J. Neurotrauma [JOURNAL]
Sun
200 papers
Systemic Administration of an Anti-CD18 Antibody Prevents the Accumulation of Peripheral Leukocytes in Pericontusional Tissue, but Does Not Improve Outcome after Traumatic Brain Injury in Mice.
Guo Y, Hu S, Wang Z … +6 more , Seker FB, Sienel RI, Magdane Boldoczki F, Düring M, Plesnila N, Schwarzmaier SM
J Neurotrauma · 2026 May · PMID 42138114 · Publisher ↗
The formation of brain edema is one of the key factors that determine patient outcomes following traumatic brain injury (TBI). Despite decades of research, no causal treatment is available to date. Among the many factors...
The formation of brain edema is one of the key factors that determine patient outcomes following traumatic brain injury (TBI). Despite decades of research, no causal treatment is available to date. Among the many factors discussed, inflammation is believed to facilitate brain edema formation. Following brain trauma, leukocytes become activated, interact with the vascular endothelium, and transmigrate into pericontusional tissue. It was hypothesized that this process may affect the permeability of the blood-brain barrier and facilitate vasogenic brain edema formation. Thus, our study aimed to investigate the role of leukocyte adherence and migration in brain edema formation after experimental TBI by inhibiting the integrin CD18. Male C57BL/6 mice ( = 7/group) underwent controlled cortical impact (CCI) and were randomly assigned to one of three groups: (1) sham operation, (2) CCI + control IgG, or (3) CCI + anti-CD18 antibody. Treatment was administered 30 min before and 24 h after CCI. The anti-inflammatory effect of the anti-CD18 treatment was verified using two-photon microscopy and immunohistochemistry 48 h after CCI ( = 5/group). Lesion volume and brain edema formation were assessed by T2 and free-water diffusion magnetic resonance imaging longitudinally at 1, 2, 3, 5, and 7 days after the trauma or sham operation. Neurological function was determined daily using the Modified Neurological Severity Score. Vasogenic brain edema formation was detectable up to 7 days after trauma; no edema formation occurred in animals that underwent a sham operation. Anti-CD18 treatment reduced leukocyte-endothelium interaction and leukocyte migration into the brain after trauma to nearly control levels; however, it did not reduce lesion volume or brain edema formation. Preventing the adhesion of circulating leukocytes to cerebral vessels and their migration into the brain parenchyma does not reduce the formation of vasogenic brain edema and lesion volume after TBI in mice.
Modulation of Respiration-Triggered Trans-Spinal Magnetic Stimulation on Diaphragmatic Motor-Evoked Potentials Following Cervical Spinal Cord Contusion in Rats.
Lee KZ, Chen RY, Vinit S … +1 more , Liou LM
J Neurotrauma · 2026 May · PMID 42116690 · Publisher ↗
The current investigation aimed to establish a respiration-triggered trans-spinal magnetic stimulation configuration and examine its modulatory effect on bilateral diaphragmatic motor-evoked potentials following cervical...
The current investigation aimed to establish a respiration-triggered trans-spinal magnetic stimulation configuration and examine its modulatory effect on bilateral diaphragmatic motor-evoked potentials following cervical spinal cord injury. Diaphragmatic motor-evoked potential responses were assessed during inspiration- and expiration-triggered trans-spinal magnetic stimulation under different respiratory drives (i.e., normocapnia and hypercapnia) in both spinal-intact and cervical spinal cord contused rats. The results demonstrated that inspiration-triggered trans-spinal magnetic stimulation elicited a greater bilateral diaphragmatic motor-evoked potential response compared with expiration-triggered trans-spinal magnetic stimulation in uninjured animals. Moreover, heightened respiratory drives induced by hypercapnia diminished the bilateral diaphragmatic motor-evoked potential response during respiration-triggered trans-spinal magnetic stimulation. Notably, high-intensity inspiration-triggered trans-spinal magnetic stimulation mitigated diaphragmatic bursting that occurred after motor-evoked potentials (i.e., post-motor-evoked potential activity). Cervical spinal cord contusion not only reduced inspiratory diaphragmatic activity but also influenced trans-spinal magnetic stimulation-induced diaphragmatic motor-evoked potentials. Specifically, the respiratory modulatory effect of trans-spinal magnetic stimulation on diaphragmatic motor-evoked potentials was blunted in the diaphragm ipsilateral to the lesion. Additionally, the inhibitory impact of inspiration-triggered trans-spinal magnetic stimulation on post-motor-evoked potential activity was also attenuated in contused animals. These results suggest that the effect of trans-spinal magnetic stimulation on diaphragmatic motor-evoked potentials is modulated by respiratory phases and drives. Respiration-triggered trans-spinal magnetic stimulation may serve as a tool to evaluate changes in diaphragm excitability and spinal respiratory circuits following cervical spinal cord injury.
Machine Learning Prediction for 6-Month Outcomes in Traumatic Cerebral Venous Sinus Thrombosis.
Li Z, Wang J, Huang Y … +8 more , Wu C, Li J, Chen L, Mu S, Shen X, Tian X, Wang S, Wei L
J Neurotrauma · 2026 May · PMID 42116686 · Publisher ↗
This study developed and externally validated a multicenter machine learning framework to predict 6-month poor functional outcome (modified Rankin Scale score ≥2) in patients with traumatic cerebral venous sinus thrombos...
This study developed and externally validated a multicenter machine learning framework to predict 6-month poor functional outcome (modified Rankin Scale score ≥2) in patients with traumatic cerebral venous sinus thrombosis (tCVST) complicating moderate-to-severe traumatic brain injury. A retrospective cohort ( = 165, 2015-2020) and a prospective cohort ( = 78, 2020-2024) were assembled from three tertiary centers. Thirty-one admission variables underwent recursive feature elimination and LASSO regression, yielding nine key predictors. Five machine learning algorithms-support vector machine, logistic regression, random forest, extreme gradient boosting, and light gradient boosting machine (LightGBM)-were trained and optimized using nested five-fold cross-validation, with Borderline-Synthetic Minority Oversampling Technique applied to address class imbalance. Model performance was further assessed in the prospective cohort, and bootstrap resampling (2,000 iterations) was used to estimate confidence intervals. Among the evaluated models, LightGBM showed the best predictive performance, with an internal mean area under the receiver operating characteristic (ROC) curve of 0.91 ± 0.03 and an external validation area under the curve (AUC) of 0.86 (95% CI, 0.76-0.94), together with a sensitivity of 0.74, specificity of 0.86, and F1 score of 0.81. SHapley Additive exPlanations analysis was used to improve interpretability and quantify the contribution of individual predictors. In addition, an online risk calculator was developed to facilitate individualized risk estimation. These findings suggest that an explainable machine learning framework may provide useful support for early prognostic stratification in tCVST and may assist clinical decision-making in this complex neurotrauma population.
