Journal of Neurotrauma

BackgroundSpinal cord injury (SCI) results in neurodegeneration both at and above the lesion site. While cervical cord atrophy is well characterized in populations of mixed cervical, thoracic and/or lumbar injuries, the remote morphological changes in cervical cord following thoracic SCI remain unclear. The present study aimed to quantify cervical spinal cord morphology at C2-C3 in individuals with thoracic SCI and compare these metrics to matched controls. MethodsParticipants were 60 adults with chronic thoracic SCI and 60 neurologically healthy controls matched for age and sex. Extracted cervical metrics included mean cross-sectional area (CSA), antero-posterior (AP) and right-left (RL) diameters, eccentricity, solidity, orientation, and cord length. Group differences were assessed using linear mixed models adjusted for age, sex and scanning sites. Impacts of experiencing SCI-related chronic neuropathic pain on these metrics were explored. ResultsCompared to controls, the thoracic SCI group showed significantly reduced cervical CSA, along with smaller AP and RL diameters, consistent with remote atrophy. Eccentricity was increased, indicating a more flattened cord profile. Solidity, orientation, and cord length showed no group differences, supporting metric reliability and the absence of segmentation artefacts. Compared to controls, increased eccentricity was driven by people with SCI who experience chronic neuropathic pain. The presence of chronic neuropathic pain did not significantly influence other morphometric outcomes. ConclusionsThoracic SCI is associated with significant remote cervical cord degeneration, even in the absence of direct cervical injury. Results highlight that neurodegenerative processes propagate along ascending and descending spinal pathways. Cervical morphometry metrics, particularly CSA and eccentricity, may represent biomarkers of distal neurodegeneration following thoracic SCI, and inform future therapeutic strategies.

Spinal cord injury (SCI) in humans can robustly dysregulate healthy autonomic nervous system function, including thermoregulation. Despite this, the relationship between SCI and autonomic dysfunction remains incompletely understood and is often overlooked in rodent models that emphasize locomotor recovery. One notable autonomic output in rodents is stress-induced hyperthermia, which is a transient core temperature increase caused by an acute stressor. Here, we tested whether SCI in rats dysregulates stress-induced hyperthermia. To assess SCI-induced thermoregulatory dysfunction, we continuously monitored core temperature in male and female rats using implantable telemetry devices before and after a T8 contusion SCI (or sham surgery including laminectomy). Prior to surgery, stress—in response to handling and cage changes— resulted in transient hyperthermia that peaked ∼1°C higher than baseline and lasted 60-90 minutes. Sham-operated rats retained typical stress-induced hyperthermia beginning immediately after surgery. In contrast, SCI transiently abolished stress-induced hyperthermia in both sexes, indicating a profound disruption in autonomic regulation acutely after injury. Within 3-4 weeks after SCI, the stress-induced hyperthermic response gradually returned and reached pre-injury levels by week seven. Therefore, thoracic SCI in rats abolishes stress-induced hyperthermia, which gradually recovers over time post-injury. Overall, this study underscores the impact of incomplete SCI on autonomic function and highlights the need for future research focused on autonomic outcomes.HighlightsHandling and care procedures elicit stress-induced hyperthermia in ratsStress-induced hyperthermia was abolished in rats after spinal cord injuryStress-induced hyperthermia gradually returned over the subsequent weeksBy 7 weeks, the hyperthermic response had returned to pre-injury levels

BackgroundNearly every individual sustaining traumatic spinal cord injury receives multiple types and classes of medications to manage a litany of secondary complications. Prior clinical studies and evidence from animal models suggest that several of these medications could enhance or impede endogenous neurological recovery. However, there is a knowledge gap surrounding the spectrum of pharmacologic agents typically administered in the routine management of spinal cord injury. ObjectiveTo systematically determine the types of medications commonly administered, alone or in combination, in the acute to subacute phase of spinal cord injury. MethodsWe conducted an analysis of two largescale cohorts (the Sygen interventional trial and the SCIRehab observational cohort study) to determine what constitutes " standards of acute pharmacological care" after spinal cord injury. Concomitant medication use, including dosage, timing and reason for administration, was tracked. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. ResultsAcross 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in the Sygen trial received 9.9 {+/-} 4.9 (range 0-34), 14.3 {+/-} 6.3 (range 1-40), 18.6 {+/-} 8.2 (range 0-58), and 21.5 {+/-} 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Patients enrolled in the SCIRehab cohort study received on average 1.7 {+/-} 1.7 (range 0-11), 3.7 {+/-} 3.7 (range 0-24), 8.5 {+/-} 6.3 (range 0-42), and 13.5 {+/-} 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). ConclusionsTo our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, with potential to both positively and negatively impact neurological recovery. This data may provide key insight to achieve better understanding of how the acute pharmacological management of spinal cord injury affects long-term recovery. All results can be interactively explored on the RXSCI web site (https://jutzelec.shinyapps.io/RxSCI/) and GitHub repository (https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/).

