic critical illness [CCI] versus rapid recovery), which likely oversimplify the true heterogeneity of postinjury organ dysfunction trajectories and their underlying immune-biologic drivers. We hypothesized that severely injured trauma patients demonstrate multiple, distinct organ dysfunction phenotypes distinguished by unique immune signatures. METHODS We performed a prospective, longitudinal, observational cohort study of severely injured trauma patients at high risk for multiple organ dysfunction at a single Level 1 trauma center. Organ dysfunction was quantified daily through 28 days, death, or discharge using a trauma-specific modified Sequential Organ Failure Assessment (mSOFA) score excluding the neurologic subdomain to isolate systemic organ dysfunction from traumatic brain injury. We utilized group-based trajectory modeling to identify longitudinal mSOFA phenotypes. Plasma immune protein trajectories were compared across phenotypes using mixed-effects models with time interaction. RESULTS Sixty-nine patients were enrolled. Trajectory modeling identified five mSOFA phenotypes (c1-c5) with differences in resuscitation requirements, shock severity, and 28-day mortality, but not baseline demographics, injury severity, or early physiologic parameters. The phenotypes revealed organ dysfunction heterogeneity not fully captured by CCI/rapid recovery classification. Forty of 92 measured immune markers showed phenotype-differentiated trajectories (FDR<0.1). The most fulminant phenotype (c5) was distinguished by IL-17C, CXCL5, and CXCL6, implicating epithelial-barrier and neutrophil-trafficking mechanisms. The phenotype with highest CCI incidence (c3) was distinguished by rising CXCL9, ARTN, and TWEAK, implicating Th1 polarization and tissue-inflammation/repair signaling. The clinically distinct, older-age phenotype (c4) carried the largest differentiating signature (29 proteins), spanning renal injury/repair, endothelial activation, and adaptive lymphocyte modulation. CONCLUSIONS Organ dysfunction after severe trauma is more biologically heterogeneous than traditional clinical classifications suggest. Distinct mSOFA trajectory phenotypes correspond to distinct immune signatures, supporting separable pathobiology rather than a single axis of injury severity, with implications for phenotype-targeted precision immunomodulatory approaches in critical illness.

Spinal cord injury (SCI) is an incurable neurological condition in which post-traumatic edema contributes to secondary ischemic damage because the spinal cord is confined within the rigid vertebral canal. However, glymphatic transport in the healthy and injured spinal cord remains poorly characterized. We hypothesized that spinal cerebrospinal (CSF) and glymphatic transport is shaped by anatomy, administration route, and molecular size of the tracer; is disrupted after SCI; and is further impaired by loss of aquaporin-4 (AQP4). CSF tracers were administered by cisterna magna or lumbar intrathecal injection to anesthetized adult C57BL/6 mice. Dynamic contrast-enhanced MRI, ex vivo fluorescence imaging, and histology were used to characterize tracer distribution, influx, and clearance. Constrictions of the spinal subarachnoid space at C3-C7, T6-T12 and L5-S1 spinal segments accelerated contrast-agent dispersion, demonstrating that local anatomy regulates spinal CSF transport. Tracer influx into the cord itself occurred primarily along periarterial pathways.Tracer distribution depended on the administration route: cisterna magna injection preferentially labeled white matter in the upper spinal cord, whereas lumbar injection preferentially labeled grey matter in the lower spinal cord. Gadobutrol and ovalbumin penetrated and dispersed throughout the parenchyma, whereas fibrinogen remained confined to the meninges. Under physiological conditions, intraparenchymal tracers cleared within 24 h. SCI was modeled using a minimally invasive NMDA-induced lesion at T11 that produced focal necrosis while preserving the dura and vertebral structures. Glymphatic transport, lesion volume, and motor recovery were compared between wild-type and AQP4-knockout mice using imaging, the Basso Mouse Scale, and voluntary wheel running. After SCI, intrathecal contrast propagated more rapidly, especially at T7-T8 segments and at the S1 segment, but tissue clearance was profoundly impaired, with tracer retention persisting for up to seven days. AQP4-knockout mice showed greater clearance impairment, larger lesions, and poorer motor recovery than wild-type controls compared at 24 h. These findings define major determinants of spinal glymphatic transport and show that accelerated tracer propagation after SCI does not indicate effective clearance. Instead, SCI produces glymphatic dysfunction that is exacerbated by loss of AQP4 and associated with greater tissue damage and functional impairment. The results extend the glymphatic framework to the spinal cord and identify fluid-clearance pathways as potential therapeutic targets for limiting edema and secondary injury. Future studies should determine whether restoring glymphatic function improves neurological recovery after SCI.

