Journal of Neurotrauma

IntroductionOlder age is associated with worse outcome after traumatic brain injury (TBI). Whether this association is entirely driven by frailty, or clinicians reluctance to give specific treatments to older patients is unclear. Therefore, we aimed to confirm the association between age and worse outcome, and to assess the association between age and received high-intensity treatment (HIT). MethodsWe included TBI patients aged 16 and older from the CENTER-TBI study. The association between age and HIT, and between age and outcome (the Glasgow Outcome Scale Extended (GOSE) at 6 months), was analyzed using multivariable ordinal and logistic regression respectively. In the overall cohort, HIT was defined as receiving emergency intracranial surgery, or ICU admission. In the subset of patients admitted to the ICU, HIT was defined as receiving metabolic suppression, intensive hypocapnia, hypothermia below 35 {degrees}C, decompressive craniectomy, or intracranial surgery not scheduled on admission. We adjusted for pre-injury health, injury severity (Glasgow Coma Scale (GCS) motor score and pupillary reactivity at baseline; major extracranial injury (MEI); Marshall CT classification), and in the subset of ICU patients for the median ICP before receiving any HIT. ResultsIn total, 4349 patients were included. Of these, 1999 patients (46%) were admitted to the ICU. The median age was 51 years. Every ten-year increase in age for patients over 65, was associated with worse outcome (OR = 0.6, CI = 0.5 - 0.7, OR in the subset of ICU patients = 0.5, CI = 0.3 - 0.5). Furthermore, every ten-year increase in age for patients over 65 was associated with a lower likelihood of receiving emergency intracranial surgery (OR = 0.4, CI = 0.3 - 0.6), and ICU admission (OR = 0.6, CI = 0.5 - 0.8). Similarly, in the subset of ICU patients, every ten-year increase in age for patients over 65, was associated with a lower likelihood of receiving neuromuscular blockade (OR = 0.6, CI = 0.4 - 0.9), intensive hypocapnia (OR = 0.2, CI = 0.1 - 0.9), decompressive craniectomy (OR = 0.4, CI = 0.2 - 0.8), and intracranial surgery (OR = 0.5, CI = 0.3 - 0.8). ConclusionOlder patients have poorer outcome, and were less likely to receive high-intensity treatments, independent of patient and injury characteristics. Clinicians should not withhold high-intensity treatments solely based on older age. Educating clinicians about this delicate topic, and performing further comparative effectiveness research focusing on older patients may improve diagnosis, treatments, and understanding of TBI outcomes in this group.

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).

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.

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

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

Background and ObjectivesSevere Traumatic Brain Injury (TBI) is associated with secondary injury and poor outcomes, but the underlying mechanisms are poorly understood. Vascular mechanisms may be important. We aimed to characterise how blood vascular endothelial growth factor A (VEGF-A) levels are affected by TBI, and its associations with secondary injury and functional outcome. MethodsWe retrospectively analysed data from two multi-centre, international, prospective observational studies (CREACTIVE and BIO-AX-TBI) with follow-up of up to 1 year. These cohorts comprised adults with moderate-severe TBI (Mayo classification), recruited on admission to hospital (BIO-AX-TBI) and the intensive care unit (ICU) (CREACTIVE). Controls included non-TBI trauma (NTT) and uninjured adults. Plasma VEGF-A levels and TBI biomarkers (Neurofilament light [NFL], glial fibrillary acidic protein [GFAP], total Tau, UCH-L1, S100B) were measured on ICU admission and [~]5 days later (CREACTIVE), or at 5 timepoints from admission to 12 months post-TBI (BIO-AX-TBI), and compared to NTT and control groups. In BIO-AX-TBI, MRI assessment was performed at subacute and chronic timepoints. Functional outcomes (Glasgow Outcome Scale-Extended) were measured at 6 and 12 months. Plasma VEGF-A was measured using the OLINK(R) Target 96 Inflammatory platform, which reports in arbitrary standardised units (NPX), and TBI biomarkers were measured using Simoa(R) or Millipore platforms. ResultsData was available from 195 TBI (21% female, mean age 45.30years), 24 NTT (8%, 43.98) and 89 CON (44%, 42.39) in BIO-AX-TBI, and 1146 TBI (25%, 56.29) in CREACTIVE. Plasma VEGF-A was elevated acutely after both TBI (estimated mean difference=0.45NPX, SE=0.09, p<0.001) and NTT (estimated mean difference=0.74NPX, SE=0.16, p<0.001), but remained raised after the initial timepoint only in TBI patients, peaking at day 16. Higher acute VEGF-A was associated with increased odds of refractory raised intracranial pressure (r-rICP) (maximum Odds Ratio for r-rICP=1.69, p=0.031), higher lesion volume (estimated increased lesion volume=20.14ml, SE=8.20ml, p=0.02), and worse functional outcomes (maximum Odds Ratio for worse outcome category=2.51, p<0.001). DiscussionThere is a sustained rise in plasma VEGF-A after TBI, which is associated with r-rICP and chronic injury markers, suggesting vascular pathophysiology is important after TBI. Further research is needed to explore mechanisms.

