J. Neurotrauma [JOURNAL]
Sun
200 papers
Early Predictors of Walking Recovery in Patients after Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis.
Cao L, Ou J, Miaoyuan Z … +4 more , Wang X, Sheng C, Tan X, Dai Z
J Neurotrauma · 2026 Feb · PMID 41700668 · Publisher ↗
To identify, categorize, and rank the predictors of walking recovery in patients with traumatic spinal cord injury (SCI). We prospectively registered (CRD42023443454) this review and followed the Preferred Reporting Item...
To identify, categorize, and rank the predictors of walking recovery in patients with traumatic spinal cord injury (SCI). We prospectively registered (CRD42023443454) this review and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Embase, Cochrane, and Web of Science until July 2025. We assessed study eligibility, extracted data, appraised study quality using the Quality In Prognostic Studies, and evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation. We meta-analyzed adjusted effect estimates within the same stratification when data from two or more studies were available; when meta-analysis was not appropriate, we presented the results qualitatively. Fifty-four studies met the inclusion criteria. Study quality levels were rated as poor (3 [5.6%] of 54 studies), fair (40 [70%]), and good (11 [20.4%]) quality. Predictor variables were classified into five categories: (1) sociodemographic factors, (2) injury-related factors, (3) magnetic resonance imaging parameters, (4) serum/cerebrospinal fluid (CSF) biomarkers, and (5) treatment-related factors. American Spinal Injury Association Impairment Scale (AIS) and neurological level of injury (NLI) were found to be the most significant predictors of walking recovery (odds ratio [OR] = 3.70; 95% confidence interval [CI]: 2.86-4.79; = 0.001; = 2%; high certainty) and (OR = 2.81; 95% CI: 1.54-5.14; = 0.008; = 0%; moderate certainty), respectively. Patients with diabetes were less likely to regain ambulatory ability after SCI (OR = 0.64, 95% CI: 0.42-0.98; = 0.038; = 0.0%; moderate certainty). Other widely studied predictors, such as age and timing of surgery, showed inconsistent results across cutoffs. In conclusion, the initial severity of injury (AIS and NLI) was the strongest predictor of walking recovery, indicating that patients with less severe impairment at admission had a higher probability of walking recovery.
Triggering Receptor Expressed on Myeloid Cell 2-Mediated Microglial Phagocytosis in the Subacute Phase of Traumatic Brain Injury Exacerbates Impaired Memory.
Xia J, Sun CY, Su T … +3 more , Xia SY, Zhao SZ, Zhang YM
J Neurotrauma · 2026 Feb · PMID 41700019 · Publisher ↗
Traumatic brain injury (TBI) induces severe neuropsychiatric complications. Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for microglial-mediated synaptic engulfment. This study aimed to clarify t...
Traumatic brain injury (TBI) induces severe neuropsychiatric complications. Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for microglial-mediated synaptic engulfment. This study aimed to clarify the unique role played by microglial TREM2 in memory dysfunction during the subacute phase of TBI. Behavior tests were conducted to assess post-TBI memory impairment in male Sprague-Dawley (SD) rats. The activity of microglia in different phases of TBI was observed via detecting Iba1 immunoreactivity by immunofluorescence and microglial markers by quantitative reverse transcription polymerase chain reaction. Pharmacological inhibition of microglia regulates its activity during the subacute phase. Additionally, we employed male Trem2 knockout mice in the C57BL/6J genetic background, as well as male wild-type C57BL/6J mice subjected to brain stereotaxic injection of TREM2 small interfering RNA. Rats subjected to TBI showed impaired memory retention in the Morris water maze test. Microglia activation and TREM2 expression peaked in the subacute phase, especially in Cornu Ammonis1 (CA1). Pharmacological inhibition of microglia in SD rats attenuated cell apoptosis and synaptic loss caused by TBI. Further studies demonstrated that selective knockdown of TREM2 in CA1 reduced microglia-mediated phagocytosis of synapses and enhanced synaptic plasticity, improving memory dysfunction associated with TBI. Our findings suggest that upregulation of TREM2 exacerbated TBI-induced memory dysfunction by promoting excessive microglial phagocytosis and synaptic loss in the subacute phase.
Civilian Traumatic Brain Injury Is Associated with Longitudinally Increased Risk of PTSD, Suicidality, and Other Mental Health Diagnoses.
Halabi C, Mills H, DiGiorgio AM … +4 more , Schenk G, Israni S, Peek-Asa C, Manley GT
J Neurotrauma · 2026 Feb · PMID 41689233 · Publisher ↗
In this prospective longitudinal multiple-cohort study, we investigated mental health outcomes in patients with traumatic brain injury (TBI) or Orthotrauma (fracture excluding head/neck) using data from six University of...
In this prospective longitudinal multiple-cohort study, we investigated mental health outcomes in patients with traumatic brain injury (TBI) or Orthotrauma (fracture excluding head/neck) using data from six University of California civilian healthcare settings between 2013 and 2022. Trauma cohorts were propensity matched 1:1 by age, race and ethnicity, sex, site, insurance coverage, area deprivation index, and number of visits within the year preceding injury diagnosis in the health record (index), then propensity matched to unexposed individuals. International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes identified patients and study mental health outcomes (depression, anxiety, post-traumatic stress or PTSD, suicidality, bipolar disorder, schizophrenia). Cox proportional hazard models generated hazard ratios (HR) from 1 year pre- to 7 years post-index for 3 groups: TBI vs unexposed, Orthotrauma vs unexposed, and TBI vs Orthotrauma. Analyses included patients with pre-index mental health outcomes and were adjusted for documented suicide attempt. Age and sex stratifications were explored. Results included 174,384 patients (99,356 female [57.0%]; 10,584 Black [6.1%]), including 43,596 each in TBI and Orthotrauma cohorts and 87,192 unexposed (all median [IQR] age, 57.0 [42.0-70.0] years). Compared to Orthotrauma, TBI affected post-index HRs most strongly for PTSD (HR range 1.75-2.59 through Year 6, pre-index 1.74-1.84) and suicidality (HR range 2.34-6.17 through Year 7, pre-index 1.51-1.95) with particularly elevated suicidality risk within 6-12 months of index. Mental health diagnoses served as precursors to and consequences of TBI. Patients with traumatic injuries should be screened and treated for mental health conditions. Etiologic studies are urgently needed.