Neuropathological and Behavioral Effects of Mild Traumatic Brain Injury at High Altitude.
Browne CA, Korotcov A, Cramer NP … +12 more , Gangolli M, Xu X, Jaiswal S, Bosomtwi A, Hatch K, Olsen C, Groen K, Stimpson CD, Dardzinski BJ, Perl DP, Dickstein DL, Galdzicki Z
J Neurotrauma · 2026 May · PMID 42116682 · Publisher ↗
OBJECTIVE: In lowlanders, ascent to and prolonged stay at high altitude (HA) can trigger maladaptive changes in neurovascularization, immune function, and hippocampal-dependent cognitive impairment. Mild traumatic brain...
OBJECTIVE: In lowlanders, ascent to and prolonged stay at high altitude (HA) can trigger maladaptive changes in neurovascularization, immune function, and hippocampal-dependent cognitive impairment. Mild traumatic brain injury (mTBI) induces similar neuropathological and behavioral alterations. The primary objective of this study was to characterize the impact of mTBI at HA on behavioral and neuropathological outcomes in controlled murine models. METHODS: Baseline magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and [F]fluorodeoxyglucose positron emission tomography (PET) were conducted in male C57BL/6J mice prior to exposure to either sea level (SL) or chronic HA (12 weeks, 5000 m simulated in a hypobaric chamber). Mice were then assigned to mTBI (three repetitive closed head injuries) or Sham groups. The impact of HA-mTBI on novel object recognition and contextual fear memory recall, analogs of human subcategories of memory altered at HA, was evaluated 9-12 days postinjury, followed by imaging. RESULTS: Relative to their post-HA imaging assessment, HA-mTBI cerebral blood flow within the cortex, hippocampus, and thalamus was reduced, as was global brain volume. Moreover, statistical parametric mapping analysis detected clear HA-mTBI interactions in glucose uptake with reductions at the injury site and contralateral increases in the cortex and amygdala. Significant clusters were identified by MRI and DTI in the cortex, caudate, and corpus callosum for T2 values, trace, and radial diffusivity in HA-mTBI animals relative to their post-HA assessments. The principal component analysis and Pearson's correlations reveal distinct imaging signatures associated with HA exposure and TBI hippocampal integrity and thalamocortical connectivity, which may contribute to deficits in spatial memory and alterations in exploratory behavior. SUMMARY: The combined burden of chronic HA exposure and mTBI induces a complex neuropathological interaction, evidenced by region-dependent white matter vulnerability, gray matter alterations, and impaired cerebral glucose metabolism. Although HA exposure and mTBI independently produced behavioral deficits, a synergistic behavioral effect was not detected, revealing a critical dissociation between structural/metabolic injury and functional outcomes.
Role of Circular RNAs in Traumatic Brain Injury and Spinal Cord Injury.
Arruri V, Mehta SL, Vemuganti R
J Neurotrauma · 2026 May · PMID 42104786 · Publisher ↗
Circular RNAs (circRNAs) are a unique class of noncoding RNAs that are formed post-transcriptionally, unlike all other classes of ncRNAs that are transcribed from the genome. They are the only class of RNAs that are clos...
Circular RNAs (circRNAs) are a unique class of noncoding RNAs that are formed post-transcriptionally, unlike all other classes of ncRNAs that are transcribed from the genome. They are the only class of RNAs that are closed loops with no 5' and 3' ends. Recent studies showed that mammals form >100,000 unique circRNAs that contain only exons, only introns, or both exons and introns. circRNAs are formed and degraded by various mechanisms, which are specific to this class of RNAs. This review article discusses the functional significance of circRNAs in the pathophysiology of traumatic brain injury and spinal cord injury, with an emphasis on their functionality in controlling mechanisms such as inflammation, oxidative stress, apoptosis, autophagy, neuronal plasticity, neuroprotection, and functional recovery, which are all important for outcomes after an acute central nervous system injury.
Ecological Momentary Assessment of Activity Demand and Time-of-Day Effects on Post-Concussion Symptoms.
Tracey AJ, Rabinowitz AR
J Neurotrauma · 2026 May · PMID 42104590 · Publisher ↗
Engaging in mentally and/or physically demanding activities post-injury may play a role in post-concussion symptom expression; however, the temporal effects of activity demand on post-concussion symptoms in adults with p...