BackgroundThe most common assessment modalities to determine the level of injury following a traumatic brain injury (TBI) includes computerized tomography (CT) scans and/or magnetic resonance imaging (MRI). Evidence is mixed as to whether single photon emission computed tomography (SPECT) is specific and accurate in identifying TBI. ObjectivesThis study systematically assessed recent evidence of the clinical utility of SPECT in the diagnosis of TBI and examined the diagnostic accuracy of SPECT in TBI and its performance in comparison to other imaging modalities (e.g., CT and MRI). MethodsPubMed, MEDLINE, and Embase databases were systematically searched for published articles from December 2012 to July 2022. Randomized controlled trials (RCTs) and observational studies published in English that used SPECT to evaluate patients with all severity of TBIs were eligible for inclusion. Titles and abstracts were screened, and 111 selected full-text articles were independently screened based on predefined inclusion/exclusion criteria (guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PRISMA) and assessed for quality using the Newcastle-Ottawa Scale. ResultsFourteen eligible studies, all observational, reporting location of lesions on brain SPECT were included, reporting data from 21632 participants of which 20,746 participants were from one study; the remaining 886 participants were from the remaining13 studies. The heterogeneity of the data precludes a meta-analysis. There was no consensus among experts from the thirteen smaller studies; however, the largest study indicated that the specificity of visual readings was 54%. In particular, abnormalities and brain perfusions may lead to false positives. Quantitative analysis theoretically increases the reliability of findings for brain SPECT, but error rates are unknown and not published. ConclusionThere is a lack of evidence to support the clinical utility of brain SPECT for the diagnosis and treatment of TBI.

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.

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.

