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.

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.

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.

Acute traumatic spinal cord injury comprises a primary mechanical injury followed by a delayed secondary cellular injury cascade. No current monitoring modality directly detects ongoing cellular damage or its response to treatment. Essentially all spinal serotonin derives from descending raphe-spinal projections that travel alongside spinal motor and sensory pathways. Experimental spinal cord injury results in a robust release of serotonin into the surrounding interstitial tissue. We therefore asked whether cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), the stable metabolite of serotonin, tracks primary and secondary spinal cord injury in humans. In this prospective observational cohort study at a single level-one trauma center, cerebrospinal fluid was collected at 8-hour intervals for up to 5 days through indwelling lumbar drains from 11 participants with acute cervical or thoracic traumatic spinal cord injuries (American Spinal Injury Association Impairment Scale [AIS] grade A-C) and from 7 non-injured control participants. Cerebrospinal fluid 5-HIAA was quantified by high-performance liquid chromatography. Participants with acute traumatic spinal cord injury demonstrated a reproducible rise in cerebrospinal fluid 5-HIAA within 12 hours of injury that regressed toward control values. Two participants neurologically declined during the 5-day observation period, and in both a delayed secondary 5-HIAA elevation accompanied the decline; in one participant this elevation coincided with a documented episode of critical spinal cord hypoperfusion and resolved within 8 hours of its correction. Across the cohort, the 5 participants with a secondary 5-HIAA elevations above 400 nM more than 36 hours after index trauma were AIS A at 12 months regardless of initial injury severity, whereas all 6 participants without a secondary elevation in cerebrospinal fluid 5-HIAA levels were AIS C or better. In this small exploratory cohort, cerebrospinal fluid 5-HIAA was associated with the presence of acute traumatic spinal cord injury, with acute secondary neurological decline, and with long-term motor outcome. Unlike glial fibrillary acidic protein and neurofilament light chain, whose concentrations evolve over days to weeks, 5-HIAA rose and regresses within hours, a kinetic profile compatible with real-time detection of secondary injury and confirmation of treatment response. These findings are hypothesis-generating and require validation in larger, multicenter cohorts before clinical application.

Traumatic brain injury (TBI) is a leading cause of death and long-term disability in children, with many experiencing persistent symptoms even after mild TBIs. Exposure to adverse childhood experiences (ACEs) can have physiological effects that may alter how the brain responds to injury, yet the effects of ACEs on white matter injury and recovery processes remain unclear. This study examined whether a history of ACEs is associated with patterns of longitudinal change in white matter microstructure in children with mTBI. Ninety-six concussed adolescents (mean age=14.9 years, range =11.4-17.9, 51% female) from the CARE4Kids consortium completed the Pediatric ACEs and Related Life-Events Screener and underwent diffusion-weighted MRI at baseline (7-35 days after injury) and follow-up (2 months later). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI), and intracellular volume fraction (ICVF) were estimated using tract-based spatial statistics and harmonized across sites. Differences in the magnitude and direction of change in diffusion metrics over time were examined in 15 tracts of interest. Higher ACE exposure was associated with smaller absolute change in AD, MD, ODI, and ICVF across several white matter tracts, including the corpus callosum, internal and external capsules, corona radiata, and posterior thalamic radiation. Groups did not differ in the direction of white matter change for any tract-metric combination. These findings suggest that ACE exposure may blunt white matter reactivity to injury and/or reorganization during recovery processes.