Younger Age of First Exposure to American Football Is Associated with Worse Informant-Reported Clinical Outcomes in Older Age Brain Donors.
Nosek SB, Gonzalez Gil S, Abdolmohammadi B … +16 more , Layden R, Nowinski CJ, Tripodis Y, Martin BM, Palmisano JN, Torres A, Dwyer BC, Katz DI, Goldstein LE, Cantu RC, Stern RA, Stein TD, McKee AC, Mez J, Alosco ML, Daneshvar DH
J Neurotrauma · 2026 Feb · PMID 41688863 · Full text
Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examine...
Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examined the association between AFE to football and clinical outcomes before and after age 60 at death, to isolate the potential role of decreased neuropathological resilience in older age. This study included 677 deceased male football players who donated their brains to the Understanding Neurologic Injury and Traumatic Encephalopathy Brain Bank. Informants completed modified scales assessing cognition, function, behavior, and neuropsychiatric features with dementia adjudicated through consensus conferences. Regressions tested the association between AFE and dementia, chronic traumatic encephalopathy (CTE) pathology, and each scale, adjusted for multiple testing. Analyses were stratified by age 60, adjusting for age at death, duration of play, and neuropathology. Most donors (mean age = 60.9, standard deviation = 19.8) played college or professional football ( = 509, 76%). CTE was the most prevalent neuropathology ( = 471, 70%). AFE was not associated with neurodegenerative disease pathology. Among those older than 60 at death, younger AFE was associated with cognitive composite score impairment (odds ratio: 0.897, 95% confidence interval [CI]: 0.814-0.988, = 0.027) and worse cognitive (beta: 0.04, 95% CI: 0.01-0.069, = 0.009), neurobehavioral (beta: 0.032, 95% CI: 0.002-0.062, = 0.035), and neuropsychiatric (beta: 0.032, 95% CI: 0.00-0.064, = 0.048) composite scores. Younger AFE was only associated with worse informant-reported clinical outcomes in older deceased football players, independent of neurodegeneration. Our findings offer a potential explanation for the mixed literature on AFE and clinical outcomes. The effects of AFE may only manifest in older adults when cognitive reserve is depleted, neuropathological resilience is reduced, or age-related vulnerabilities interact with prior head injury exposure, worsening clinical outcomes.
The Impact of Sex on the Dysfunction of Endogenous Pain Control after Traumatic Brain Injury.
Irvine KA, Ferguson AR, Clark JD
J Neurotrauma · 2026 Feb · PMID 41631718 · Full text
Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior w...
Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α-adrenoceptors) and atipamezole (α-adrenoceptors), and the serotonin 5-HT receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α- to an α-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.
Adverse Childhood Experiences Exacerbate Neurobehavioral and Post-Traumatic Stress Disorder Symptoms Among Survivors of Intimate Partner Violence-Related Head Trauma.
Jain D, Carlsson E, Baird CL … +21 more , Carter EE, Chase S, Clark E, Cwiek A, Dorman K, Méndez-Fernández AP, Lan X, Lockhart FV, Mullin HA, Read EN, Rebuck E, Sakamoto MS, Velez C, Wilde M, Koerte IK, Marshall AD, Tate DF, Lin AP, Wilde EA, Hillary FG, Esopenko C
J Neurotrauma · 2026 Feb · PMID 41626812 · Full text
At least 27% of women who report a history of intimate partner violence (IPV) also report experiencing IPV-related head trauma (IPV-HT) or probable brain injury (IPV-BI). Prior studies of non-IPV-related traumatic BI and...
At least 27% of women who report a history of intimate partner violence (IPV) also report experiencing IPV-related head trauma (IPV-HT) or probable brain injury (IPV-BI). Prior studies of non-IPV-related traumatic BI and IPV-BI suggest that adverse childhood experiences (ACEs) may be associated with the severity of common neurobehavioral symptoms after the injury, potentially due to their association with elevated post-traumatic stress disorder (PTSD) symptoms. This study sought to examine PTSD symptom severity as an intermediary of the relationship between ACEs and measures of symptoms commonly reported after HT among 121 women with exposure to IPV-HT. Linear regressions examined the association between ACEs and neurobehavioral symptoms assessed by the Rivermead Postconcussion Symptoms Questionnaire (RPQ), Headache Impact Test-6 (HIT-6), and Quality of Life in Neurological Disorders Cognitive Function-Version 2 (Neuro-QoL), while adjusting for other common influences on the severity of these symptoms: IPV-HT and other HT severity, time since most recent, worst IPV-HT (determined using the Brain Injury Screening Questionnaire), past year partner abuse frequency (determined using the Revised Conflict Tactics Scale), and age. Cross-sectional mediation analyses examined whether ACEs indirectly covaried with neurobehavioral symptoms via PTSD symptom severity (determined using the PTSD Checklist for DSM-5 [PCL-5]). ACE score was significantly associated with RPQ score (b = 1.65, < 0.001) and Neuro-QoL T-score (b = -0.64, = 0.03). The association between ACE score and RPQ score, and ACE score and Neuro-QoL T-score indirectly covaried by PCL-5 score (unstandardized indirect effect [bootstrapped 95% confidence interval]: RPQ: 0.680 [0.221,1.308]; Neuro-QoL: -0.658 [-1.255,-0.113]). The findings suggest that ACEs are associated with worse symptoms after IPV-HT, potentially by way of the association between ACEs and heightened PTSD symptom severity. Longitudinal studies are needed to determine the causality of these relationships. However, our findings suggest that ACEs and elevated PTSD symptoms may be important considerations for individuals reporting symptoms associated with IPV-HT. As such, providers of these individuals may want to consider whether childhood adversity may be impacting current symptom burden in conjunction with IPV, PTSD, and associated HT/BI.