Engaging in mentally and/or physically demanding activities post-injury may play a role in post-concussion symptom expression; however, the temporal effects of activity demand on post-concussion symptoms in adults with persistent post-concussion symptoms (PPCS) are unclear. The purpose of this study was to examine activity demand and time-of-day effects of post-concussion symptoms in individuals with PPCS using ecological momentary assessment (EMA). We enrolled 40 adults (60.5% female; mean age = 42.53 ± 11.36 years) with PPCS in our prospective observational study with repeated measures. Participants completed a 20-day EMA period in which they responded to a smartphone app five times per day to report PPCS symptoms and the activities they were currently engaged in. PPCS symptoms were reported using the Post-Concussion Symptom Scale (PCSS), a 22-item symptom inventory that includes total symptoms (possible range = 0-132) and symptom clusters: cognitive-migraine-fatigue (possible range = 0-66), affective (0-18), sleep (0-12), and somatic (0-12). For each activity reported by participants, they were asked to characterize it as mentally demanding, physically demanding, both, or neither. Descriptive statistics captured PCSS scores and characterizations of activity demand. Linear mixed-effects models (LMMs) examined the effects of time of day and activity demand on PCSS symptom scores. During the EMA period, PCSS scores were in the clinically significant range (mean = 24.68 ± 21.04; range = 0-106). Mean symptom domain scores were 16.53 ± 13.84 for cognitive-migraine-fatigue (range = 0-63), 3.25 ± 4.05 for affective (range = 0-18), 1.69 ± 2.59 for sleep (range = 0-12), and 1.05 ± 1.72 for somatic symptoms (range = 0-10). Across all observations ( = 2,984), among the four activity characterization options, activities were most frequently characterized as neither mentally nor physically demanding ( = 1,675, 44.3%), and most participants ( = 26, 68.4%) characterized activities in this category most frequently. Open-ended responses elaborating on activities in this category included "doing nothing," "sleeping/relaxing," "watching TV," and "eating." Linear mixed-effects model (LMM) results (based on 38 participants with >33% response rates) showed that activity demands were significantly associated with symptoms. Mentally demanding activities were associated with increases in total and cognitive-migraine-fatigue symptoms, whereas physically demanding activities were associated with decreases in these symptoms. Mentally demanding and combined mentally and physically demanding activities were also associated with increased affective symptoms. Additionally, time of day was significantly associated with cognitive-migraine-fatigue symptoms, with increases in symptoms later in the day compared with early in the morning. The present findings extend existing literature by demonstrating the utility of EMA for capturing real-time associations between contextual factors and symptom expression in traumatic brain injury populations. We also provide evidence that time-of-day and activity demands are associated with symptom expression in individuals with PPCS. Collectively, these findings have implications for informing symptom management strategies in PPCS.
From Cortical Impact to Inattention: Real-Time Acetylcholine Disruption Links Brain Trauma to Attentional Deficits.
Moschonas EH, Annas EM, Domyslawski VD … +7 more , Young HJ, Metwally SAH, Capeci HE, Cheng JP, Sun D, Kline AE, Bondi CO
J Neurotrauma · 2026 May · PMID 42099132 · Publisher ↗
Attentional deficits are prevalent and persistent after traumatic brain injury (TBI), yet our understanding of their etiology is incomplete. In uninjured rats, microdialysis studies show that task-evoked increases in ac...
Attentional deficits are prevalent and persistent after traumatic brain injury (TBI), yet our understanding of their etiology is incomplete. In uninjured rats, microdialysis studies show that task-evoked increases in acetylcholine (ACh) in the medial prefrontal cortex (mPFC) correlate with enhanced attentional performance. The goal of this study was to test the hypothesis that TBI decreases task-evoked ACh in the mPFC, compromises nucleus basalis of Meynert (nbM) cholinergic neuron morphology, and impairs attention. Adult male Sprague-Dawley rats trained on the three-choice serial reaction time (3-CSRT) task and then received either a controlled cortical impact or sham injury ( = 10/group). Dialysate samples were collected by microdialysis before and during the 3-CSRT task, and ACh levels were quantified using high-performance liquid chromatography. Cholinergic neurons in the contralateral/ipsilateral nbM were reconstructed and analyzed using the IMARIS software. The findings revealed a task-evoked decrease in ACh in the TBI group, a significant reduction in soma area/volume in the ipsilateral nbM, and impaired sustained attention as measured by performance on the 3-CSRT task. The findings support the hypothesis that TBI-induced attentional impairments are linked to disrupted real-time cholinergic signaling in the mPFC and associated structural changes in cholinergic neurons. These insights could inform the development of targeted interventions to improve quality of life for TBI survivors.
Systematic Review with Qualitative Synthesis of Gut Microbiota Alterations after Acute Brain Injury.
Occhiali E, Renard D, Molkhou C … +4 more , Kerdelhué G, Clavier T, Baulier C, Achamrah N
J Neurotrauma · 2026 May · PMID 42099129 · Publisher ↗
Acute brain injury (ABI), traumatic or nontraumatic, profoundly disrupts the gut microbiota (GM). To provide intensive care physicians with a clearer understanding of this phenomenon, we conducted a systematic review wit...
Acute brain injury (ABI), traumatic or nontraumatic, profoundly disrupts the gut microbiota (GM). To provide intensive care physicians with a clearer understanding of this phenomenon, we conducted a systematic review with qualitative synthesis. Due to significant heterogeneity in study designs, populations, and outcomes, a meta-analysis was not feasible. Instead, findings were synthesized thematically, focusing on study types, microbiota metrics, and clinical associations. Across studies, ABI is consistently associated with reduced microbial diversity, a decline in the relative abundance of several species, and increased interindividual variability in GM composition. Notably, phyla, such as Pseudomonadota, Bacteroidota, and Verrucomicrobiota, are frequently enriched, whereas Bacillota tends to be depleted. These patterns of dysbiosis appear largely consistent regardless of ABI etiologies. Furthermore, GM alterations can occur within a few hours postinjury and often return to baseline levels within months. The review highlights the metabolic, immune, and neuronal disruptions induced by ABI, which may contribute to gastrointestinal dysfunction and negatively influence patient prognosis. Moreover, standard intensive care unit (ICU) therapies may exacerbate GM disturbances. Importantly, dysbiosis has been linked to adverse clinical outcomes (delayed recovery, increased mortality). Emerging therapeutic strategies (metabolite supplementation, fecal microbiota transplantation) have shown potential to modulate the GM and support postinjury recovery. However, the underlying mechanisms of ABI-related dysbiosis and its consequences remain incompletely understood. Future research should aim to clarify the pathophysiological drivers of GM disruption, explore the potential prognostic value of GM dynamics, and assess how ICU therapies influence GM evolution. Developing GM-targeted interventions may offer novel opportunities to modulate ABI-related complications and improve patient outcomes.
Effects of Docosahexaenoic Acid and Sex on Inflammatory Markers, Phagocytic Capacity, and Oxidative Stress After Controlled Cortical Impact in Rat Pups.
Schober ME, Terry CR, Monts JK … +3 more , Jones GC, Ritzel RM, Loane DJ
J Neurotrauma · 2026 Apr · PMID 42093200 · Publisher ↗
Traumatic brain injury (TBI) is a leading cause of acquired neurological disability in children of both sexes. Little is known about sex-dependent differences in oxidative stress and inflammatory response, two important...
