J. Neurotrauma [JOURNAL]
Sun
200 papers
Test-Retest Reliability of the Blast Exposure Threshold Survey in United States Service Members and Veterans.
Lange RT, French LM, Lippa SM … +5 more , Gillow K, Baschenis S, Bailie JM, Hungerford L, Brickell TA
J Neurotrauma · 2026 Jun · PMID 41264354 · Publisher ↗
The Blast Exposure Threshold Survey (BETS) is a recently developed measure of lifetime blast exposure. Although promising, it is considered a fundamental tenet to establish that the BETS (and other measures like it) have...
The Blast Exposure Threshold Survey (BETS) is a recently developed measure of lifetime blast exposure. Although promising, it is considered a fundamental tenet to establish that the BETS (and other measures like it) have good psychometric properties before it can be recommended for clinical use. The purpose of this study was to examine the test-retest reliability of the BETS in a military sample. Participants were 83 United States service members and veterans prospectively recruited from three military medical treatment facilities and from the community. Participants were classified into two broad groups as part of a larger study: traumatic brain injury (TBI; = 41; mild-severe TBI) and controls ( = 42; injured and non-injured controls). Participants completed the BETS, Neurobehavioral Symptom Inventory, and a brief structured interview to gather basic demographic, military, and injury-related information (e.g., age, education, deployments, etc.). In addition, participants completed the BETS on a second occasion (T2) 3 weeks following the first administration (T1). Using Spearman rho correlation analyses, the test-retest reliability of the BETS Generalized Blast Exposure Value (GBEV) was classified as "acceptable" ( = 0.76). However, when comparing individual responses across T1 and T2, 33% of the sample reported significant inconsistencies in the endorsement of the five weapons categories. The most problematic inconsistency (∼10% of the sample) related to the failure of some participants to consistently endorse, or not endorse, exposure to a weapons category at T1 and T2 (e.g., T1 = exposure present; T2 = exposure absent). Less problematic, but also of concern, was the failure of some participants (∼23%) to consistently report the same number of years in which they were exposed to a weapons category from T1 and T2 (e.g., T1 = 10 years; T2 = 5 years). Factors associated with inconsistent reporting from T1 to T2 included higher GBEV scores, older age, higher number of years in the military, higher number of deployments, and higher blast exposure. This is one of the first studies to comprehensively examine the test-retest reliability of the BETS GBEV. Overall, the test-retest reliability of the GBEV was considered statistically acceptable and provides support for the use of the GBEV in both clinical and research settings. Concerningly, however, substantial inconsistencies were found in the basic reporting of weapons exposure in 33% of the sample that need to be addressed. Future researchers should identify ways to improve the BETS to increase response consistency over time.
A Ferret Model of Blast-Induced Traumatic Brain Injury with Biochemical and Neurobehavioral Outcome Measures.
Phuyal G, Govindarajulu MY, Al-Lami A … +5 more , Samdavid Thanapaul RJR, Pundkar C, Sajja VS, Long JB, Arun P
J Neurotrauma · 2026 Apr · PMID 41250846 · Publisher ↗
Although blast-induced traumatic brain injury (bTBI) is considered as the signature injury of recent combat operations such as Operations Iraqi Freedom and Enduring Freedom, no precise biomechanical and biological mechan...
Although blast-induced traumatic brain injury (bTBI) is considered as the signature injury of recent combat operations such as Operations Iraqi Freedom and Enduring Freedom, no precise biomechanical and biological mechanisms of injury have been identified. Consequently, to date, there are no FDA-approved countermeasures for the treatment of bTBI. Animal models that are highly translatable to humans are required for studying the injury mechanisms underlying bTBI. As a small animal with a gyrencephalic cerebral cortex, the ferret has been increasingly used for studying the mechanisms of neurological disorders in recent years, especially for mechanically induced brain injuries such as traumatic brain injury. In this study, we used a ferret model to understand both biochemical and neurobehavioral outcome measures following closely coupled blast exposure at ∼19 psi. The neurobehavioral battery was used to assess activity and thigmotaxis (open field test), short-term memory (novel object recognition test), motor and gait (CatWalk XT system), and sleep patterns (actigraphy) up to 1 month post-exposure. For biochemical outcome measures, enzyme-linked immunosorbent assays were performed for the estimation of levels of phosphorylated neurofilament heavy chain (pNFH) protein and corticosterone in the serum at 24 h and 1-month post-blast. Western blotting was performed to measure the differential expressions of known biomarkers of brain injury such as pNFH, neurofilament light chain (NFL) protein present in the neurons undergoing degeneration, phosphorylated protein, and glial fibrillary acidic protein at 24-h and 1-month post-blast. The results revealed that blast exposure caused significant anxiety-like behaviors, short-term memory loss, disrupted front and hind limbs movements, and disturbed sleep pattern in a time-dependent manner. Levels of both pNFH and corticosterone increased in the plasma post-blast. Western blotting revealed that blast exposure increased the levels of the biomarker proteins evaluated in different brain regions. Overall, we observed changes in biochemical and neurobehavioral outcomes after blast exposure that together suggest that ferret is a potentially valuable animal model for understanding the mechanism of bTBI and developing effective countermeasures.