BACKGROUND: One in three adolescents with a concussion history report experiencing long-lasting somatic, sleep, emotional, and/or cognitive disturbances (persisting symptoms after concussion (PSaC)). Cognitive difficulties, such as attentional problems, are common symptoms and can interfere with ongoing development. Clinically, psychiatric symptoms also present in youth with PSaC. A concussion causes diffuse functional and microstructural alterations to neural networks. To develop targeted treatments for PSaC (e.g., neurostimulation), we need to understand how and where structural alterations and neural dysfunction intersect to cause long-lasting symptoms. OBJECTIVES: 1) Identify functional and microstructural properties in intrinsic connectivity networks, as well as neuropsychological outcomes, that differentiate adolescents with concussion with PSaC from those who do not have PSaC. 2) Determine whether neural activity within intrinsic connectivity networks mediates the relationship between network microstructure and specific neuropsychological features in adolescents with concussion. METHODS: CAMBY is a prospective study of adolescents aged 12 to 18 years with a history of concussion. Participants are allocated based on recovery status (PSaC vs. No-PSaC (recovered controls)). Advanced structural (magnetic resonance imaging; MRI) and functional (magnetoencephalography; MEG) neuroimaging and neuropsychological measures will be collected one month or more after concussion. Microstructural and functional features will be computed within intrinsic connectivity networks, then compared between PSaC and recovered control groups and related to symptom domains and neuropsychological profiles. IMPACT: This will be the first study to integrate MRI, MEG, and neuropsychology in adolescents with PSaC to identify disrupted networks underlying PSaC. This observational study is a necessary step towards future clinical trials that accurately target promising therapeutic neurostimulation protocols.

Importance: Brain MRIs are routinely acquired following moderate or severe traumatic brain injury (TBI) because of their high sensitivity for detecting traumatic brain lesions. However, there is no standard framework for their interpretation, and their clinical utility is unproven. Objective: Here, we test whether MRI-based quantification of traumatic brain lesions improves outcome prediction relative to the best tools currently available to clinicians. Design, Setting and Participants: We analyzed hemorrhagic contusions and axonal injury in four prospective studies of moderate or severe TBI, validating results in a fifth held-out dataset. Exposure: Contusion volume was measured via manual segmentation. Axonal injury volume was quantified with diffusion tensor imaging, by measuring the volume of skeletonized fractional anisotropy significantly lower than that of healthy controls. Main Outcomes and Measures: Functional outcomes were assessed at 6 months with the Glasgow Outcome Scale-Extended; values [&le;] 4 were considered unfavorable. Results: Among 201 patients with MRI (mean age: 41, median Glasgow Coma Scale (GCS) score on admission: 7, MRI obtained median 14 days post-injury), MRI-measured contusion volume discriminated outcomes better than CT Marshall score (AUC 0.81 vs 0.64; p=0.001), and remained associated with unfavorable outcomes controlling for multiple commonly-measured clinical variables. Quantitative axonal injury volume discriminated outcomes better than manual MRI grading (AUC 0.82 vs 0.62; p<0.001) and remained associated with unfavorable outcomes independent of other clinical predictors. The prognostic discrimination of traumatic lesion volumes was not improved by accounting for the location or normative connectivity of either lesion type. In a multivariate model, contusion and axonal injury volumes were independently predictive, with age-dependent volume thresholds for 90% probability of unfavorable outcome, and strong discrimination in an external cohort (N=27; AUC 0.83, p<0.001). Replacing all CT-based measures with MRI lesion volumes in the IMPACT model significantly improved out-of-sample prognostic performance (AUC 0.85 vs 0.64; p<0.05). Conclusions and Relevance: MRI-based lesion quantification improves prognostic discrimination relative to measures currently available to clinicians treating patients with TBI. Global functioning at 6-months is driven more by the volume than the location or connectivity of traumatic lesions. These findings support integrating MRI-based lesion quantification into clinical workflows and updated TBI classification frameworks.