Traumatic brain injury (TBI) is a leading cause of acquired neurological disability in children of both sexes. Little is known about sex-dependent differences in oxidative stress and inflammatory response, two important variables in the developing brain after TBI. Using controlled cortical impact (CCI) in 17-day-old male rats to model pediatric TBI, we showed that docosahexaenoic acid (DHA) improved neurological outcomes and decreased markers of post-injury day 1 (D1) oxidative stress and D3 pro-inflammatory microglial activation. Sex affects DHA metabolism, TBI outcomes, and neuroinflammation. Whether DHA sex-dependently affects markers of oxidative stress or brain inflammation in immature pups after TBI is unknown. We hypothesized that DHA would decrease oxidative stress and increase markers of inflammation resolution after CCI in male pups only and would not affect control (CON) pups of either sex. We analyzed CD11b+ cells from rat brains at D1, D3, and D7 for inflammation-related protein expression, DHR123 oxidation as a marker of reactive oxygen species (ROS) production, and phagocytic capacity. In CCI males, DHA increased macrophage phagocytic capacity at D1 and D7. DHA abrogated increased ROS after CCI in macrophages of both sexes at D1 but at D3 decreased ROS only in males. DHA instead increased ROS in female CCI macrophages at D3 and D7. DHA decreased ROS in male D7 CCI microglia but not in females. In both sexes, DHA increased the relative abundance of CCI macrophages expressing IL-10 and CD206, proteins associated with inflammation resolution. In CON rats, DHA decreased phagocytic capacity in D3 male microglia and in D7 female macrophages. DHA increased ROS in D3 and D7 female microglia. Collectively, in males DHA was associated with increased phagocytosis and inflammation-resolving protein expression together with decreased ROS in macrophages after CCI, markers often associated with neuroprotection. In females, DHA had opposite effects on ROS in CCI macrophages. Contrary to our hypothesis, DHA affected CON microglia. We present preliminary data showing that DHA affected phospholipid abundance for some specific classes in both sexes and, in males only, for others. Our findings raise the importance of using sex-matched injured and control subjects when researching putative neurotherapeutics targeting inflammation and oxidative stress after pediatric TBI.
Association Between Plasma Glial Fibrillary Acidic Protein, Ubiquitin Carboxy-Terminal Hydrolase-L1, S100B, and High-Sensitivity C-Reactive Protein Levels, Clinical Findings, and Imaging Abnormalities in Children with Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.
Godfrey D, Bambrick M, Hotz G … +8 more , Jain S, Yuh EL, Rincon S, Sun X, Fortes C, Manley GT, Duhaime AC, TRACK-TBI Investigators
J Neurotrauma · 2026 Apr · PMID 42093199 · Publisher ↗
Blood-based biomarkers have shown utility in discriminating adult patients with and without traumatic brain injury (TBI). Biomarker levels vary with severity, time since injury, and imaging findings (computed tomography...
Blood-based biomarkers have shown utility in discriminating adult patients with and without traumatic brain injury (TBI). Biomarker levels vary with severity, time since injury, and imaging findings (computed tomography [CT] and magnetic resonance imaging [MRI]). However, the association of specific biomarkers with clinical and imaging findings in children across the age spectrum and with different injury severities and presentations is not fully understood. To better characterize biomarker and clinical associations, we studied pediatric blood biomarker patterns within the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (ClinicalTrials.gov #NCT02119182). TRACK-TBI is an observational multisite study that prospectively enrolled TBI patients across the lifespan and injury spectrum, from 2014 through 2018. Two centers enrolled children (ages 0-17 years). All participants underwent a head CT or MRI at the discretion of treating clinicians as part of acute clinical care, and the majority underwent a study MRI 2 weeks after injury. For this TRACK-TBI pediatric cohort, blood sampling was optional with informed consent provided by guardians. For the purposes of this study, only pediatric subjects with study-specific neuroimaging and plasma biomarkers were included. Plasma biomarkers assessed included glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and high-sensitivity C-reactive protein (hsCRP). Biomarker levels were compared between participants with and without radiographical traumatic intracranial findings (day-of-injury CT-positive versus CT-negative and 2-week study MRI-positive versus MRI-negative) and between participants with different clinical indices of injury. Of 158 pediatric participants, 75 consented to blood collection and underwent biomarker analysis. Of these, 65 had acute CT scans (within 24 h of injury) and 43 had standardized study-related MRI scans at 2 weeks (±3 days) from injury; thus, 70 subjects had biomarker levels and study-reviewed CTs and/or MRIs and are included in the present analysis. Univariate analyses showed significant differences in plasma GFAP, UCHL1, S100B, and hsCRP with respect to time since injury and CT findings. GFAP levels differed by Glasgow Coma Scale (GCS) severities and MRI findings; S100B levels differed by GCS and loss of consciousness. Multivariable linear regression models confirmed a significant association of GFAP, UCH-L1, and S100B levels with CT-positive findings and a significant association of GFAP with 2-week MRI-positive findings. Among the biomarkers evaluated in our study, GFAP was the strongest predictor of imaging findings using receiver operating characteristic analysis. Significant age effects were seen for S100B and NSE, with higher values in younger children. Multivariable associations were observed for specific day-of-injury plasma biomarkers and radiographical traumatic intracranial findings on CT and MRI in children with acute TBI. These biomarkers have potential utility to aid in TBI screening by helping to triage which patients are likely to have intracranial findings on neuroimaging.
Quality of Life and Psychological Health after Recovery From Disorders of Consciousness: A Traumatic Brain Injury Model Systems Study.
Gilmore N, Murtaugh B, Bogdanova Y … +11 more , Choo M, Faerman A, Giacino JT, Gonçalves JV, Hammond FM, O'Brien K, Rabinowitz A, Shapiro-Rosenbaum A, Nakase-Richardson R, Whyte J, Bodien YG
J Neurotrauma · 2026 Apr · PMID 42093198 · Publisher ↗
Patients with disorders of consciousness (DoC) resulting from severe traumatic brain injury (TBI) may recover consciousness and independence years later. There is a prevailing belief that recovery, when limited to the re...