Sport-related concussions (SRC) are heterogenous injuries that produce a variety of symptoms and recovery trajectories. This heterogenous nature and focus on group-level analyses in current literature may obscure individual level results that could better inform clinical SRC management. In a prospective case-control study, we used diffusion magnetic resonance imaging (dMRI) to quantify longitudinal, whole-brain microstructural white matter changes reflecting axonal injury and inflammation and structural network-level alterations following SRC in adolescent athletes. Differential tractography assessed individual white matter track changes from acute injury to clinical recovery on an individual level. Acutely after SRC, but not after recovery, concussed adolescents demonstrated increased (i) quantitative anisotropy, (ii) restricted diffusion imaging, and (iii) isotropy, indicating increased microstructural disruptions early after injury. At the network level, differences were seen not acutely but after clinical recovery: whole brain network structure was more similar with reduced capacity for information spread among the concussed adolescents compared with controls. At the individual level, consistent patterns of damaged white matter tracks persisted in the concussed males but not in the concussed females. These results indicate that adolescent athlete brains are impacted acutely at the microstructural level following SRC, but that macroscale network disruptions appear after microstructure damage resolution, and they can persist beyond clinical recovery. Sex differences in the brains microstructural response to SRC, highlight the need for future research to include individualized and sex-stratified analyses to guide targeted SRC management.

Footballers are routinely exposed to repeated non-concussive head impacts with (soccer) heading, the acute neurobiological consequences of which remain poorly characterised. Current evidence for acute changes in biofluid markers following heading is tempered by design limitations including inadequate impact exposure monitoring, uncontrolled confounders (e.g. exercise), the lack of a control group and heterogeneity in sampling times. This study attempts to address these limitations with a novel combination of serial sampling measuring biomarkers across five timepoints (pre and 0.5, 2, 4 and 24 h post heading), a within-subject, time-matched resting control condition and participant-level finite element modelling used for impact quantification. In a counter-balanced crossover design, twelve male football players aged 18-31 completed a heading session with 10 verified rotational headers delivered from a ball launcher at 10 m and a control condition. Impact kinematics were captured with instrumented mouthguards and modelled using the Edinburgh finite element head model (EdiFEHM). Additional monitoring measures included near point convergence (NPC) at each timepoint and the sport concussion assessment tool (SCAT6) at the pre, 0.5 and 24 h timepoints. The Quanterix Simoa N4PD Advantage Plus assay was used to quantify plasma concentration of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and brain-derived tau (BD-tau) measured for the first time in this context. GFAP and BD-tau showed significant main effects of time (both P < 0.005) but no effect of heading. UCH-L1 was excluded and NfL restricted to descriptive analysis as both fell near or below the minimum assay quantification level. NPC alongside SCAT6 symptom and cognitive scores remained unaffected by heading. Tissue strain modelling showed a mean peak MPS95 of 0.099 (range: 0.074-0.144) consistent with low magnitude non-concussive impact exposure across participants. These findings provide a methodological framework and anchor point for non-concussive impact research employing biofluid sampling while highlighting sensitivity limitations of current multiplex Simoa assays in certain biomarkers for healthy young-adult populations. Design elements including time-matched controls, serial sampling and individualised mechanical exposure outcomes are essential for characterising exposure and avoiding spurious findings. The study was preregistered with the ISRCTN registry (ISRCTN44241334).

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.

Objective We aimed to evaluate the performance of the recently updated Sequential Organ Failure Assessment Score-2 (SOFA-2) on organ dysfunction classification and prognostication compared to SOFA-1 in critically injured trauma patients. Methods Adult trauma patients admitted to critical care at four urban Major Trauma Centres between 2011 and 2024 were included. Daily organ dysfunction scoring was performed using SOFA-1 and SOFA-2 until death or discharge. The primary outcome was MODS, defined as SOFA score [&ge;]6. Results In 2162 severely injured patients (median Injury Severity Score 25 [IQR, 17-34]), SOFA-2 reduced the proportion of patients classified as having MODS compared with SOFA-1 (61.6% vs 68.5%, p<0.001). SOFA-2 scores on the first day after admission were lower than SOFA-1 (median 6 [IQR, 3-8] vs 7 [IQR, 4-10], p<0.001), driven predominantly by lower respiratory and cardiovascular scoring. Critical care mortality in trauma patients was increased in respiratory, cardiovascular and renal components of SOFA-2 at the higher ends of the scores, consistent with the aims of the SOFA-2 reclassification. A group of 159 severely injured patients (7.3%) classified as MODS by SOFA-1 were reclassified to no-MODS by SOFA-2. Despite this reclassification, these patients had substantially higher ICU mortality (7.5% vs 0.7%, p<0.01), greater ventilator and vasopressor requirements, and longer hospital stays than patients classified as no-MODS by both systems. Conclusions SOFA-2 reduces MODS prevalence in severely injured patients and changes organ dysfunction classification, with lower rates of severe respiratory and cardiovascular dysfunction. This represents an important update in trauma MODS measurement and has implications for future trauma trial design. However SOFA-2 reclassification generates a small cohort a small but clinically significant group with occult MODS that warrants further evaluation in severely injured trauma patients.