More than a third of women in the United States are estimated to experience abuse from an intimate partner, in which blows to the head, strangulation, and therefore brain injuries are common. Among 207 survivors of such physical violence, two-thirds reported a partner-inflicted brain injury. These women performed substantially worse than the general population across most cognitive measures, including memory and reaction time. Cognitive performance declined as injury count increased. Translated into cognitive age, survivors with the most partner-inflicted brain injuries performed over two decades older than the general population, and a decade older than survivors with no history of brain injury. Importantly, the cognitive assessment discards scores it judges unreliable, yet these came primarily from the most impaired women, suggesting that the true harm is likely greater than reported here. Such cognitive deficits may limit these women's capacity to live to their potential, including keeping safe from abuse. These findings underscore partner-inflicted brain injury as a major, under-recognized source of cognitive harm, potentially affecting more women than brain injury in professional football or the military while lacking comparable clinical recognition and care.

Sex differences in mortality after traumatic brain injury (TBI) have been inconsistently reported, even after accounting for age, injury severity, and other injury related factors. Understanding the sources of this heterogeneity is important for prognostic research and the development of data-driven clinical decision-support tools. We conducted a systematic review and meta-analysis of sex-specific mortality after adult TBI and used explainable machine learning (ML) to investigate potential modifiers of between-study effect estimates. We searched eight databases from inception to August 25, 2025, for studies reporting mortality estimates adjusted for at least age and injury severity. Risk of bias was assessed using the Quality in Prognosis Studies tool. Male-to-female mortality estimates were pooled using random-effects meta-analysis. Three explainable ML algorithms were used to identify important modifiers of study-level effect estimates. Among 9,418 records identified, 21 studies comprising 899,813 participants and 98,286 deaths met the inclusion criteria. Pooled analyses showed lower mortality among females than males (OR 0.88, 95% CI 0.80-0.98; HR 0.76, 95% CI 0.59-0.98). Lower mortality among females was also observed for in-hospital mortality (OR 0.86, 95% CI 0.76-0.97) and overall or unspecified mortality (OR 0.83, 95% CI 0.78-0.88). Substantial residual heterogeneity remained across analyses. Explainable ML identified mean age, study sex composition, and study quality as important modifiers of reported effect estimates. These findings were consistent across sensitivity analyses. Female sex was associated with lower mortality after adult TBI, although substantial between-study heterogeneity remained. Explainable ML identified demographic and methodological factors that may contribute to variation in reported associations. These findings highlight the importance of population characteristics and study context when developing, validating, and interpreting explainable digital prognostic tools for TBI. PROSPERO: CRD420251252136.

Background: Head acceleration events (HAEs) are common in contact sports, but season-long exposure and its relationship with cognitive performance in amateur British American football remain poorly characterised. Methods: Thirty male players were recruited from three British American football teams. Cognitive performance was assessed pre-season, mid-season, and post-season using the Sport Concussion Assessment Tool 6 and computerised Stroop, 2-back, Go/No-go, and visual-search tasks. Seasonal cognitive analyses included 23 participants with available data. HAEs were quantified using helmet-mounted accelerometers; exposure-linked analyses were restricted to 19 participants who provided sufficiently complete sensor recordings across contact training sessions and competitive matches. Seasonal cognitive changes were assessed using mixed-effects models. Associations of in-season HAE metrics and previous contact-sport seasons with global cognitive change were examined using simple linear regression and elastic-net regression. Results: In the 19-participant exposure-linked cohort, prior contact-sport exposure showed the strongest nominal univariate association with worse global cognitive change (r squared = 0.337, p = 0.009), although this did not remain significant after correction for multiple comparisons (Benjamini-Hochberg-adjusted p = 0.055). Corrected nested cross-validation indicated little out-of-sample performance for the multivariable elastic-net model (r = 0.144, predictive R squared = -0.008). Although previous contact-sport seasons had the largest standardised coefficient in the final full-cohort fit, predictor retention varied substantially across resamples. Conclusion: Prior contact-sport exposure showed the strongest exploratory association with relatively worse global cognitive change, whereas in-season HAE metrics showed weaker associations. However, the multivariable model did not demonstrate useful out-of-sample predictive performance, and the small exposure-linked cohort precludes firm conclusions regarding the relative importance of individual predictors.