IntroductionPsychopathology following traumatic brain injury (TBI) is a common and debilitating consequence that is often associated with reduced functional and psychosocial outcomes. There is a lack of evidence regarding the neural underpinnings of psychopathology following TBI, and whether there may be transdiagnostic neural markers that are shared across traditional psychiatric diagnoses. The aim of this systematic review and meta-analysis is to examine the association of MRI-derived markers of brain structure and function with both transdiagnostic and specific psychopathology following moderate-severe TBI. Methods and analysisA systematic literature search of Embase (1974-2022), Ovid MEDLINE (1946-2022) and PsycINFO (1806-2022) will be conducted. Publications in English that investigate MRI correlates of psychopathology characterised by formal diagnoses or symptoms of psychopathology in closed moderate-severe TBI populations over 16 years of age will be included. Publications will be excluded that: a) evaluate non-MRI neuroimaging techniques (CT, PET, MEG, EEG); b) comprise primarily a paediatric cohort; c) comprise primarily penetrating TBI. Eligible studies will be assessed against a modified Joanna Briggs Institute Critical Appraisal Instrument and data will be extracted by two independent reviewers. A descriptive analysis of MRI findings will be provided based on qualitative synthesis of data extracted. Quantitative analyses will include a meta-analysis and a network meta-analysis where there is sufficient data available. Ethics and disseminationEthics approval is not required for the present study as there will be no original data collected. We intend to disseminate the results through publication to a high-quality peer-reviewed journal and conference presentations on completion. PROSPERO registration numberCRD42022358358 Article SummaryStrengths and limitations of this study: O_LIThis is a comprehensive review of MRI markers of psychopathology among adults with moderate - severe traumatic brain injuries. C_LIO_LIWe will investigate neural correlates across the spectrum of psychopathology rather than focusing on specific diagnoses, allowing for transdiagnostic investigations of brain structure and function alterations after TBI with comorbid psychopathology. C_LIO_LIWe will be restricting eligible studies to English language. C_LIO_LIWe will capture pre-injury psychopathology where data are available and analyse the associations with post-injury psychopathology and neural correlates. C_LI

BackgroundTherapeutic hypothermia as a neuroprotective strategy can reduce secondary injury after acute traumatic spinal cord injury (SCI). Although promising in animal models, its clinical effectiveness and safety remain uncertain. We conducted a systematic review and meta-analysis on human studies to evaluate the impact of systemic or local hypothermia on neurological outcomes, mortality, and length intensive care hospitalization. MethodsSystematic and comprehensive search in PubMed, Scopus, Web of Science, Embase, and Cochrane Trails with no limitation of time and language performed. Following PRISMA 2020 guidelines, two independent reviewers screened records across four databases up to 20 September 2025. Eligibility was determined using PICOS criteria: adults with acute traumatic SCI (P), receiving any hypothermic protocol (I), compared with standard normothermic management (C), with reported functional, sensory, or survival outcomes (O), and original human clinical designs (S). Animal experiments, case reports, and conference abstracts without full texts were excluded. Data extraction and risk-of-bias evaluation were performed independently using the Joanna Briggs Institute (JBI) checklist. Pooled relative risks (RR) or mean differences (MD) were calculated with random-effects models (DerSimonian-Laird) using RevMan 4.5.1 ResultsFrom 612 initial records, six human studies met inclusion criteria: three systemic hypothermia trial and one local extradural protocol, plus two supportive cohorts providing timing and assessment data. Intervention methods included surface, and endovascular techniques maintaining body temperature at 32-34 Celsius for 24-72 hours, initiated between 1.6 -70 hours post-injury. pooled analyses showed Mortality with RR = 0.57 (95 % CI 0.05 -5.88), indicating no significant difference but a trend favoring hypothermia. AIS grade improvement with RR = 2.96 (95 % CI 0.01-939.31); direction toward neurological benefit though statistically imprecise. ICU length of stay with MD = -1.27 days (95 % CI -2.46 to -0.07), suggesting shorter intensive care duration. complications included pneumonia, hypotension, and bradycardia, with no hypothermia-related deaths were reported. Early initiation (< 6 h) was consistently linked with superior functional improvement. Overall methodological quality was low-to-moderate; none of the studies were randomized. ConclusionsResults from six human studies reveal that therapeutic hypothermia may be feasible, safe, and effective as an intervention in acute traumatic SCI. While current evidence cannot yet demonstrate mortality benefit, the observed results were directed toward neurological improvement, especially when therapy is initiated early and systemically, supports ongoing investigation. Until large randomized data are available, hypothermia should be regarded as an experimental yet promising neuroprotective additional therapeutic option and complementing early decompression.