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.

Introduction Post-cardiac arrest brain injury (PCABI) patterns across patients are heterogeneous, and conventional clinical variables incompletely capture in vivo injury severity. Here, we evaluated whether anatomically resolved diffusion-weighted MRI (DWI) lesion patterns identify biologically distinct PCABI phenotypes. Methods We conducted a retrospective study of patients with PCABI who underwent brain MRI and intraparenchymal PbtO2; monitoring (n = 24). Ischemic lesion burden was quantified using an MNI atlas-based apparent diffusion coefficient pipeline with a voxel intensity threshold of <650 x 10-6 mm2/s and was summarized at whole-brain, hemispheric, tissue-class, and segment levels. Principal component analysis (PCA) and k-means clustering were used to identify MRI-derived injury patterns for downstream physiological analysis. Results Greater whole-brain lesion burden was associated with lower mean PbtO2 (r = -0.49, p = 0.014), with concurrent associations in the left hemisphere (r = -0.50, p = 0.012), right hemisphere (r = -0.48, p = 0.019), grey matter (r = -0.48, p = 0.018), and white matter (r = -0.49, p = 0.016). PCA identified a dominant lesion-pattern axis associated with PbtO2; (r = 0.48, p = 0.0169). K-means clustering in PC1-PC2 space identified three MRI-derived injury patterns with distinct regional signatures and progressively greater whole-brain lesion burden (p < 0.001). Discussion Greater MRI-defined lesion burden was associated with lower PbtO2 post-cardiac arrest. Anatomically resolved DWI/ADC lesion mapping identified three MRI-derived injury patterns that differed in cerebrovascular physiology, lesion patterning and whole-brain injury burden. Integrating quantitative MRI, intraparenchymal neuromonitoring, and blood biomarkers improved the characterization of the heterogeneity observed in PCABI patients.

Abstract Background: Traumatic brain injury (TBI) is a leading cause of mortality and long term neurological disability worldwide. Adult mammals have limited regenerative capacity following central nervous system (CNS) injury, but zebrafish have a remarkable regenerative potential, providing an opportunity to identify molecular mechanisms associated with successful CNS repair. Methods: We have integrated publicly available acute phase TBI transcriptomic datasets from human, mouse, rat, and zebrafish studies published up to April 2026. Differential expression data were combined using restricted maximum likelihood (REML) based random effects meta analysis to account for biological and technical heterogeneity. Following ortholog mapping, we compared conserved injury responses with transcriptional programmes preferentially enhanced in zebrafish. Results: The acute molecular response to TBI is largely conserved across vertebrate species with predominant activation of cell cycle regulation, chromosome segregation, and interferon-mediated immune signalling genes. A conserved injury-responsive gene set further highlighted enrichment of mitotic and JAK-STAT signalling. In contrast, 54 zebrafish-enhanced genes displayed preferential activation of wound healing, extracellular matrix remodelling, integrin mediated signalling, and regulated immune responses. Protein protein interaction analysis identified STAT1, STAT3, FN1, CD44, ANXA2, and AXL as central hub genes connecting these injury and repair associated responses. Conclusions: Our study suggest that successful CNS regeneration is not driven by unique injury pathways but rather by coordinated modulation of conserved injury responses and additional molecular programmes that promote tissue remodelling and repair. These regeneration associated networks provide potential targets for future functional studies and may contribute to the development of regenerative therapeutic strategies for traumatic brain injury.