Background: Depression symptoms following traumatic brain injury (TBI) are common and strongly associated with adverse overall outcomes in military service members, veterans, and civilians. Cognitive behavioral therapy for depression (CBT-D) is considered a first-line treatment for depression symptoms in many contexts. However, costs associated with CBT-D can be substantial, and there are insufficient numbers of providers trained to perform CBT-D. In contradistinction, digital therapeutic interventions such as smartphone apps have virtually unlimited availability and low per-patient costs. However, evidence for efficacy of digital interventions providing CBT-D in the context of TBI is limited. The aims of this study were to design, develop, and test a novel smartphone app to provide CBT-D intended for military service members with depression symptoms and history of mild TBI. Results: We designed a novel smartphone app featuring digital avatar coaches to provide CBT-D intended for military service members with depression symptoms and history of mild TBI. Key features and goals of the 12 weekly CBT lessons included stigma minimization, personal engagement, and 1-2 hours per week of personal challenge homework assignments. We performed a randomized controlled trial initially involving military service members and veterans. Inclusion criteria were later relaxed to allow for civilian participation due to practical constraints . The control group received an app providing educational lessons about concussions and depression which did not include the therapeutic components of CBT. There was no difference between the groups randomized to CBT-D (n=19) vs. educational app control (n=23) in self-reported depression symptoms. Nevertheless, there was a statistically significant benefit of the CBT-D intervention in self-reported insomnia severity at the 16-week follow-up (four weeks post intervention) assessment (Cohens D=0.45, p=0.0064). There were also statistically significant positive correlations (r= 0.46 to 0.76, p=0.046 to 0.001) between changes over time in depression symptoms and changes over time in both insomnia and PTSD symptoms in the CBT-D group. There were no such correlations in the control group. Participants reported higher therapeutic alliance (p=0.0001) and overall mobile application user rating (p=0.036) for the CBT-D app than for the control education app. More favorable therapeutic alliance and mobile application user ratings correlated significantly with greater improvements in depression symptoms in the CBT-D group (r=0.53 to 0.66, p=0.02 to 0.002). However, dropout was substantial (40/59 in the CBT-D group and 31/54 in the control group) and results may not be fully representative of the population at risk. Conclusions: There remains a major unmet need for widely available, low-cost, effective interventions for depression symptoms in the context of mild TBI. The challenges of designing and rigorously assessing the effects such interventions remain formidable. However, the lessons learned from this study and indications of benefit in a highly relevant secondary outcome measure (insomnia) suggest that remote app-based interventions remain therapeutically viable. Trial Registration: clinicaltrials.gov NCT05147506, submitted 20 July 2021, posted 7 December 2021.

Chronic pain is frequently accompanied by anxiety and other affective disturbances, but the molecular and cellular changes linking peripheral injury to persistent alterations in brain function remain incompletely defined. The hippocampal extracellular matrix (ECM) regulates synaptic plasticity, cellular signaling, and neuroimmune interactions and may therefore contribute to pain-related central plasticity. We used a tibial fracture/cast immobilization model to examine temporal changes in hippocampal ECM, glial morphology, and affective behavior following peripheral injury. Behavioral testing was performed at 3, 7, and 20 weeks after injury, while high-dimensional morphometric analysis of microglia and astrocytes was performed at 1, 3, 7, and 20 weeks. Hippocampal ECM associated molecular signals were mapped at the chronic stage using decellularization coupled with MALDI-TOF mass spectrometry imaging. Injured mice developed mechanical hypersensitivity and reduced exploration in two anxiety related paradigms during the early and chronic stages, with these behavioral phenotypes no longer detected at 20 weeks. At 7 weeks, injury was associated with changes in hippocampal ECM-associated peptide signals, including reduced signals corresponding to four ECM-associated proteins. Microglia and astrocytes exhibited distinct, time-dependent changes in density and multidimensional morphology, with some alterations persisting after behavioral measures returned toward control levels. In vitro, BV2 microglia exhibited rigidity-dependent changes in morphology, phagocytic behavior, and calcium signaling. Together, these findings define a temporally evolving hippocampal ECM and glial phenotype following peripheral injury and identify matrix biomechanics as a candidate regulator of microglial function.