BackgroundTraumatic brain injury (TBI) remains a leading cause of morbidity and mortality worldwide, with secondary brain damage driven by inflammation and oxidative stress. Vitamin D is increasingly recognized for potential neuroprotective effects in TBI, while data regarding vitamin E remain limited. ObjectiveTo systematically review and meta-analyze the effects of vitamin D supplementation, and qualitatively review evidence for vitamin E, on clinical and functional outcomes after moderate to severe TBI. MethodsA comprehensive search was carried out in PubMed, Scopus, Embase, Web of Science, and Google Scholar up to January 2025. Studies reporting on vitamin D or E supplementation in clinical TBI were eligible. Risk of bias was assessed using JBI checklists. A meta-analysis of randomized controlled trials reporting pre- and post-treatment GCS scores following vitamin D supplementation was performed with a fixed-effect model. ResultsFrom 4,546 records, nine clinical studies met criteria; three RCTs on vitamin D (n=151 patients) were included in the meta-analysis, which found that vitamin D supplementation significantly improved GCS scores versus controls (SMD{square}= {square}1.02, 95% CI: 0.68-1.36, p{square}< {square}0.0001; I2{square}= {square}0%). Narrative analysis suggested that vitamin D may improve functional outcomes, reduce inflammatory biomarkers, and lower mortality in select studies. Evidence for vitamin E in TBI is currently limited to a small number of heterogeneous studies, with early data suggesting possible benefits for acute recovery and oxidative stress reduction, but insufficient for quantitative synthesis. ConclusionVitamin D supplementation may confer short-term improvement in neurological and functional outcomes following moderate to severe TBI. Existing evidence for vitamin E is insufficient to support robust conclusions. Larger, rigorously designed RCTs--particularly for vitamin E--are required to clarify effectiveness, optimal dosing, and long-term outcomes.

ImportanceCurrent approaches to functional outcome assessment in persons with severe traumatic brain injury (TBI) may not reflect the perspectives of persons with TBI or TBI caregivers. ObjectiveDetermine the lowest level of functional recovery after severe TBI that is perceived to be acceptable by persons with TBI and TBI caregivers. DesignCross-sectional crowdsourcing online survey disseminated May-July 2024. SettingUnited States. ParticipantsPersons with a history of TBI requiring assistance with basic daily activities and TBI caregivers. Exposure(s)History of severe TBI. Outcome(s)/Measure(s)An expanded version of the Glasgow Outcome Scale-Extended (GOSE) designed to determine the level of acceptability of 11 TBI outcome milestones and the minimally acceptable outcome (MAO). ResultsThe survey was completed by 252 persons with TBI (mean[SD] age 39.8[13.5] years; 67% female; 75% white; 11.9[12.0] years post-TBI) and 256 TBI caregivers (41.0[12.1] years; 57% female; 65% white). Among the outcomes selected most frequently as the MAO by persons with TBI (i.e., "recovery of yes/no communication" and "conscious, but does not communicate") and TBI caregivers (i.e., "recovery of yes/no communication" and "alive, but permanently unconscious"), recovery of reliable yes/no communication was selected as acceptable by most respondents (persons with TBI: 36% vs 12%; Z=-7.1, p<0.0001; TBI caregivers 40% vs 14%, Z=-7.1, p=<0.0001). Recovery of reliable yes/no communication was therefore identified as the MAO by both cohorts. This outcome was rated as acceptable or somewhat acceptable by 65% of persons with TBI and 72% of caregivers. Outcomes representing disability greater than "completely independent in the home" were selected as the MAO more frequently than this common cut-off for "favorable" outcome, which was selected as the MAO by 5.6% and 3.9% persons with TBI and caregivers, respectively. Conclusions/RelevancePersons with TBI and TBI caregivers identified recovery of yes/no communication, an outcome that is well below the traditional cut-off for "favorable," as the MAO. Persons with lived experience appear more accepting of a greater burden of disability than TBI investigators and providers. Recognizing this disparity in perspectives may influence clinical decision-making regarding goals of care and suggests the need for a more person-centered approach to TBI outcome assessment.

Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. BDNF DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brains response and help identify TBI-specific epigenetic patterns relevant to later recovery. Therefore, the purpose of this study was to examine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Data were derived from the Epigenetic Effects on TBI Recovery (EETR) study, a prospective, longitudinal cohort study conducted at UPMC Childrens Hospital of Pittsburgh. Children aged 3 to 18 years hospitalized at a minimum of overnight for complicated mild to severe TBI or OI without head trauma were enrolled. Exclusion criteria included prior hospitalization for TBI, pre-existing neurological or psychiatric conditions, or sensory or motor impairments precluding study participation. Blood samples were collected during hospitalization (mean=31.6 hours post-injury) and at 6 (mean=216.9 days) and 12 months (mean=405.9 days) post-injury. The primary outcome variable was DNAm assessed via pyrosequencing at five quality-controlled CpG sites in the BDNF gene (chromosome 11, hg38 positions 27722033, 27722036, 27722047, 27701612, and 27701614). The primary exposure was injury type (TBI vs. OI), with severity (measured via Glasgow Coma Scale [GCS]) examined as a secondary exposure within the TBI group. Primary covariates included age, sex, and race; secondary covariates included pubertal status, age-adjusted BMI, non-head injury severity, socioeconomic status, and psychosocial adversity. The final analysis sample included n=189 participants with TBI and n=105 participants with OI. Participants were 66.3% male, 83.2% White, and had a mean age of 10.6 ({+/-}4.4) years at the time of enrollment. Acutely, children with TBI showed significantly lower DNAm at three of five sites (3.17%- 5.83% lower; p=0.0044 to 6.48E-06) while controlling for age, sex, and race. One site remained significantly lower at 12 months (8.56% lower; p=0.0045); no significant differences were observed at 6 months. Observed differences remained robust across sensitivity models adjusting for secondary covariates. GCS-measured TBI severity was not associated with DNAm at any time point. These findings suggest that BDNF DNAm differs between children with TBI and those with OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.

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.

ObjectiveThis systematic review aimed to evaluate the impact of gut microbiota modulation including probiotics, dietary interventions, and enteral nutrition strategies on neurological recovery, functional outcomes, morbidity, and mortality in patients with traumatic brain injury (TBI). MethodsThe review was conducted according to PRISMA 2020 guidelines and registered in PROSPERO. A comprehensive search was performed across PubMed, Embase, Web of Science, Scopus, and Cochrane Library up to September 2025. Inclusion criteria comprised original clinical studies in human TBI patients that investigated microbiota related interventions and reported neurological, gastrointestinal, or microbiome outcomes. Risk of bias was assessed using the Joanna Briggs Institute (JBI) tools. ResultsAmong five eligible studies (four RCTs and one cohort; n = 725), early or individualized enteral nutrition and probiotic supplementation were generally associated with better metabolic and inflamatory profiles, fewer gastrointestinal complications, and a non significant trend toward improved neurological scores (GCS, GOS). However, effect sizes weres mall and certainty low due to limited sample sizes and methodological heterogeneity. ConclusionModulation of the gut brain axis, particularly through early and tailored enteral nutrition, appears to improve clinical outcomes and mitigate complications in TBI patients. Probiotics demonstrate safety and potential benefit, though evidence remains preliminary. Larger, multicenter randomized controlled trials are warranted to confirm efficacy, define optimal timing and formulations, and assess longterm neurological recovery.