Prevalence and Risk of Anxiety and Depression after Concussion: A TRANSCENDENT Study.
van Ierssel JJ, Kutcher SA, Johnston S … +16 more , Pham NK, Lamoureux M, Dodd AB, Mullan M, Yeates KO, Ledoux AA, Liu BC, Lalonde C, Master CL, Howell DR, Chintoh A, Mikolić A, Beauchamp MH, Silverberg ND, Zemek R, TRANSCENDENT Concussion Integrated Discovery Program
J Neurotrauma · 2026 Feb · PMID 41622503 · Publisher ↗
Anxiety and depression are associated with high symptom burden, functional limitations, and poor quality-of-life. Understanding the prevalence and risk factors for mental health symptoms after concussion is essential for...
Anxiety and depression are associated with high symptom burden, functional limitations, and poor quality-of-life. Understanding the prevalence and risk factors for mental health symptoms after concussion is essential for early identification and targeted treatment. The objective of this study was to estimate the prevalence and risk factors associated with moderate-to-severe anxiety (msANX) symptoms and depression (msDEP) symptoms after concussion. This prospective observational study recruited participants from three specialty concussion clinics within the TRANSCENDENT Concussion Research Program. Adolescents and adults aged 13 years and older diagnosed with a physician-confirmed concussion who presented for routine care within a learning health system were eligible if they completed mental health measures at intake assessment between April 2024 and July 2025. Primary outcomes were msANX (Generalized Anxiety Disorder-7 [GAD-7] ≥10) and msDEP (Patient Health Questionnaire-9 [PHQ-9] ≥10) symptoms at intake assessment. Multivariable logistic regression assessed the association between symptoms and patient-related and injury-related factors. Models were adjusted for known predictors. Of 1,639 participants ( = 1,051 [64%] female; median [interquartile range, IQR] age, 28 [17-45] years; median [IQR], 21 [12, 42] days since injury), 45.2% (95% confidence intervals, CI, 42.8-47.7) had msANX (median [IQR] score, (15 [12-18]) and 60.7% (95% CI, 58.3-63.0) had msDEP (median [IQR] score, (16 [12-19]). Risk factors included injury setting (motor vehicle collision [msANX: OR, 3.68; 95% CI: 2.56-5.30; < 0.001; msDEP: OR, 3.15; 95% CI: 2.11-4.74; < 0.001], workplace [msANX: OR, 2.85; 95% CI: 1.90-4.30; < 0.001; msDEP: OR, 2.73; 95% CI: 1.74-4.35; < 0.001], and assault [msANX: OR, 2.24; 95% CI: 1.07-4.82; = 0.03] compared with playing sports, having preinjury anxiety (msANX: OR, 1.97; 95% CI, 1.41-2.75; < 0.001; msDEP: OR, 1.87; 95% CI: 1.31-2.70; < 0.001), sleep difficulties (msANX: OR, 1.44; 95% CI: 1.36-1.52; < 0.001; msDEP: OR, 1.62; 95% CI: 1.53-1.73; < 0.001), being female (msANX: OR, 1.38; 95% CI: 1.08-1.77; = 0.01; msDEP: OR, 1.34; 95% CI: 1.04-1.72; = 0.03), and time since injury (msANX: OR, 1.16; 95% CI: 1.07-1.26; < 0.001; msDEP: OR,1.10; 95% CI: 1.01-1.20; = 0.03). Leveraging data collected during routine care, this study suggests that existing prevalence estimates likely underestimate the high levels of anxiety and depression symptoms at specialty clinic intake that warrant active treatment. Clinicians should routinely screen for mental health conditions and prioritize higher-risk patients for closer monitoring, including those injured in a motor vehicle collision or at work, female patients, and those with preinjury anxiety or postinjury sleep difficulties. Timely referral to mental health professionals is needed to prevent chronic mental health problems and optimize recovery.
Alterations in CSF Amyloid-β and Tau Biomarkers in Former College and Professional American Football Players: Findings from the DIAGNOSE CTE Research Project.
Jansson D, Shofer J, Colasurdo E … +22 more , Schindler A, Li G, Adler CH, Balcer L, Bernick C, Daneshvar D, Katz D, McClean M, Mez J, Palmisano J, Ashton N, Blennow K, Zetterberg H, Tripodis Y, Alosco ML, Cummings JL, Reiman EM, Shenton M, Stern RA, Iliff J, Peskind ER, DIAGNOSE CTE Research Project
J Neurotrauma · 2026 Apr · PMID 41612558 · Full text
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Curren...