The validation of objective neurophysiological monitoring of concussion from diagnosis to return to play has the potential to improve the clinical care of athletes. Extracted from event-related potentials (ERP), brain vital signs offer a non-invasive objective neurophysiological measure of three well established ERP responses that complement existing clinical assessments: 1) the N100 response related to auditory sensation; 2) the P300 response related to basic attention; and 3) the N400 response related to cognitive processing. The N400, in particular, has increasingly been demonstrated to be sensitive to head impact related cognitive impairment. Accordingly, brain vital sign measures were collected in n =165 rugby league players from two Australian professional National Rugby League clubs (NRL), with concussed players (n =26) being subsequently assessed over a total of five separate time points (Baseline, Day 2, Day 5, Day 10, and Day 42). This timeline aligned with acute (Day 2), NRL mandatory minimum return-to-play (RTP) guidelines (Day 10), and an extended post RTP period. Relative to baseline, the results revealed significant N400 cognitive processing latency delays at Day 2 post-concussion (p =0.002). The N400 latency delays persisted past day 5, significantly returning to baseline values at Day 10, consistent with the RTP mandatory minimum requirement. The findings indicated that neurophysiological recovery occurred in this cohort within an approximate 10-day time frame. Future studies monitoring brain vital sign changes across the trajectory of injury to recovery are needed in sports related concussion management.

Background and Purpose: Neonatal hypoxia-ischemia (NHI) is a leading cause of mortality and long-term neurodevelopmental disability. Therapeutic hypothermia (TH) is currently the only established treatment for NHI; however, its efficacy remains limited, underscoring the need for adjunctive neuroprotective strategies. Lactate is now regarded as a major metabolic substrate of the brain and has previously been shown to exert neuroprotective effects following experimental NHI. We investigated whether lactate enhances hypothermia-induced neuroprotection and evaluated the optimal timing of administration and potential underlying mechanisms. Methods: Postnatal day 7 Wistar rats were subjected to NHI using the Rice-Vannucci model and treated with TH alone (2h at 32{degrees}C), sodium L-lactate alone, or combined L-lactate-TH. Animals underwent longitudinal magnetic resonance imaging (MRI) and behavioral assessments, complemented by histological, immunohistochemical, and Western blot analyses, including assessment of protein lactylation. The effect of sodium L-lactate administration timing relative to TH was also evaluated. Results: Lactate significantly enhanced the neuroprotective effects of TH, particularly when administered before hypothermia, resulting in greater lesion recovery, reduced neuroinflammation and apoptotic cell death, preserved neuronal integrity, and improved long-term motor and cognitive outcomes. Combined treatment preserved neuronal lactate transporter, prevented NHI-induced astrocytic glutamate transporter upregulation, modulated lactylation markers, supporting coordinated metabolic and epigenetic adaptations following NHI. Conclusions: Early lactate administration enhances the neuroprotective efficacy of TH following NHI. These findings identify lactate as a promising adjunct to TH and support its translational potential as a metabolic strategy to improve outcomes following NHI brain injury.