Patients with disorders of consciousness (DoC) resulting from severe traumatic brain injury (TBI) may recover consciousness and independence years later. There is a prevailing belief that recovery, when limited to the restoration of independence in activities of daily living, will be accompanied by poor self-reported quality of life (QOL) and psychological health. This perception may influence early clinical decision-making related to the provision of life-sustaining treatment and access to specialized rehabilitation. In this observational study, we utilized data from the multisite TBI Model Systems (TBIMS) to evaluate the outcomes of QOL (Satisfaction With Life Scale [SWLS]), anxiety (Generalized Anxiety Disorder-7 Scale [GAD-7]), and depression (Patient Health Questionnaire-9 [PHQ-9]) in participants who were admitted to inpatient rehabilitation with DoC and recovered the ability to provide self-report on these measures by 1 year post-TBI. Among 887 TBIMS participants admitted to inpatient rehabilitation with DoC (defined as the absence of command-following; 74% male; mean [standard deviation, SD] age = 36.82 [17.87] years; days post-injury on rehabilitation admission = 33.63 [22.51]), 50% regained the capacity to respond to questions on self-report measures at the 1-year follow-up time point. The mean (SD) total scores were as follows: SWLS = 20.38 (7.81), GAD-7 = 4.00 (5.66), and PHQ-9 = 5.22 (5.04). A minority of patients endorsed dissatisfaction (15%) or extreme dissatisfaction (9%) with life, and similarly, only 14% and 16%, respectively, reported anxiety and depression symptoms above the clinical cutoff points. The results were similar at the 2- and 5-year follow-up time points. In summary, at the group level, QOL and psychological health in persons who recover from DoC are similar to those of individuals with less severe brain injuries and to the general population. These findings challenge the assumption that recovery from DoC is associated with poor QOL and psychological health. Clinicians should be aware that patients with a broad range of residual disability after DoC are unlikely to report dissatisfaction with life or have significant anxiety and depression up to 5 years post-TBI.
Labor and Disability: A Nation-Wide Analysis of Pregnancy Outcomes after Spinal Cord Injury.
Michles MJ, Lomba WC, Sun FW … +11 more , Tang OY, Reavis J, Leary OP, Bergsneider B, Bispo F, Wang EJ, Sastry RA, Fridley JS, Oyelese AA, Gokaslan ZL, Sullivan PLZ
J Neurotrauma · 2026 May · PMID 42076945 · Publisher ↗
Spinal cord injury (SCI) is a challenging clinical entity necessitating multidisciplinary management. While the impact of SCI on male fertility is relatively well-understood, its impact on prepartum, peripartum, and feta...
Spinal cord injury (SCI) is a challenging clinical entity necessitating multidisciplinary management. While the impact of SCI on male fertility is relatively well-understood, its impact on prepartum, peripartum, and fetal outcomes remains understudied. This study seeks to elucidate prepartum and delivery-related outcomes associated with a history of SCI in pregnant patients. We identified all pregnant patients admitted to United States hospitals with and without a history of SCI in the National Inpatient Sample from 2016 to 2019. For all patients, five outcomes were analyzed: in-hospital death, discharge disposition, prepartum complications, length of stay (LOS), and cost. For patients undergoing delivery during admissions, five additional outcomes were studied: preterm labor, epidural anesthesia administration, performance of cesarean section (CS), delivery-related complications, and fetal outcome. Unadjusted outcomes were summarized using survey-weighted estimates. Adjusted associations between SCI and maternal outcomes were estimated using stabilized inverse probability of treatment weighting (IPTW) with doubly robust models. We identified 367 unweighted SCI admissions, corresponding to a survey-weighted national estimate of 1,835 SCI admissions (0.01%) among 15,073,815 pregnancy admissions. 91.6% of admissions were for delivery, with 32.5% undergoing CS. Pregnant patients with SCI had an average age of 30.3 years, and a plurality of injuries was lumbosacral (20.7%). Among all pregnant admissions, patients with a history of SCI had higher odds of inpatient mortality (OR = 45.54 [95% CI: 8.45-245.40], < 0.001), lower rates of routine discharge disposition (OR = 0.17, < 0.001), greater LOS (+50%, < 0.001), and elevated costs (+49%, < 0.001). SCI patients were more likely to have prepartum complications of venous thromboembolism (VTE) (OR = 4.01, = 0.041) and genitourinary infections (OR = 4.26, < 0.001). SCI patients were significantly less likely to be admitted electively (39.5% vs. 47.9%, < 0.001) or for delivery (OR = 0.38, < 0.001). Among admissions for delivery, there were no differences in preterm labor or epidural anesthesia administration, but patients with SCI were less likely to experience delivery-related complications (OR = 0.56, = 0.017) and stillbirth (OR = 0.05, = 0.003). SCI patients had significantly higher odds of undergoing CS (OR = 1.88, = 0.006). These findings suggest that SCI confers substantial excess maternal risk, particularly for mortality, as well as VTE, urinary tract infection, CS, and overall resource utilization. Future work using SCI-specific registries with detailed neurological characterization and longitudinal follow-up is needed to refine risk stratification and inform multidisciplinary guidelines for pregnancy management in this population.
Normative Gray Matter Stiffness Gradients in the Human Brain Predict Patterns of Cortical Injury after Concussion.
Hirad AA, Meyers SP, Venkataraman A … +3 more , Alshareef AA, Mix D, Mahon BZ
J Neurotrauma · 2026 Apr · PMID 42059633 · Publisher ↗
Finite-element modeling and MR strain mapping show that mechanical strain concentrates in the cortex, and late-life neurodegenerative sequelae of traumatic brain injury (TBI) are predominantly gray matter disorders. Non...