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.

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.

BackgroundSevere traumatic brain injury (TBI) frequently disrupts cerebral autoregulation, rendering cerebral perfusion pressure highly dependent on systemic hemodynamics. Vasopressors are a cornerstone of TBI management, yet norepineph-rine and vasopressin may exert divergent effects on cerebral autoregulation and systemic cardiovascular function. Their comparative impact in this population remains poorly defined. ObjectiveThe REGULATE trial is a randomized, controlled study designed to investigate the effects of norepinephrine, vasopressin, and their combination on cerebral autoregulation and advanced systemic hemodynamics in patients with severe TBI. MethodsThis quadruple-blinded, parallel-group trial will enroll 450 adults with severe TBI (Glasgow Coma Scale [≤] 8) requiring vasopressor support. Participants will be randomized (1:1:1) to norepinephrine, vasopressin, or combination therapy. Continuous multimodal monitoring will include intracranial pressure, arterial pressure, near-infrared spectroscopy, and advanced cardiac output assessment. Co-primary outcomes are (1) cerebral autoregulation, quantified as the area under the curve of the pressure reactivity index over 48 hours, and (2) systemic hemodynamics, defined as the area under the curve of cardiac output and effective arterial elastance over 48 hours. A prespecified interaction analysis will evaluate treatment effects on the relationship between cerebral autoregulation and systemic hemodynamics. Secondary outcomes include cerebral oxygenation indices, intracranial pressure burden, vasopressor dose exposure, organ perfusion markers, adverse events, and clinical outcomes (mortality, ICU length of stay, neurological recovery at 3 months). ConclusionsREGULATE is the first adequately powered trial to systematically compare norepinephrine, vasopressin, and their combination on cerebral autoregulation and systemic cardiovascular performance in severe TBI. Results are expected to inform individualized vasopressor strategies to optimize cerebral and systemic physiology while minimizing secondary injury. Trial registrationClinicalTrials.gov (forthcoming).

A physical trauma to the spinal cord produces an immediate massive depolarizing injury potential accompanied both by a transient episode of spinal hypoxia, and an extensive cell loss at the level of injury, which interrupts conduction of longitudinal input along white matter tracts. Afterwards, the transient hypotonia and areflexia characterize the following spinal shock phase. The relationship between the extent of injury potentials and spinal cord injury (SCI) progression, as well as the potential pharmacological modulation of the immediate consequences of a trauma, have not yet been explored. To limit the peak of injury potentials and speed up recovery of reflex motor responses, we serially applied selective neurochemicals in the exact moment of an experimental physical trauma delivered through a calibrated device impacting the mid-thoracic cord of an entire CNS preparation of neonatal rats. Continuous lumbar root recordings monitored baseline DC-levels and reflex responses elicited by trains of electric pulses applied to sacrocaudal afferents. In uninjured preparations, each agent showed distinct effects on baseline polarization, modulation of synaptic responses, and appearance of bursting activity. Interestingly, neurochemicals acting on glutamatergic-, adenosinergic-, glycinergic- or GABAergic receptors, did not affect the monitored outcome when each parameter was normalized against pre-injury values. Conversely, the selective TRPV4 antagonist, RN1734, unlike the TRPA1 antagonist, AP18, reduced peak of injury potentials and speeded up full recovery of reflex responses within 1 min from trauma. Similarly, blockage of gap junctions quickly, yet partially, restored motor reflexes, while antagonism of GABAA receptors restored full reflexes, though slightly later. The current study indicates that both mechanosensitive TRPV4 receptors and GABAergic transmission reduce the immediate pathological consequences of a trauma when applied at the moment of impact, envisaging a clinical translation for preventing accidental spinal lesions during the most delicate spinal surgeries.

Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulations, and depressive symptoms) among 3,174 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom played organized soccer. HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms, and that assessed cognitive performing via computerized tests. Multivariable linear and logistic regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Among the former soccer players, longer duration of soccer play, higher level of play, and greater estimated cumulative heading frequency were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity (range of significant unstandardized B coefficients: 0.02 to 0.52). Higher estimated cumulative heading exposure was associated with higher odds of clinically meaningful elevations on subjective measures (OR range: 1.05 to 1.13) There were no associations between any of the RHI proxies and performance on the objective computerized cognitive assessments. Among middle-aged women who played organized soccer, cumulative RHI exposure was associated with small but statistically significant effects for measures of subjective cognitive complaints, behavioral functioning, and depressive symptoms. We found no associations for objective outcomes of cognitive function. Continued monitoring of this large cohort of female former soccer players will improve understanding of long-term consequences of soccer play.

Autonomic dysfunction is common after spinal cord injury, though differing from motor and sensory function, there are currently no established batteries of tests to comprehensively characterize these deficits. Further, while individual established autonomic tests have a long history and sound scientific background, translating these autonomic testing results to inform clinical understanding is a major barrier. Herein, we outline a battery of six laboratory autonomic tests which were carefully curated to collectively describe the ability of individuals with spinal cord injury to inhibit and recruit sympathetic activity through the injured spinal cord. Presenting normative control data in 23 uninjured individuals completing this testing battery, we further demonstrate the utility of extracting three key testing metrics for each test, comparing these control results to 11 individuals with spinal cord injury. Results demonstrate strong normality of data with testing psychometrics suggesting reliable reproducibility on repeat testing. Further, even in this preliminary sample of individuals with spinal cord injuries, clear differences begin to emerge. This illustrates the ability of this collective testing battery to characterize autonomic regulation after spinal cord injury. To aid in clinical translation, we further present a graphical representation, an autonomic phenotype, which serves as a snapshot of how normal or abnormal sympathetic inhibition and recruitment of activation may be after spinal cord injury. Utilizing these autonomic phenotypes, three example cases of individuals with spinal cord injury highlight evidence of varied degrees of autonomically complete spinal cord injury. Together, this represents a key advancement in our understanding of autonomic function after spinal cord injury.

BackgroundAdverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common following blast exposure and contribute to decreased quality of life, but underlying mechanisms and prophylactic/treatment options remain limited. The dynorphin/kappa opioid receptor (KOR) system helps regulate behavioral and inflammatory responses to stress and injury; however, it has yet to be investigated as a potential mechanism in either humans or animals exposed to blast. We hypothesized that blast-induced KOR activation mediates adverse outcomes related to inflammation and affective behavioral response. MethodsC57Bl/6 adult male mice were singly or repeatedly exposed to either sham (anesthesia only) or blast delivered by a pneumatic shock tube. The selective KOR antagonist norBNI or vehicle (saline) was administered 72 hours prior to repetitive blast or sham exposure. Serum and brain were collected 10 minutes or 4 hours post-exposure for dynorphin A-like immunoreactivity and cytokine measurements, respectively. At one-month post-exposure, mice were tested in a series of behavioral assays related to adverse outcomes reported by humans with blast trauma. ResultsRepetitive but not single blast exposure resulted in increased brain dynorphin A-like immunoreactivity. norBNI pretreatment blocked or significantly reduced blast-induced increase in serum and brain cytokines, including IL-6, at 4 hours post exposure and aversive/anxiety-like behavioral dysfunction at one month post exposure. ConclusionsOur findings demonstrate a previously unreported role for the dynorphin/KOR system as a mediator of biochemical and behavioral dysfunction following repetitive blast exposure and highlight this system as a potential prophylactic/therapeutic treatment target.

Background: Prognostication 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. Methods: We 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. Results: The 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. Conclusion: A 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.