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only , but can present with an array of cognitive, behavioral, mood, and motor symptoms. However, traumatic brain injury is also associated with increased risk of Alzheimer's disease (AD) and may lead to comorbid neuropathology. Characterization of the biomarkers of CTE is a necessary next step to facilitate accurate diagnoses. We examined the profile of cerebrospinal fluid (CSF) biomarkers of amyloid-β, total tau (tTau), and phospho-tau (pTau) in a cohort of former professional (PRO, = 100) and college (COL, = 40) football players at high risk of CTE compared to asymptomatic unexposed controls (UE, = 43). CSF was collected under controlled conditions using collection, processing, and cryostorage kits provided by the DIAGNOSE CTE Research Project Biomarker Core, and concentrations of Aβ, Aβ, tTau, and pTau (pTau, pTau, pTau) were measured at the University of Gothenburg, Sweden, using immunoassays. Associations between CSF biomarker levels with football history, and diagnosis of traumatic encephalopathy syndrome (TES) were examined using linear regression, and corrected for age, education, -ε4 allele status, race, and body mass index. Our analysis revealed that football exposure affected both CSF Aβ ( = 0.039) and Aβ ( = 0.038), particularly among those under 60 years of age in the PRO compared to the UE exposure group. Among former football players, estimates of RHI exposure were not generally associated with CSF Aβ, tTau, and pTau biomarker levels. CSF Aβ ( = 0.0041) and Aβ ( = 0.011) were lower in former football players with TES diagnosis compared to unexposed participants, although CSF Aβ, tTau, and pTau biomarker levels did not differ between former players with and without a TES diagnosis. Among former football players, reduced CSF Aβ ( = 0.011) and Aβ (p = 6e-04) were observed in those with cognitive impairment compared to those with neurobehavioral dysregulation. The findings of significant associations of reduced CSF Aβ levels with RHI in elite football players are in line with recent studies; however, the lack of relationship with CSF tTau and pTau species observed to be altered in the setting of AD suggests that the pathological features of CTE reflected in fluid biomarkers are complex and require further study. The overlapping comorbid age-dependent features of neurodegeneration that occur in those at risk for CTE suggest that tau pathology in CTE is not reliably reflected by currently available fluid biomarkers and that the use of multiple biomarkers related to the compound characteristics of CTE may be required for early detection.
Atorvastatin Regulates the Efferocytosis of Macrophages to Promote Hematoma Absorption and Inflammation Resolution in Experimental Subdural Hematoma.
Tong S, Dong S, Wang Y … +5 more , Wu C, Tian Y, Wang B, Nie M, Jiang R
J Neurotrauma · 2026 Jan · PMID 41609140 · Publisher ↗
Macrophage-mediated efferocytosis is crucial for hematoma absorption and inflammation resolution in intracranial hemorrhages. We previously demonstrated that atorvastatin (ATO) expedites the absorption of subdural hemato...
Macrophage-mediated efferocytosis is crucial for hematoma absorption and inflammation resolution in intracranial hemorrhages. We previously demonstrated that atorvastatin (ATO) expedites the absorption of subdural hematoma (SDH); however, the extent to which this therapeutic effect is associated with ATO-mediated modulation of macrophage efferocytosis remains unclear. In this study, we established a rat model of SDH through autologous blood transfusion into the subdural space. We used primary bone marrow-derived macrophages (BMDMs) to investigate the roles of heme and ATO. The results of enzyme-linked immunosorbent assay and flow cytometry demonstrated that, in addition to its proinflammatory effect, heme also inhibits macrophage efferocytosis. However, ATO reversed this inhibition of efferocytosis in both and experiments. Transcriptomic analysis of BMDMs revealed that ATO promotes Krüppel-like factor 4 (KLF4) expression and is mainly enriched in phagocytosis and lysosome-related pathways. Finally, ATO restored the heme-induced reduction in the macrophage phagocytic rate and impairment of lysosomal function. However, KLF4 knockout abolished the beneficial effects of ATO. In conclusion, this study demonstrated that ATO ameliorates heme-inhibited efferocytosis via KLF4, thereby promoting hematoma absorption. We demonstrated a novel mechanism of ATO in the treatment of SDH, providing a new therapeutic prospect for patients (IRB2022-YX-007-01).
Sex-Specific Associations Between Repetitive Head Impact Exposure and Cerebral Blood Flow Among Active Amateur Soccer Players.
Li Z, Asiares AV, Betz A … +5 more , Schuhmacher LS, Joyce J, Lohmann L, Sollmann N, Koerte IK
J Neurotrauma · 2026 Jan · PMID 41593837 · Publisher ↗
Repetitive head impacts (RHIs) in soccer have been associated with long-term risk for neurodegenerative disease. The pathophysiology is largely unknown. This study aims to investigate alterations in cerebral blood flow (...
Repetitive head impacts (RHIs) in soccer have been associated with long-term risk for neurodegenerative disease. The pathophysiology is largely unknown. This study aims to investigate alterations in cerebral blood flow (CBF) in athletes exposed to RHI compared with athlete controls (CTL). Given that females are known to exhibit higher CBF than males, we also explore sex-specific differences. Finally, we investigate the relationship between CBF and neuropsychological functioning and RHI measures. This study includes 82 amateur athletes (mean age 22.8 ± 1.6 years; 48.9% female). Participants underwent 3T magnetic resonance imaging and completed neuropsychological testing, including questionnaires on stress, resilience, and sleep quality, and computerized assessment of executive function, memory, and processing speed. CBF was assessed using MR pulsed arterial spin labeling. Analysis of covariance was applied to assess the effect of RHI exposure and sex on CBF. Associations between CBF and neuropsychological functioning were analyzed using linear regression models. The analysis was conducted hierarchically, beginning with global gray matter CBF (level 1), followed by cortical and deep gray matter (level 2), and finally brain lobes (level 3). Correction for multiple comparisons was applied at each hierarchical level using false discovery rate, with a significance threshold set at < 0.05 after correction. We found higher CBF in athletes with RHI exposure (RHI group) compared with athletes with <5 years of exposure to RHI (CTL group; Δ 95% confidence interval [95% CI] = 3.9 [0.5, 7.3] mL/100g/min, = 0.027). Female athletes with RHI exposure exhibited higher CBF in the global gray matter compared with female CTL (Δ[95% CI] = 6.6 [1.6, 11.5] mL/100g/min, = 0.013). Among males, individuals with RHI exposure demonstrated higher CBF in the occipital lobe compared with male CTL (Δ[95% CI] = 4.9 [0.3, 9.5] mL/100g/min, = 0.047). There were no statistically significant associations between CBF and neuropsychological functioning. In the RHI group, years of soccer play were positively associated with whole-brain CBF. Results from this study suggest an association between RHI exposure and higher CBF, a measure of brain activity. Furthermore, we report sex-specific patterns of higher CBF in individuals exposed to RHI, with more widespread elevated CBF in women and more localized higher CBF in men. While these findings highlight the importance of investigating sex-specific effects, there were no associations between CBF and neuropsychological functioning. Future studies are warranted to determine the clinical relevance of the observed sex-specific effects to RHI.