Finite-element modeling and MR strain mapping show that mechanical strain concentrates in the cortex, and late-life neurodegenerative sequelae of traumatic brain injury (TBI) are predominantly gray matter disorders. Nonetheless, evidence of acute gray matter damage after mild TBI (mTBI) has remained elusive. The empirical gap derives from a limitation of conventional diffusion tensor metrics, which are blind to the cortex's isotropic yet mechanically relevant solid-phase matrix of soma (glial and neural), dendrites, and extracellular scaffold. Here, we leveraged constrained spherical deconvolution (CSD)-derived "total" apparent fiber density (AFD) to index this solid-phase microarchitecture to test two predictions: (1) regional AFD covaries with magnetic resonance elastography (MRE)-derived cortical stiffness, and (2) AFD can detect gray matter injury that tensor metrics miss. We tested the first hypothesis by relating AFD from 349 healthy adults who underwent diffusion MRI to measures of shear modulus from an independent cohort of 59 healthy adults scanned with MRE. The regional distribution of AFD explained 74% of the variance in MRE-measured shear stiffness, indicating AFD is strongly coupled to the microarchitectural features that influence tissue rigidity. We then tested the clinical utility of AFD in three cross-sectional mTBI cohorts-acute (∼72 h), subacute (2 weeks to 90 days), and chronic (>90 days)-each compared with age- and sex-matched controls. Effect sizes were thresholded using Cohen's ; parcels or tracts with || ≥ 2.0 were chosen to isolate effects that are both statistically extreme and robust to distributional effects and technical noise. Using those criteria, 11 cortical parcels in the acute cohort showed decreased AFD. This expanded to 116 parcels in the subacute group and 106 parcels in the chronic cohort; fractional anisotropy detected no parcels, and mean diffusivity flagged only 7-9 parcels. MRE-based stiffness estimates in healthy controls further stratified the observed abnormalities: compliant cortex (∼1.6 kPa) showed AFD gains during recovery; by contrast, the stiffest cortex (∼3.0 kPa) showed persistent decreases, with baseline modulus accounting for >50% of variance in ΔAFD. Across parcels, baseline stiffness from healthy controls predicted the magnitude of AFD change in both the subacute and chronic cohorts: stiffer cortex showed larger AFD decreases; less stiff cortex showed AFD increases (Spearman ρ ≈ -0.72 to -0.74, < 0.001). AFD also revealed robust abnormalities in 12 major white matter tracts across all mTBI cohorts, outperforming diffusion tensor metrics. Because MRE and diffusion MRI were acquired in independent cohorts, these findings should be interpreted as showing that normative region-wise stiffness gradients predict the direction and magnitude of postinjury AFD alterations. This is the first evidence that joint diffusion MRI and MRE analysis sharpens mechanistic interpretations of gray matter microarchitecture and detects gray matter disruption across the mTBI timeline.
Blast Exposure Does Not Increase Blood Biomarkers of Neurodegeneration in Service Members and Veterans with and Without Uncomplicated Mild TBI.
Lippa SM, Gill J, Lai C … +6 more , Kennedy J, Hungerford L, Bailie JM, Brickell T, French L, Lange R
J Neurotrauma · 2026 Apr · PMID 42032849 · Publisher ↗
Prior investigations of how lifetime blast exposure relates to blood biomarkers of brain injury have been limited by small sample sizes and have produced conflicting results. This investigation examined how lifetime blas...
Prior investigations of how lifetime blast exposure relates to blood biomarkers of brain injury have been limited by small sample sizes and have produced conflicting results. This investigation examined how lifetime blast exposure relates to glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, and hyperphosphorylated tau (p-tau) in service members and veterans (SMVs) with and without uncomplicated mild TBI (mTBI). Participants were 422 SMVs prospectively enrolled in a Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence Longitudinal TBI Study. Participants were divided into four groups based on self-reported lifetime blast exposure history as assessed by a single question: none ( = 93), low ( = 136), medium ( = 71), and high ( = 122). Analysis of Covariance was used to examine group differences on GFAP, UCH-L1, NfL, tau, and p-tau. There was a significant effect of blast exposure group on NfL ( = 0.002, η = 0.034) and GFAP ( = 0.035, η = 0.021), but not UCH-L1, tau, or p-tau. comparisons with Bonferroni correction indicated NfL was higher in the No Blast group compared with the Low Blast ( = 0.004) group, but not the Medium Blast ( = 0.069) or High Blast ( = 1.0) groups. GFAP did not significantly differ between the groups after Bonferroni correction (ps > 0.05). Overall, the lone finding that survived correction for multiple comparisons suggested that participants with low levels of self-reported blast exposure exhibited lower levels of NfL than participants with no history of blast exposure. There were no differences in UCH-L1, tau, or p-tau based on self-reported blast exposure in a large sample of SMVs with and without mTBI.
Reappraisal of Computerized Tomography Scoring Systems for Outcome Prediction in Traumatic Brain Injury: A Comparative Analysis of Young and Older Adults.
Castaño-Leon AM, Gomez PA, Paredes I … +8 more , Munarriz PM, Hilario Barrio A, Maldonado Luna M, Baciu AE, Tosi Ugarte L, Loynaz Cardona CE, Martinez Molina S, Lagares A
J Neurotrauma · 2026 Apr · PMID 42010750 · Publisher ↗
BACKGROUND: Several computerized tomography (CT)-based scoring systems have been developed to grade traumatic brain injury (TBI) and predict outcome. However, most were derived from younger populations, and their perform...
BACKGROUND: Several computerized tomography (CT)-based scoring systems have been developed to grade traumatic brain injury (TBI) and predict outcome. However, most were derived from younger populations, and their performance in older adults-who represent an increasing proportion of TBI patients-remains unclear. This study evaluated the prognostic performance of different CT-based models for short- and long-term outcomes in younger versus older adults (≥65 years). METHODS: We retrospectively analyzed 1935 consecutive TBI patients admitted between 2013 and 2024. Individual components of each CT scoring system were recorded from the first CT scan obtained within 24 h after injury. The Marshall CT classification, Neuroimaging Radiological Interpretation System (NIRIS), Rotterdam, Helsinki, and Stockholm CT scores were evaluated. Outcomes included short-term outcomes (TBI-related in-hospital mortality, surgical evacuation of intracranial lesions, intracranial pressure monitoring, and intracranial lesion progression) and long-term outcomes (mortality and unfavorable outcome [Glasgow Outcome Scale {GOS} 1-3] at 6 months). Model performance was assessed using discrimination, calibration, and overall fit. Explanatory contribution of CT findings was evaluated through proportional explained variance. Published equations were applied when available to validate long-term outcome predictions. Internal validation was performed using optimism-corrected bootstrap resampling (1000 iterations). RESULTS: Long-term outcome data were available for 1798 patients (1243 younger and 555 older adults). Overall, prognostic performance was significantly better in younger than in older adults across all outcome measures. The Helsinki CT score demonstrated the best overall performance, with area under the receiver operating characteristic curve values ranging from 0.805 to 0.877. While the Marshall and Rotterdam scores performed comparably to the Helsinki score in predicting in-hospital and 6-month mortality in younger adults, they were significantly less accurate for predicting unfavorable outcomes. The Rotterdam score showed particularly poor performance in older adults. For identifying patients at risk of Marshall CT class deterioration or requiring intracranial pressure monitoring, the NIRIS and Stockholm CT scores performed better, respectively, and maintained noninferior performance in older adults. CONCLUSIONS: CT-based prognostic models show reduced accuracy in older adults compared with younger patients. Among the evaluated tools, the Helsinki CT score provided the most reliable prediction of mortality and unfavorable outcome across age groups, including the older adults.