BackgroundPrediction of which traumatic and hypoxic brain injuries will progress to brain death is currently based predominantly on history, physical examination and radiographic findings. We investigated how accurately purely objective measures including three neurologic serum markers and algorithmic CT (computed tomograph) scan analysis can predict brain death and differentiate its etiology. MethodsThis prospective observational study enrolled 51 isolated trauma subjects and 19 clinically brain dead subjects that were further divided by mechanism of injury into high-velocity trauma with presumed diffuse axonal injury, cardiopulmonary/respiratory arrest, and found down groups. Levels of glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and S100 Calcium-Binding Protein B (S100B) were compared, and algorithmic analysis of CT scan imaging was performed using an open-source deep learning software (BLAST-CT). FindingsThe prognostic value of various biomarker combinations in identifying subjects progressing to brain death was assessed using machine learning. Prediction accuracy for GFAP, UCH-L1, and S100B and algorithmic CT analysis in combination to predict brain death from among all other cohorts yielded an area under the receiver operator curve of 0.98 versus all other brain injury subjects. This model was also able to distinguish brain death attributed to cardiopulmonary/respiratory arrest from combined non-trauma controls and diffuse axonal injury with an area under the curve of 0.99. InterpretationSerum concentrations of GFAP, UCH-L1, and S100B measured within 32 hours of traumatic and hypoxic brain injury (cardiopulmonary/respiratory arrest) and algorithmic CT analysis have utility in prognosticating brain death and predicting its mechanism of injury as either hypoxic or traumatic/unknown (diffuse axonal injury/found down). FundingAbbott Labs and the Minnesota State Office of Higher Education.

BackgroundRepetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined acute and chronic outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction. MethodsIn this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. ResultsRepetitive blast exposure resulted in both similar and disparate patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited chronic adverse behavioral outcomes. DiscussionRepresenting a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar yet divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

BackgroundTraumatic spinal cord injury (SCI) is a major cause of long-term neurological disability, with limited pharmacological therapies targeting secondary inflammatory and neurodegenerative injury mechanisms. Minocycline, a tetracycline derivative with anti-inflammatory and neuroprotective properties, has been investigated in both experimental and clinical settings; however, its therapeutic efficacy in acute traumatic SCI remains uncertain. MethodsA systematic review was conducted in accordance with PRISMA 2020 guidelines. Major electronic databases were comprehensively searched to identify preclinical animal studies and human clinical studies evaluating minocycline, alone or in combination therapies, for acute traumatic SCI. Risk of bias was assessed using Joanna Briggs Institute (JBI) critical appraisal tools tailored to study design. Qualitative synthesis included all eligible studies, while quantitative synthesis was restricted to clinical studies reporting extractable effect estimates for neurological improvement. ResultsA total of 11 studies met inclusion criteria for qualitative synthesis, including experimental animal studies and human clinical investigations. Preclinical studies demonstrated consistent biological effects of minocycline on inflammatory markers, oxidative stress, and histopathological outcomes, particularly in combination therapies, although functional recovery with minocycline monotherapy was inconsistent. Clinical studies indicated that minocycline was generally well tolerated; however, most trials did not demonstrate statistically significant improvements in neurological or functional outcomes. Only two clinical studies provided suitable data for meta-analysis, yielding a pooled odds ratio of 1.70 (95% CI 0.95-3.06) for neurological improvement, which did not reach statistical significance. ConclusionCurrent evidence suggests that while minocycline exhibits promising biological activity and an acceptable safety profile in acute traumatic SCI, robust clinical efficacy has not been conclusively demonstrated. Well-designed, adequately powered randomized controlled trials with standardized outcome reporting are required to determine whether these biological effects translate into meaningful functional recovery.