Spinal cord injuries (SCI) are traumatic lesions of the spinal cord that commonly result from physical trauma. They can lead to severe and permanent impairments in motor, sensory, and/or autonomic functions, often resulting in paraplegia or tetraplegia. Despite advances in this field, effective restorative treatments for SCI remain limited. Over the past few years, several therapeutic strategies have been investigated to promote functional recovery after SCI, including neuromodulation approaches. Repetitive magnetic stimulation has emerged as a promising non-invasive strategy, with encouraging results when the stimulation is applied directly over the spinal cord. However, most studies have focused on high-intensity stimulation, while the key parameters underlying its therapeutic efficacy remain poorly understood. In this study, we investigated the effects of low-intensity repetitive trans-spinal magnetic stimulation (LI-rTSMS) following SCI in mice, using BMS, histological and RNA sequencing approaches. We aimed to determine the optimal protocol by comparing three stimulation patterns (10 Hz, iTBS and BHFS) and two coil sizes. Our results show that LI-rTSMS modulates the injured spinal cord in a pattern- and coil size-dependent manner, with distinct effects on fibrotic, neural, and inflammatory responses. Notably, the BHFS pattern produced the most marked tissue-remodeling effects, reducing fibrosis, reactive astrogliosis, and phagocytosis of myelin debris. This reduction in phagocytosis was also observed with a smaller coil, supporting an effect of LI-rTSMS on this process. We also identified distinct inflammatory signatures depending on the stimulation pattern and time after injury. Transcriptomic analyses revealed a common early inflammatory response to LI-rTSMS, whereas each stimulation pattern subsequently led to distinct molecular signatures after 2 weeks stimualtion. In addition, ependymal cells are known to retain endogenous regenerative potential following SCI. We found that LI-rTSMS increased ependymal cell proliferation and migration toward the lesion site, without detectable changes in their differentiation. Finally, we assessed c-Fos expression as a marker of early transcriptional changes in neurons. LI-rTSMS did not result in significant changes, suggesting that the observed effects were unlikely to be mediated by early, widespread neuronal activation. Altogether, this study provides mechanistic insights into the pattern-dependent effects of LI-rTSMS and highlights its potential role for future clinical translation.

Purpose. Prognostic assessments after acute brain injury are largely narrative, and how prognostic language relates to subsequent care has not been measured at scale. We quantified where it is written and its association with a subsequent code-status limitation. Materials and Methods. Multidatabase observational study of adults with acute brain injury or a related neurologic emergency, using MIMIC-IV (2008-2019; discharge summaries and radiology reports) and a timestamped MIMIC-III cohort (notes and code-status orders). The exposure was documented prognostic language; outcomes were its association with a subsequent full-code-to-limitation transition, note-stream location, and completeness of documented command-following relative to structured Glasgow Coma Scale (GCS) motor scores. Results. Among 31,993 admissions (27,054 patients; median age, 69 years; 54.9% male), prognostic language in the timestamped cohort (MIMIC-III) was associated with a subsequent code-status limitation after multivariable adjustment (adjusted hazard ratio, 4.3; 95% CI, 2.9-6.5; unadjusted 14-day cumulative incidence, 40% vs 8.5%), including the comfort-measures component (3.9), a higher-risk subgroup (4.4), and after acute-physiology adjustment (4.1); the association was concentrated in the first 3 days. Non-prognostic severity language showed no comparable association (hazard ratios, 1.1-1.3). Prognostic language localized almost entirely to the narrative (4.9% of discharge summaries vs 0.015% of radiology reports); command-following was undocumented in 55.7% of summaries, and no final-24-hour GCS motor score was charted in 72.8%. Conclusions. Documented prognostic language after acute brain injury was written in the narrative, not structured fields, and was associated with a subsequent code-status limitation after multivariable adjustment. This observational association cannot establish causation but warrants prospective study.

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.