The Neurological Impact of Repetitive Low-Level Blast Overpressure Exposure.
Sutherland A, McDonald SJ, Spitz G … +3 more , Kelaher C, O'Brien TJ, Shultz SR
J Neurotrauma · 2026 Apr · PMID 42010363 · Publisher ↗
Repetitive low-level blast overpressure exposure is an increasingly recognized occupational hazard for military, law enforcement, and specialist breaching personnel. Unlike high-level blast exposures that commonly result...
Repetitive low-level blast overpressure exposure is an increasingly recognized occupational hazard for military, law enforcement, and specialist breaching personnel. Unlike high-level blast exposures that commonly result in overt traumatic brain injury, acute low-level blast events have not been demonstrated to produce clinically detectable concussion or neurological injury in isolation. Nevertheless, growing concern has emerged that repeated low-level blast exposure may impart cumulative biomechanical stress, capable of producing biologically and clinically meaningful adverse brain effects over time. This narrative review synthesizes human epidemiological, clinical, neuroimaging, and biomarker evidence published between 2010 and 2025, regarding the neurological impact of repetitive low-level blast exposure. We review exposure contexts and operational epidemiology, blast physics, and candidate mechanistic pathways, including axonal and glial stress, cerebrospinal fluid-tissue interface effects, and blast-related vascular perturbation with blood-brain barrier dysfunction, that are supported by converging human translational findings. Clinical manifestations are examined across cognitive, vestibular, oculomotor, auditory, headache, and psychological domains, highlighting the subtle, cumulative, and often subclinical nature of observed effects. We further evaluate emerging fluid biomarkers and advanced neuroimaging modalities that provide evidence of astroglia activation, axonal stress, neurovascular perturbation, and network-level dysfunction in occupationally exposed cohorts. Importantly, current evidence does not demonstrate that repetitive low-level blast exposure alone is sufficient to cause neurodegenerative disease. Rather, findings support a model in which cumulative low-level blast may act as a modifier of neural vulnerability, particularly in individuals with mixed exposure histories or additional risk factors. We conclude by identifying critical gaps in exposure quantification, longitudinal data, and dose-response modeling, and discuss implications for future research and occupational brain-health surveillance.
Analgesic Modulation of Neuroendocrine and Region-Specific Neuropathological Responses Following Blast-Induced Traumatic Brain Injury in Rats.
Samdavid Thanapaul RJR, Govindarajulu MY, Patel MY … +8 more , Krishnan JKS, Menon D, Pundkar C, Phuyal G, Anderson LM, Samineni S, Long JB, Arun P
J Neurotrauma · 2026 Apr · PMID 41992868 · Publisher ↗
Blast-induced traumatic brain injury is a significant health concern among military personnel and civilians exposed to explosive devices. Although analgesics are routinely used in laboratory animal studies, their effects...
Blast-induced traumatic brain injury is a significant health concern among military personnel and civilians exposed to explosive devices. Although analgesics are routinely used in laboratory animal studies, their effects on neuroendocrine and neuropathological responses to blast remain insufficiently understood. This study investigated how preinjury administration of buprenorphine (BUP) or meloxicam (MEL) modulates hypothalamic-pituitary-adrenal axis activation, axonal injury, tau phosphorylation, and astroglial responses following blast exposure. Male Sprague Dawley rats were assigned to sham, blast, blast + MEL, or blast + BUP groups and subjected to two tightly coupled ∼19-psi blast waves using an advanced blast simulator. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy chain (pNFH) were quantified on days 1 and 30, alongside regional (cortex, hippocampus, cerebellum, brainstem) protein expression of pNFH, pTau (Ser396), and glial fibrillary acidic protein (GFAP). Repeated blast exposure caused strong acute elevations in corticosterone, ACTH, and pNFH. BUP suppressed both hormones, whereas MEL selectively reduced ACTH. Both analgesics significantly attenuated acute increases in pNFH, while MEL further mitigated chronic regional elevations in pNFH and GFAP, indicating stronger long-term suppression of axonal and astroglial pathology postblast. Tau hyperphosphorylation was predominantly an acute event, with MEL producing modest region-specific reduction. Region-dependent analyses revealed persistent cortical and brainstem axonal injury, biphasic hippocampal responses, and minimal cerebellar involvement. By day 30, endocrine and CSF biomarkers showed biochemical normalization in analgesic-treated animals but remained elevated in untreated blast-exposed rats. Our findings indicate that routine laboratory analgesics substantially modulate key biomarkers of blast-induced neurotrauma, introducing methodological and interpretive confounds that can impact cross-study reproducibility. Thus, the study should be interpreted primarily as evidence of analgesic-induced biomarker modulation rather than therapeutic neuroprotection.
Early Predictors of Long-Term Outcomes in Pediatric "Mild" Traumatic Brain Injury: A Machine Learning Approach.
Nathaniel U, Erhardt EB, Sasi Kumar D … +14 more , Wu J, Miller SD, Chauhan P, Keskin R, Wick TV, Yeates KO, Master CL, Meier TB, van der Horn HJ, Quinn DK, Davis WA, Phillips JP, Sapien RE, Mayer AR
J Neurotrauma · 2026 Apr · PMID 41992864 · Publisher ↗
While most children recover from pediatric "mild" traumatic brain injury (pmTBI), up to one-third experience persisting symptoms after concussion (PSaC) that interfere with school, social, and emotional functioning. Clin...