ImportanceRecovery of command-following after traumatic brain injury (TBI) is an important prognostic indicator, however, the relationship between time to command-following and long-term functional outcome is not clear. ObjectiveEvaluate the association between command-following and outcome 1-year after TBI. Design Cohort study of participants with moderate-severe TBI in the TBI Model Systems (TBIMS) who were followed 1-year post injury, and validation in an independent dataset from the Brain Trauma Research Center (BTRC) database. SettingTBIMS is a multi-center study of participants with moderate-severe TBI treated in an inpatient rehabilitation hospital. The BTRC database is derived from a single US level 1 trauma center and includes patients with severe TBI. ParticipantsTBIMS: N=9,052 (mean{+/-}SD age 38{+/-}18 years, 76% male, 67% white); BTRC: N=228 (mean age 37{+/-}17 years, 76% male, 91% white). Participants did not follow commands on acute hospital admission and survived to discharge. ExposureDays to command-following during hospitalization. Main OutcomeGlasgow Outcome Scale Extended (GOSE) score <4 (i.e., death or dependency) 1-year post TBI. ResultsParticipants in TBIMS were more likely than those in BTRC to follow commands during acute hospitalization (90% vs 63%; p<0.001) and had a shorter median time to command-following (5 vs 9.5 days; p< 0.001). For each additional week without command-following, the odds ratio for death or dependency at 1 year was 1.30 (95% CI: [1.26,1.35]; p<0.001) in TBIMS and 1.49 ([1.15, 1.97]; p=0.003) in BTRC. Time to command-following had an AUC of 0.61 [0.59, 0.63] in TBIMS and 0.65 [0.53, 0.76]) in BTRC. Each additional day without command-following was associated with a 1.18% (1.16%, 1.20%) increase in the proportion of participants with death or dependency at 1-year in TBIMS and 1.05% (0.99%, 1.11%) in BTRC. ConclusionTime to command-following after moderate-severe TBI is associated with 1-year outcomes, but the predictive accuracy of absence of command-following on any single post-injury day is limited. In two independent cohorts, the likelihood of death or dependency increased by [~]1% for each additional day without command-following. Clinicians should be cautious when prognosticating based on the absence of command-following in the first five weeks after TBI.

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.

Traumatic brain injury (TBI), particularly sports- and recreational activity related mild TBI (mTBI), is common in young adults and can be followed by persistent attentional and executive complaints. This study investigated chronic ([&ge;]6 months post-injury) structural brain alterations in gray matter (GM) and white matter (WM) and their associations with self-reported inattentive and hyperactive/impulsive symptoms, with a focus on sex-differentiated patterns. Structural brain properties in gray matter (GM) and white matter (WM) were acquired from 44 subjects with TBI and 45 matched controls, by utilizing structural MRI and diffusion tensor imaging techniques. Behavioral measures assessing severities of post TBI inattentive and hyperactive/impulsive symptoms were collected from each participant. Between-group and sex-specific differences of these brain and behavioral measures were conducted. Interactions among the TBI-induced significant brain- and behavioral-alterations, and their sex-specific patterns, were assessed as well. Male-dominated pattern of increased cortical thickness in superior parietal lobule (SPL) and female-dominated pattern of higher superior longitudinal fasciculus and superior fronto-occipital fasciculus (sFOF) fractional anisotropy (FA) were observed in the TBI group, when compared to controls. In males with TBI, greater SPL cortical thickness was significantly correlated with increased inattentive behaviors. In females with TBI, higher FA of sFOF was significantly correlated with decreased hyperactive/impulsive behaviors. Findings suggest that TBI-induced superior parietal cortical GM abnormalities may significantly cause attention deficits in patients with TBI, especially in males; while optimal post-TBI WM recovery in sFOF significantly contributes to maintenance of inhibitive control in patients with TBI, especially in females.

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.

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.

Repeated exposure to hypoxia (oxygen levels below sea-level atmospheric conditions, [~]21%) alternated with regular voluntary exercise, known colloquially as Living High, Training Low, or simply High-Low, is used by elite athletes to boost exercise benefits and athletic performance. While paradigms of High-Low training have been utilized by Olympic athletes for decades, the therapeutic potential of a High-Low regimen in the context of neurotrauma has yet to be investigated. This long-term experiment evaluated the independent and combined effects of repeated hypoxic exposure and voluntary exercise on functional outcomes within the context of preclinical spinal cord injury (SCI). We hypothesized that combinatorial High-Low training enhances functional recovery, beyond either exercise or repeated exposures to hypoxia alone, to improve outcomes after SCI. Adult female rats (n=62) underwent a high-cervical hemisection (LC2H) to model spinal cord injury. At 6 weeks post-SCI, treatment (access to exercise wheel, repeated exposure to normobaric hypoxia at rest, or alternation of both) began in the surviving subjects (n=49). Despite initiation of treatment beyond the acute post-injury phase, High-Low therapy significantly improved respiratory function and prevented the development of SCI-associated anxiety-like behaviors. Notably, repeated in vivo exposure to normobaric hypoxia induced a shift in peripheral T cell profiles, characterized by increased CD4+ and reduced CD8+ expression. These findings indicate that combining repeated exposure to hypoxia with voluntary exercise as a therapy could promote recovery in the existing spinal cord-injured population. Collectively, this work provides a foundational first step for further investigation of High-Low training as a rehabilitation therapy for individuals living with SCI.