Comparative Evaluation of Resting-State and CO-Induced Cerebrovascular Reactivity in Patients with Traumatic Brain Injury.
Kim D, Kim JJ, Kim Y … +5 more , Duncan D, Amyot F, Kenney K, Diaz-Arrastia RR, Choi JY
J Neurotrauma · 2026 Jun · PMID 41468176 · Publisher ↗
Cerebrovascular reactivity (CVR) mapping is a promising biomarker for evaluating vascular dysfunction following traumatic brain injury (TBI). Traditional CVR assessment requires carbon dioxide (CO) administration. Assess...
Cerebrovascular reactivity (CVR) mapping is a promising biomarker for evaluating vascular dysfunction following traumatic brain injury (TBI). Traditional CVR assessment requires carbon dioxide (CO) administration. Assessing CVR from resting-state blood-oxygen-level-dependent (BOLD) sequences (RS-CVR) offers a task-free alternative, but its validity in TBI has not yet been established. We aimed to evaluate whether RS-CVR can reliably detect cerebrovascular impairment in patients with TBI by comparing it with CO-inhalation CVR (CO-CVR). We enrolled 23 chronic moderate-to-severe TBI patients and 13 healthy controls (HC) who underwent both CO-CVR and RS-CVR imaging using BOLD functional magnetic resonance imaging (BOLD fMRI). RS-CVR maps were computed using a voxel-wise general linear model (GLM) across 120 bandpass filters. Spatial correlations between RS-CVR and CO-CVR were calculated to identify the optimal frequency bands. Z-score analyses and lesion-based comparisons were performed to assess CVR reductions in TBI. In the TBI cohort, lesion-based CVR was correlated with clinical outcomes using GLM adjusted for age and sex. The highest whole-brain spatial correlation between RS-CVR and CO-CVR in HC occurred at [0-116.4 mHz] (r = 0.5239 ± 0.1107). In TBI, the peak correlation slightly shifted to [0-74.5 mHz] (r = 0.5217 ± 0.1108) but remained comparable at [0-116.4 mHz] (r = 0.5093 ± 0.1263). As expected, regions of encephalomalacia, fluid-attenuated inversion recovery hyperintensity, showed CVR reductions on RS-CVR and CO-CVR maps, but low CVR was also identified through both methods in normal-appearing brain tissue. Across lesion areas, RS-CVR detected deficits consistent with CO-CVR, with mean z-scores of -0.217 ± 0.334 and -0.391 ± 0.294 for encephalomalacia and hyperintensities, respectively. Lesion-based CVR values were associated with clinical outcomes, with both CO-CVR and RS-CVR positively correlated with days in the intensive care unit (ICU; < 0.05) and showing negative associations with Rivermead post-concussion symptoms questionnaire scores, statistically significant for CO-CVR ( = 0.031) and trending for RS-CVR ( = 0.089). RS-CVR closely mirrors CO-CVR in both global and lesion-specific analyses, validating its use as a noninvasive method for detecting vascular deficits in TBI. This task-free and scalable tool for cerebrovascular assessment offers a valuable approach for characterizing vascular health relevant to TBI prognosis and guiding neurorehabilitation efforts.
EEG Correlates of the Confusional State after Traumatic Brain Injury.
Comanducci A, Derchi CC, Atzori T … +7 more , Valota C, Arcuri P, Trimarchi PD, Colombo MA, Chieregato A, Massimini M, Navarro J
J Neurotrauma · 2026 Jan · PMID 41468172 · Publisher ↗
Post-traumatic amnesia (PTA), recently conceptualized as part of the broader syndrome known as post-traumatic confusional state (PTCS), marks a critical phase of recovery following traumatic brain injury (TBI). Indeed, t...