While most children recover from pediatric "mild" traumatic brain injury (pmTBI), up to one-third experience persisting symptoms after concussion (PSaC) that interfere with school, social, and emotional functioning. Clinicians face the dual challenge of low PSaC rates and nonspecific symptom rating even among uninjured peers, making accurate prognosis especially challenging. We used machine learning in a large prospective pmTBI cohort ( = 321) to identify indicators of poor recovery at 4 months and 1-year postinjury. Participants completed comprehensive assessments within 11 days of injury that spanned multiple domains including demographics, injury-related factors, child and parent symptom ratings, cognitive tasks, objective performance, and symptom provocation on neurosensory tasks. Variable importance scores and 90% confidence intervals from 150 bootstraps were used to identify the best-performing assessments within each domain and then integrated into a combined model to assess overall prognostic value. Key findings suggest that retrospective self-report of symptom burden and vulnerability to symptom provocation were the most robust predictors of PSaC at both 4 months and 1-year postinjury, outperforming established risk scores. Other important measures included near point convergence, long-term memory, household size, and parental report of child symptom burden. Retrospective symptom burden and acute symptom provocation during simple tasks alongside established risk scores hold promise for improving early risk stratification and guiding individualized care. Additional research is needed to determine how to best integrate these measures into clinical workflows and validate their utility across diverse settings.
The Role of Traumatic Brain Injury on Fracture Healing in Polytrauma.
Baldini TD, Rahmati M, Shahlaie K … +5 more , Price R, Schneider P, Khan S, Lee MA, Saiz AM
J Neurotrauma · 2026 Apr · PMID 41992863 · Publisher ↗
Traumatic brain injury (TBI) has systemic consequences for patients, including a serendipitous role in enhancing fracture healing. Although most polytraumatic injuries impair bone repair, TBI has been associated with acc...
Traumatic brain injury (TBI) has systemic consequences for patients, including a serendipitous role in enhancing fracture healing. Although most polytraumatic injuries impair bone repair, TBI has been associated with accelerated fracture healing and excessive callus formation. This review explores the current understanding of brain-bone interaction and the mechanisms by which TBI may promote osteogenesis. Key contributing factors include an altered immune response, endocrine modulation, sympathetic signaling, neuropeptide signaling, increased osteogenic factors, and exosomal microRNAs. These components influence many elements of fracture healing, including macrophage polarization, osteoblast differentiation, angiogenesis, and suppression of osteoclast activity. Additionally, the overlap between mechanisms of neurogenic heterotopic ossification and fracture healing in the context of associated TBI will be reviewed. Despite substantial pre-clinical and clinical evidence supporting this phenomenon, its translation to therapeutic strategies remains limited. We will discuss future directions for fracture studies that consider the emerging mechanisms of TBI-induced accelerated fracture repair, the existing complexity and challenges in the field, and the potential role of the evidence in developing novel therapeutic options. Understanding these pathways holds promise for advancing fracture and complex musculoskeletal injury treatment, ultimately improving patient outcomes.
Treatment of Persisting Symptoms after Concussion with Repetitive Transcranial Magnetic Stimulation: A Double-Blinded, Randomized, Controlled Trial.
Campbell C, Wilson AJ, Du Plessis S … +5 more , Vergeer MH, Jobin K, Galarneau JM, Gan LS, Debert CT
J Neurotrauma · 2026 Apr · PMID 41968688 · Publisher ↗
Following a mild traumatic brain injury (mTBI), up to 30% of individuals will experience persisting symptoms beyond 3 months. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique...
Following a mild traumatic brain injury (mTBI), up to 30% of individuals will experience persisting symptoms beyond 3 months. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has shown promise as an intervention for persisting symptoms after concussion (PSaC); however, to determine efficacy, larger clinical trials are required. The objective of this study was to investigate the efficacy of high-frequency rTMS targeting the left dorsolateral prefrontal cortex as an intervention for PSaC. This randomized, double-blinded, sham-controlled study recruited adults (aged 18-75 years) experiencing PSaC for at least 3 months and up to 5 years post-mTBI. Participants were randomized 1:1 to receive 20 sessions of rTMS (10 Hz, 10 trains of 60 pulses with 45 s inter-train intervals, 100-120% resting motor threshold) using either an active or sham coil. The primary outcome was the Rivermead Postconcussion Symptoms Questionnaire (RPQ). The primary end-point was the difference in total RPQ score change from baseline at post-rTMS and 1- and 3-month follow-ups in active compared with sham rTMS. Secondary exploratory outcomes included anxiety, depression, quality of life, headache, post-traumatic stress disorder (PTSD), and cognition. To determine the effects of rTMS, a difference-in-differences approach was adopted using linear mixed models, which controlled for age, sex, and baseline stress (life stress questionnaire [LSQ]). One hundred and forty individuals were screened, and 91 participants were enrolled (mean age 41.3 ± 11.3; 61% female). For our primary end-point, there was no significant difference in differences in total RPQ score between the active and sham groups at post-rTMS (β = 1.07, 95% CI [-3.01, 5.1], = 0.607), 1 month (β = 3.81, 95% CI [-0.72, 8.3], = 0.099), or 3 months (β = -3.18, 95% CI [-7.1, 0.70], = 0.108). However, both active and sham groups demonstrated a significant improvement in total RPQ scores from baseline at post-rTMS, 1 month, and 3 months. The secondary outcomes (depression, anxiety, quality of life, headache impact, cognition, post-traumatic stress) demonstrated a significant effect of time, but no significant effect of group. Age and sex did not influence the model; however, higher baseline LSQ (>300) was associated with higher scores in both active and sham groups at all timepoints for every outcome measure other than headache impact. Lower LSQ significantly influenced response to active rTMS treatment with regard to PTSD symptoms at post-rTMS timepoint only but not in the sham group. In conclusion, there was no significant difference between active and sham rTMS when evaluating symptom severity scores. However, both treatment groups significantly improved following intervention, which was maintained up to 3 months. Lower baseline LSQ significantly influenced PTSD symptom response in the active group at post-rTMS only. Alternative neuromodulation approaches should be considered in this patient population.
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