Functional recovery after spinal cord injury depends on whether reorganizing descending circuits form adaptive, task-specific relays rather than maladaptive ones. The corticospinal tract undergoes competitive, activity-dependent refinement during a defined juvenile window, so the timing and polarity of cortical activity may dictate whether injured circuits rewire usefully. Whether biasing cortical activity during this window can steer reorganization toward recovery, and whether naturalistic rehabilitation supplies the activity such steering requires, remain unknown. In juvenile rats we delivered excitatory or inhibitory chemogenetic receptors, or a control vector, to the forelimb motor cortex at postnatal day 5, induced a right cervical hemisection at postnatal day 14, and gave oral clozapine-N-oxide during nightly rough-and-tumble play from postnatal day 20 to 50. Play, the rehabilitation common to all groups, did not differ between them, isolating cortical-activity polarity as the manipulated variable. Outcomes spanned forelimb dexterity, reaching kinematics, cortical output by intracortical microstimulation, descending architecture by intersectional viral tracing, and frequency-dependent depression of the Hoffmann reflex. In untreated injured animals, cortical output re-lateralized maladaptively toward the intact forelimb, driving the ipsilateral (intact) limb in 11 of 15 evoked responses and 3 of 5 animals. Excitation preserved selective drive to the impaired forelimb (38 of 39 responses; concordant-site proportion Kruskal-Wallis H = 9.08, exact P = 0.0031), and pure ipsilateral re-lateralization was absent from all nine treated animals (3 of 5 control versus 0 of 9 treated; Fisher's exact P = 0.027). Across behavioural, kinematic, and anatomical measures a consistent excitatory > control > inhibitory gradient emerged. Excitation enhanced wrist elevation and forward extension during reaching, restored frequency-dependent depression of the Hoffmann reflex, and selectively recruited three parallel lesion-bypassing relays: interhemispheric cortico-cortical-spinal, cortico-reticulo-spinal, and cortico-propriospinal (ipsilesional cortical relay neurons F(2,14) = 56.96, P < 0.0001). Inhibition yielded the weakest behavioural recovery and least relay recruitment, and did not restore contralesional cortical drive. Cortical-activity polarity during a juvenile window thus acts as a developmental switch governing whether descending reorganization is adaptive or maladaptive. Guided excitation, paired with behaviourally meaningful activity, reshapes diffuse sprouting into structured, lesion-bypassing relays and corrects the spontaneous re-lateralization that otherwise misdirects recovery. These findings provide a translational rationale for activity-paired neuromodulation in paediatric spinal cord injury.

Focal lesions are common after complicated mild-to-severe traumatic brain injury (cmsTBI) in children, yet it is unclear whether the location of focal damage relates to cognitive outcome beyond overall lesion burden. Combining 13 international cohorts through the ENIGMA Pediatric cmsTBI working group, we conducted voxelwise lesion-symptom mapping (VLSM) to test whether focal lesion location relates to cognitive outcome, and how this compares with overall lesion volume. From 357 patients with imaging that passed quality assurance, 67 had a focal lesion visible on T1-weighted MRI along with at least one performance-based cognitive outcome (D-KEFS Trail Making conditions and WISC/WAIS Coding). We tested whether lesion location related to cognitive outcome using VLSM, adjusting for age, sex, and time since injury, and separately tested total lesion volume as a predictor of each outcome. Lesions in the right middle frontal gyrus were associated with poorer performance on number sequencing (D-KEFS Trail Making condition 2), a timed visuomotor sequencing task (false discovery rate corrected). In separate regression analyses, greater lesion volume was associated with poorer number-letter switching and motor speed. The switching association remained significant after adjusting for injury severity, whereas the motor-speed association did not. In the largest lesion sample assembled in pediatric cmsTBI to date, focal lesion location and injury burden index separable contributions to cognitive outcome, with number sequencing linked to focal prefrontal damage and switching and motor speed to overall lesion volume, underscoring the value of precise lesion characterization for large-scale multi-site neuroimaging.

Objective To estimate the mortality proportion among patients with severe traumatic brain injury (sTBI) and to assess variation in mortality according to geographical region, study characteristics, patient populations, and mortality assessment time points. Design Systematic review and meta-analysis. Data sources PubMed/MEDLINE, Embase, Scopus, Web of Science, Google Scholar, and Cochrane Library were searched from database inception to January 2026. Eligibility criteria Studies reporting mortality among patients with severe TBI were eligible. Severe TBI was defined as a Glasgow Coma Scale (GCS) score of [&le;]8, equivalent to GCS <9 or GCS 3-8. Studies involving mixed TBI severity were included only when data for patients with severe TBI could be separately extracted. Data extraction and synthesis Two reviewers independently screened studies, extracted data, and assessed methodological quality. Mortality proportions were pooled using a random-effects model. Statistical heterogeneity was assessed using Cochran's Q and the I2 statistic. Subgroup and sensitivity analyses were undertaken where sufficient data were available. Results Twenty-five studies comprising 12,829 patients with severe TBI were included in the systematic review. Across studies, 5,550 deaths were reported. Mortality proportions ranged from 17.5% to 71.1%. The pooled mortality proportion was 40.6% (95% CI 35.7% to 45.7%), with substantial heterogeneity (I2=96.8%, p<0.001). Mortality varied considerably according to geographical region and timing of outcome assessment, with higher estimates generally observed in African settings and at longer follow-up periods. Conclusion Mortality among patients with severe TBI remains substantial, with approximately two in five patients dying across the included studies. However, the very high heterogeneity indicates that the pooled estimate should not be interpreted as a universal mortality risk. Differences in healthcare resources, patient characteristics, injury severity, management practices, and mortality assessment time points may contribute to the observed variation.