Post-traumatic amnesia (PTA), recently conceptualized as part of the broader syndrome known as post-traumatic confusional state (PTCS), marks a critical phase of recovery following traumatic brain injury (TBI). Indeed, this state is characterized not only by anterograde memory impairment but also by disorientation, agitation, and attention deficits. Given the phenotypic overlap between PTA/PTCS and delirium-both marked by fluctuating cognitive and attentional disturbances-electroencephalography (EEG) represents a promising tool for elucidating shared pathophysiological mechanisms. While delirium is typically associated with diffuse EEG slowing and the presence of slow-wave activity (SWA), thought to reflect underlying global cortical disruption, it remains unclear whether PTCS exhibits similar EEG underpinnings. In this prospective longitudinal study, we assessed dynamic EEG correlates of PTCS using the grand total EEG (GTE) score, a composite measure that incorporates background slowing and superimposed SWA. We enrolled 42 consecutive TBI patients (mean age = 40.3 ±15 years) classifying them at baseline (T0) into two groups based on the Confusion Assessment Protocol (CAP): those in PTA/PTCS ( = 22; median time from injury 24 days; median CAP total score 5) and those already emerged from PTA/PTCS (i.e., TBI controls, = 20; median time from injury 24 days; median CAP total score 0). At T0, patients with PTA/PTCS exhibited significantly higher baseline GTE scores compared with TBI controls, 16.6 ± 4.5 versus 5.1 ± 2.8; (35.75) = 10.04, < 0.0001; = 3.04, reflecting severe EEG abnormalities characterized by diffuse slowing and disrupted rhythmic activity, as captured by the GTE subdomains. Longitudinal follow-up (T1) at emergence from PTCS revealed a significant EEG improvement paralleling clinical recovery, with GTE scores dropping from 16.5 (interquartile range [IQR]: 6.5) to 8, IQR: 3.75; (21) = 8.03, < 0.0001; = 1.71, confirming EEG's sensitivity to dynamic clinical changes. Furthermore, the severity of EEG abnormalities at follow-up (T1) significantly correlated with the total duration of PTA/PTCS (ρ = 0.56, < 0.0001), underscoring EEG's potential as an objective biomarker for disease burden and for monitoring recovery trajectories. Notably, these findings were independent of pharmacological confounders, as medication regimens were not significantly different across groups and time points. Our results support a reconceptualization of PTA/PTCS as a functional (i.e., non-structural) encephalopathy that shares key clinical and neurophysiological features with delirium, with EEG slowing reflecting widespread, often reversible cortical dysfunction. By capturing these transient yet clinically critical changes, clinical EEG-quantified via the granular, multifaceted GTE-offers a novel tool for diagnosing PTA/PTCS, stratifying its severity, and objectively monitoring its evolution in intensive care unit and subacute rehabilitation settings.
Divergent Global Trends in Mild and Moderate-to-Severe Traumatic Brain Injury: A Comprehensive Burden and Attribution Analysis from 1990 to 2021.
Li X, Xu X, He K … +3 more , Wang X, Tang T, Jing C
J Neurotrauma · 2025 Dec · PMID 41468170 · Publisher ↗
Traumatic brain injury (TBI) represents a significant global health challenge, but a systematic, severity-stratified analysis of its epidemiology and risk factors is lacking. Using data from the Global Burden of Disease...
Traumatic brain injury (TBI) represents a significant global health challenge, but a systematic, severity-stratified analysis of its epidemiology and risk factors is lacking. Using data from the Global Burden of Disease (GBD) 2021 study, this study compares the burden of mild TBI (mTBI) and moderate-to-severe TBI (msTBI) from 1990 to 2021. We analyzed incidence, prevalence, and years lived with disability (YLDs) for TBI across 204 countries and territories and by sociodemographic index (SDI) quintiles. Analysis included the characterization of age and sex distributions, assessment of temporal trends, and evaluation of risk factor attributions for both mTBI and msTBI. The results revealed that while the global age-standardized incidence rate (ASIR) of TBI declined, low-SDI regions experienced rising prevalence and YLD rates despite falling incidence. The ASIR of mTBI decreased significantly (average annual percentage change [AAPC]: -0.587; 95% confidence interval [CI]: -1.211-0.059), whereas the ASIR of msTBI showed no statistically significant decline (AAPC: -0.483; 95% CI: -1.235-0.275). The absolute number of mTBI cases peaked among young and elderly males, while the ASIR of msTBI increased with age in both sexes but remained consistently higher in males. Falls and road injuries remained the leading causes; however, the absolute number of msTBI cases due to these causes continued to rise. Notably, violence-related factors-including conflict and terrorism as well as police conflict and executions-were among the most rapidly increasing risk factors for both TBI subtypes. In conclusion, the global TBI burden is characterized by a stagnant crisis of msTBI, underscoring an urgent need for severity-specific prevention strategies that target high-risk mechanisms and populations to mitigate the devastating impact of msTBI worldwide.
Multicenter Validation of a Telephone-Based Caregiver Interview for Longitudinal Assessment of Outcome after Severe Brain Injury: A Traumatic Brain Injury Model Systems Study.
Sterling A, Bodien YG, Goostrey K … +11 more , Hammond FM, Kazis LE, Nakase-Richardson R, Ni P, O'Neil-Pirozzi TM, O'Rourke J, Sanders WR, Sherer M, Waters AB, Zafonte RD, Giacino JT
J Neurotrauma · 2025 Dec · PMID 41468169 · Publisher ↗
There is limited information about long-term outcomes following severe acquired brain injury (ABI). This is due, in part, to the lack of validated longitudinal assessment measures that can be administered remotely. To ad...
There is limited information about long-term outcomes following severe acquired brain injury (ABI). This is due, in part, to the lack of validated longitudinal assessment measures that can be administered remotely. To address this gap, we developed a caregiver-administered telephone interview designed for the remote evaluation of the functional status of patients who are too impaired to provide reliable self-report. The interview comprises items drawn from three existing standardized instruments: the Coma Recovery Scale-Revised (CRS-R), Cognitive Impairment subscale of the Confusion Assessment Protocol (CAP-Cog), and Galveston Orientation and Amnesia Test (GOAT) (subsequently referred to as the CRS-RT, CAP-CogT, and GOAT-T to reflect telephone administration). The CRS-RT items evaluate the level of consciousness, while the CAP-CogT and GOAT-T items assess basic aspects of cognition. We administered the caregiver interview to 48 caregivers of persons with severe acquired disability (i.e., vegetative state to confusional state) and validated caregiver responses by conducting in-person patient examinations using the original versions of the assessment instruments. To establish the concurrent validity of the caregiver interview, we assessed the correlation between the findings from the caregiver interview and the patient examination, using Lin's concordance correlation coefficient (CCC). The mean (standard error) sensitivity, specificity, and accuracy across both sets of interview items were 0.82 (0.03), 0.68 (0.04), and 0.75 (0.03), respectively. Lin's CCC between caregiver responses to the nine interview items addressing the level of consciousness and the corresponding patient examination findings was 0.78 (95% confidence interval [CI]: 0.65, 0.90), with six items exceeding our cut-off of ≥0.70. However, the correlation between caregiver responses to the eight basic cognition items and the patient examination findings was poor (Lin's CCC = 0.37, 95% CI: -0.09, 0.82), with only three items at or above the cut-off. These results indicate that the CRS-RT can be administered remotely to caregivers of persons with severe ABI-related disability to monitor neurobehavioral status longitudinally. The CAP-CogT and GOAT-T items require further study before they can be used for clinical outcome assessment.