IntroductionThis study examines the demographic, temporal, and spatial patterns of traumatic brain injury (TBI) hospitalizations in the canton of Geneva, Switzerland, between 2012 and 2024. Particular attention is given to differences between seniors ([&ge;]60 years) and the younger or working-age population (15-59 years). MethodsHospital discharge data were analyzed in combination with geographic information systems (GIS) to explore incidence, severity, and clinical outcomes. Temporal trends were assessed across seasons and days of the week. Spatial distribution was investigated using Join Count and SPARR methods to detect clustering. Multivariate clustering further integrated socio-clinical characteristics, including age, autonomy, residential setting, and hospital trajectory. ResultsSeniors accounted for more than half of all TBI hospitalizations. Advanced age and institutional residence were strongly associated with reduced likelihood of returning home post-discharge (statistical values). Temporal analyses showed a marked increase in TBI incidence among seniors during autumn and at the beginning of the week, patterns not observed in the working-age group. Spatial analyses revealed non-random clustering of cases, with high-risk zones concentrated in specific areas, particularly for older adults. Multivariate clustering identified distinct socio-clinical profiles in both age groups, shaped by residential environment, autonomy level, and care pathways. ConclusionThe findings underscore the dual clinical and territorial dimensions of TBI, highlighting significant age-related and spatial disparities. Tailored prevention strategies, safer environmental design, and integrated care pathways are needed to reduce inequalities and improve outcomes. Addressing TBI through both a medical and public health lens is essential to support at-risk populations, particularly seniors.

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 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.

IntroductionAbout half of the world population will suffer from a traumatic brain injury (TBI) during their lifetime, of which about 90% of cases are mild TBI. About 15-40% of adults with TBI experience persistent cognitive deficits, and there is a lack of proven-effective treatment to facilitate cognitive recovery after mild TBI. Methods and analysisThis randomized placebo-controlled multi-centre clinical trial aimed to examine the safety and efficacy of herbal supplement MLC901 (NeuroAiD II) on cognitive functioning following mild TBI. Adults aged 18-65 years, who were 1-12-months post-mild TBI and experienced cognitive impairment, were assigned to receive either MLC901 (0.8g capsules/day) or placebo for 6 months in 7 research centres in Russia using centralized stratified permuted block randomization. The primary outcome was cognitive functioning as assessed by an online neuropsychological test (CNS Vital signs). Secondary outcomes included Rivermead Post-Concussion Symptoms Questionnaire (RPQ; neurobehavioral sequelae), Health Related Quality of Life (QOLIBRI), the Hospital Anxiety and Depression Scale (HADS), and adverse events. Assessments were completed at baseline and 3-, 6-, and 9-month follow-ups. Mixed effects models of repeated measures with intention to treat analysis were employed, with the primary outcome time-point of 6-months. A Least Square Mean Difference (LSMD) from baseline to 3-, 6-, and 9-month follow-up was calculated with 95% confidence intervals (CI). ResultsOne hundred and eighty-two participants (mean age 40.6{+/-}14.2 in the MLC901 group and 40.1{+/-}12.0 in the Placebo group, 50% and 47.8% females, respectively) were included in the analysis. Baseline variables were comparable between groups. Multivariate mixed effects model analysis did not reveal significant improvements in complex attention (LSMD=-1.18 [95% CI -5.40; 3.03; p=0.58] and other cognitive domains at 6-months in the MLC901 group compared to the Placebo group. There were significant improvements in RPQ, QOLIBRI, anxiety and depression in the MLC901 group compared to the Placebo group at 6 and 9-months (LSMD -4.36 [-6.46; -2.26] and -4.07 [-6.22; -1.92], 4.84 [1.58; 8.10] and 3.74 [0.44; 7.03], -1.50 [-2.29; -0.71 and -0.96 [-1.84; -0.08], -1.14 [-1.92; -0.35] and -1.14 [-1.94; -0.34], respectively. No serious adverse events were reported. ConclusionsThe 6-month treatment with MLC901 did not result in a statistically significant difference with placebo for CNS-VS measurement of complex attention and other cognitive outcomes in individuals with mild TBI. The study showed a clinically and statistically significant improvement in all clinical scales assessed by the investigators (post-concussion symptoms, quality of life, and mood). This study showed that post-mild TBI treatment with MLC901 0.8g/day is safe. Trial registrationClinicalTrials.gov identifier NCT04861688.