Structural differences observed in collision-sport athletes may reflect repetitive head-impact exposure, broader effects of athletic training, or pre-existing individual variation, making inclusion of a non-collision athlete group important for interpretation of any differences seen. Here, structural T1-weighted MRI data from 17 collegiate American football players, 16 cross-country runners, and 9 non-athletes were analyzed using FSL voxel-based morphometry (VBM), FIRST subcortical volumetry and vertex-wise shape analysis, and FAST whole-brain tissue segmentation. Spatial inference used permutation testing with threshold-free cluster enhancement and family-wise error correction, while scalar analyses used multiplicity-corrected procedures. FAST-derived absolute tissue volumes were also examined in a sensitivity analysis adjusting for FreeSurfer estimated total intracranial volume (eTIV). VBM showed recurrent brainstem-centered differences, with non-athletes showing greater local gray matter measures than both athlete groups, whereas football players showed greater brainstem measures than runners. FIRST vertex-wise analysis identified corrected differences involving the brainstem and selected subcortical structures, while no total FIRST structure volume survived false discovery rate correction. Unadjusted FAST analysis identified a CSF group effect, F(2, 24.38) = 11.46, p < .001, q = .001. After eTIV adjustment, the CSF group effect remained, F(2, 38) = 14.30, q < .001, and a white matter group effect was also identified, F(2, 38) = 9.59, q < .001; gray matter and total segmented tissue did not show corrected adjusted effects. These findings indicate that structural variation depends on anatomical scale, comparison group, and head-size adjustment and cannot be attributed uniquely to collision-sport exposure.

Background: Traumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings. Objective: We conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Methods: Paired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays. Results: Absolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone. Conclusions: These pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation, including outcome linkage and prospective evaluation, will be required before capillary DPS can be considered for clinical monitoring applications.

Tau is a microtubule-associated protein important for neuronal structure and function, with abnormal phosphorylation associated with neuronal dysfunction and degeneration. While tau pathology has been extensively studied in neurodegenerative diseases and traumatic brain injury, its role in spinal cord injury (SCI) remains unclear. This study investigates changes in the levels of tau isoforms and phosphorylation following a high lateral C2 hemisection (C2Hx) in adult female rats. Western blot analysis was performed on spinal cord tissue collected caudal to the lesion at 4 weeks post-injury. Low-molecular-weight (LMW) tau and high-molecular-weight, Big tau did not differ significantly between injured and control groups. In contrast, phosphorylated tau (p-tau), detected using the AT8 antibody, was significantly elevated after injury, suggesting a shift in tau functional state. Assessment of microtubule stability markers revealed increased acetylated tubulin and decreased tyrosinated tubulin after SCI, indicating a shift toward a more stable cytoskeletal state. Immunohistochemistry was performed on spinal cord sections at 6 weeks post-injury and dorsal root ganglia (DRG) at 8 weeks post-injury. These analyses demonstrated increased p-tau immunoreactivity within the ipsilateral dorsal horn of the injured spinal cord and a higher proportion of p-tau-positive neurons in DRGs from injured animals compared with controls. Together, these findings demonstrate that cervical SCI induces persistent tau phosphorylation without altering total tau levels, and that this modification extends beyond the lesion site into distal spinal regions and beyond the acute phase of injury. These alterations may influence neural plasticity and remodeling in the injured spinal cord.