Intrarectal Antagonism of Calcitonin Gene-Related Peptide Prevents Spinal Cord Injury-Associated Neurogenic Bowel Phenotypes.
Willits AB, Kader L, Choudhury S … +5 more , Ewald M, Meriano S, Christianson J, Baumbauer K, Young E
J Neurotrauma · 2025 Dec · PMID 41467995 · Publisher ↗
Neurogenic bowel (NB) affects roughly 60% of people with a spinal cord injury (SCI), and these patients present with slow colonic transit, constipation, and chronic abdominal pain. The mechanisms by which NB bowel develo...
Neurogenic bowel (NB) affects roughly 60% of people with a spinal cord injury (SCI), and these patients present with slow colonic transit, constipation, and chronic abdominal pain. The mechanisms by which NB bowel develops are unclear, thereby limiting interventions to being primarily symptom-focused and ineffective. Therefore, the main goal of this study was to identify the mechanisms that initiate and maintain NB after SCI as a critical step to develop evidence-based, novel therapeutic options to prevent NB. In previous studies, the neurogenic inflammatory mediator () was identified as a high-priority candidate gene. Therefore, in a midthoracic rodent spinal contusion model that presents with clinically translatable NB-like phenotypes, we conducted intrarectal antagonism of CGRP activity using CGRP (compared to vehicle administration) in mice with SCI. This was followed by histological, molecular, and functional (Ca imaging) approaches to assess the prevention of previously reported phenotypes of NB. CGRP significantly prevented colonic dysmotility and structural defects of the colon (i.e., expanded lymphoid nodules). There was also a prevention of microbial invasion into the colon wall and neuronal hyperresponsiveness to autologous fecal supernatants. These data support the role of /CGRP as a candidate mechanism for NB after SCI and highlight the potential for novel therapeutic treatments for the prevention of NB.
Beneficial Effects of Intravenous Immunoglobulin Treatment in a Mouse Preclinical Model of Severe Traumatic Brain Injury.
Chen M, Puhakka N, Edson J … +9 more , Cui X, Lai A, Romero KS, Gallo CS, Migotto MA, Edwards S, Peshtenski E, Pitkänen A, Reutens D
J Neurotrauma · 2026 Jun · PMID 41467983 · Publisher ↗
The long-term sequelae of severe penetrating traumatic brain injury (TBI) include neurological and psychiatric disability, impaired cognitive function, and the development of post-traumatic epilepsy. The present study ev...
The long-term sequelae of severe penetrating traumatic brain injury (TBI) include neurological and psychiatric disability, impaired cognitive function, and the development of post-traumatic epilepsy. The present study evaluated the therapeutic effects of intravenous immunoglobin (IVIg), a well-established immunomodulatory treatment, in a controlled cortical impact model of severe TBI in mice. The beneficial effects of IVIg treatment on acute neurological status, motor function, anxiety level, and spatial learning ability were demonstrated by reduced Neurological Severity Scores, increased Rotarod latency and cumulative movement durations in open-field tests, and improved active place avoidance performance. IVIg treatment also significantly reduced brain tissue loss, which was examined using Nissl staining at 16 weeks after TBI. Furthermore, brain microRNAs (miRNAs) were profiled to identify the biological pathways potentially associated with the actions of IVIg treatment using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. To identify potential peripheral biomarkers reflecting the changes in the brain, differentially expressed miRNAs in plasma and brain samples from the same animals were compared. Our immunostaining results showed that IVIg treatment significantly attenuated the upregulation of IL-1β and complement 3 (C3) and altered the activation of microglia and astrocytes. This proof-of-concept study provided strong evidence for the beneficial effects of IVIg treatment in severe penetrating TBI.
Comparative Validation of Scoring Systems in Acute Traumatic Central Cord Syndrome: Acute Traumatic Central Cord Syndrome Score, Central Cord Score, and Subaxial Cervical AO Spine Injury Score for Surgical Decision Making, Recovery, and Timing of Surgery.
Kumar AA, Lim HL, Saffari SE … +8 more , Zaw S, Feng QJ, Ang E, Lee ZD, Shree Kumar D, Lee L, Pillay R, Ling JM
J Neurotrauma · 2025 Dec · PMID 41457684 · Publisher ↗
Acute traumatic central cord syndrome (ATCCS) is the most common form of incomplete spinal cord injury. Treatment recommendations for ATCCS patients are largely from North America, and their applicability to Asian popula...
Acute traumatic central cord syndrome (ATCCS) is the most common form of incomplete spinal cord injury. Treatment recommendations for ATCCS patients are largely from North America, and their applicability to Asian populations remains uncertain. Scoring systems such as the Acute Traumatic Central Cord Syndrome Score (ATCCSS), Central Cord Score (CCScore), and Subaxial Cervical AO Spine Injury Score (Subaxial AOSIS) can guide treatment, standardize practice, and improve outcomes. We aimed to validate and compare the predictive capabilities of ATCCSS, CCScore, and Subaxial AOSIS in a Southeast Asian population for surgical decision making, functional outcomes, and timing of surgery. We conducted a multicenter retrospective cohort study in Singapore from 2010 to 2023. The ATCCSS, CCScore, and Subaxial AOSIS were calculated for all patients and other relevant presenting, and radiological and surgical variables were collected. The primary outcome measure was significant motor recovery in the American Spinal Injury Association motor score (AMS) on 12-month follow-up. Secondary outcomes were significant motor recovery in the AMS score on 6-month follow-up, significant improvement in the Functional Independence Measure (FIM) score on 6-month follow-up, and significant recovery in the modified Japanese Orthopaedic Association (mJOA) score on 6-month follow-up. The predictive ability of the scores in predicting surgical management, meaningful recovery, and predicting timing of surgery was evaluated using receiver operating curve, with area under the curve (AUC) along with the corresponding 95% confidence intervals (CIs). Cutoff points were described for operative management and for the timing of surgery. A total of 116 patients were included with a mean age of 64.7 years (standard deviation = 12.9). The majority (86.2%) were male, and 65 (56.0%) patients underwent operative management. There was significant AMS improvement at 12 months in 95 (84.8%) of patients, significant AMS improvement at 6 months in 94 (83.2%) of patients, significant improvement in FIM at 6 months in 73 (62.9%) patients, and significant recovery in mJOA score in 67 (57.8%) of patients at 6 months. There were no significant differences in outcomes between operative and conservative management for functional outcomes. The median ATCCSS was 2 (interquartile range [IQR] 1), CCScore was 7 (IQR 4), and Subaxial AOSIS was 8 (IQR: 6). The ATCCSS had the highest predictive performance for the decision for operative management, with an AUC of 0.81 (95% CI: 0.73-0.89) compared with the other scores. All three scores did not predict motor and functional improvements well. The scores performed well for decision making in timing of surgery, with ATCCSS performing the best in predicting early surgery (AUC = 0.88, 95% CI: 0.81-0.95). The cutoff values for early surgery were 2.5 for ATCCSS and 8.5 for CCScore. Scoring systems in ATCCS performed well in decision making for surgery and timing of surgery but did not predict motor and functional recovery in a Southeast Asian cohort.
Neurosurgical Care for Traumatic Brain Injury in Low-Resource Settings: A Multinational Review Evaluating the Influence of Health Systems Framework on Patient Outcomes.
Roach CS, Shawwa JJ, Nee C … +1 more , Lu VM
J Neurotrauma · 2025 Dec · PMID 41449920 · Publisher ↗
Traumatic brain injury (TBI) remains a leading global cause of death and disability, disproportionately impacting low- and middle-income countries (LMICs), where neurosurgical resources are often limited. In these settin...
Traumatic brain injury (TBI) remains a leading global cause of death and disability, disproportionately impacting low- and middle-income countries (LMICs), where neurosurgical resources are often limited. In these settings, foundational gaps in health system infrastructure-such as limited internet access, absence of electronic medical records (EMRs), and lack of standardized protocols-impede timely diagnosis, intervention, and continuity of care. This study evaluates the relationship between health system infrastructure and neurosurgical capacity, intervention delivery, and TBI outcomes across LMICs. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across PubMed, Embase, and Scopus to identify studies examining TBI care and system infrastructure in LMIC institutions. Extracted data were categorized across two primary domains: (1) clinical management and patient outcomes, and (2) implementation of health system components, including EMRs, information and communication technology access, and standardized care protocols. Quantitative analysis incorporated descriptive statistics, chi-square testing, Kruskal-Wallis tests, Glasgow Coma Scale-adjusted linear regression models, and machine learning classifiers to examine associations. Of the LMIC institutions reviewed, only 41% reported the presence of neurosurgical capacity. Implementation of EMRs and standardized protocols was significantly associated with increased neurosurgical capacity (odds ratio [OR] = 1.1, = 0.06; OR = 1.1, = 0.03, respectively). Among facilities with operative capacity, the median neurosurgical intervention rate was 28% (interquartile range [IQR]: 3-33%). Policy implementation predicted reduced post-TBI mortality ( = -10.8, = 0.06; = 0.56), with a median institutional mortality rate of 19% (IQR: 8-17%). Machine learning models demonstrated strong discriminatory ability to predict TBI mortality based on neurosurgical capacity and infrastructure metrics (area under the curve = 0.76). These findings highlight the potential for health system infrastructure-particularly EMRs, internet access, and standardized clinical protocols-to improve neurosurgical readiness and reduce preventable mortality following TBI in LMICs. Strategic investment in digital health tools and policy standardization could be a high-yield, scalable approach to closing global neurosurgical care gaps and improving TBI outcomes in resource-limited settings.
Intracranial Photostimulation Relieves the Learning and Memory Impairment after Traumatic Brain Injury.
Qi W, Hui J, He Z … +9 more , Feng Q, Gu X, Wang J, Huang J, Lin Y, Ge B, Weng W, Gao Y, Feng J
J Neurotrauma · 2026 Feb · PMID 41449764 · Publisher ↗
Traumatic brain injury (TBI) is both an acute health issue and a chronic disease. Cognitive impairments, particularly in learning and memory, cause significant distress for patients and their families. In this study, we...
Traumatic brain injury (TBI) is both an acute health issue and a chronic disease. Cognitive impairments, particularly in learning and memory, cause significant distress for patients and their families. In this study, we innovatively implanted a photostimulation (PS) device into the injured brain tissue of a severe TBI mouse and performed intracranial PS therapy. Intracranial PS significantly improved learning and memory function in severe TBI mice, and the implantation process did not exacerbate the brain injury. Further investigation revealed that intracranial PS might enhance oxidative phosphorylation in the injured neurons, improving energy metabolism and thereby inhibiting neuronal apoptosis. This study provides a novel direction for clinical treatment of learning and memory deficits following TBI.
From a Patient's Perspective, the Term "Mild," Fails to Capture the Complexity and Severity of Brain Injury.
Getty LS
J Neurotrauma · 2026 Feb · PMID 41449732 · Publisher ↗
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