A Spatial Gene Expression Signature of the Mouse Brain Post-Injury at the Focal Point of Contusion.
Kounelis-Wuillaume SK, Frank AM, Goguet E … +6 more , Alba C, Sukumar G, Wilkerson MD, Dalgard CL, McCabe JT, Doughty ML
J Neurotrauma · 2026 Mar · PMID 41250842 · Publisher ↗
Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially dependent manner. In this study, we investigated the topographical relationship of early transcriptional responses to a sin...
Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially dependent manner. In this study, we investigated the topographical relationship of early transcriptional responses to a single, focal TBI in mice by controlled cortical impact. Guided by the presence of the anterior commissure (AC) in coronal sections at the rostro-caudal point of impact, we compared gene expression changes in the neocortex (CTX) and corpus callosum-external capsule (CC-EC), striatum (STR), and AC. Injury-induced gene expression changes were detected in the CTX, CC-EC, and STR but not AC and were principally segregated based on cytoarchitecture and secondarily by proximity to the site of impact. In addition, unbiased spatial clustering revealed a positive relationship between proximity to the impact and the number of acutely differentially expressed genes within the laminar CTX. Gene pathways for interferon gamma response and for leukocyte-mediated migration and immunity were acutely enhanced across the injured CTX, CC-EC, and STR. Within 1 week post-injury, transcriptional responses to injury in the CTX and CC-EC included gene pathways for adaptive T- and B cell mediated immunity, whereas gene expression changes in the STR were largely resolved. Next, we examined the effects of systemic depletion of neutrophils and monocytes on spatial gene expression changes in the injured brain. The systemic depletion and attenuated infiltration of these immune cells into the damaged brain post-injury led to the upregulation of gene pathways functioning in synaptic transmission and an alternating down- and then upregulation of genes functioning in ribosomal messenger RNA translation and aerobic metabolism in mitochondria. These data suggest that infiltrating neutrophils and monocytes play an evolving, multifaceted role in modulating the metabolic, transcriptional, and synaptic activity of brain tissue post-injury.
The Protective Effects of the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LP17 on Experimental Acute Brain Injury: A Systematic Review and Meta-Analysis Based on Animal Models.
Huang L, Zhang S, Wang C … +1 more , Wang F
J Neurotrauma · 2026 Apr · PMID 41250791 · Publisher ↗
Acute brain injury (ABI) is a severe neurological disorder in which inflammation and immune responses play a key role, with the Triggering Receptor Expressed on Myeloid Cells-1 (TREM1) being involved. Inhibition of TREM1...
Acute brain injury (ABI) is a severe neurological disorder in which inflammation and immune responses play a key role, with the Triggering Receptor Expressed on Myeloid Cells-1 (TREM1) being involved. Inhibition of TREM1 can alleviate neuroinflammation and damage, but the evidence from these pre-clinical studies remains unclear. This study summarizes and evaluates the results of animal experiments on the treatment of ABI with the TREM1 inhibitor LP17, exploring the effects of using LP17 to treat ABI animal models on neurological function, inflammatory indicators, and brain barrier function. As of April 30, 2025, this review conducted a detailed search of eight databases for studies on LP17 in ABI animal models. It performed a systematic review and meta-analysis of the included studies. The literature was independently screened, and data were extracted and assessed. RevMan 5.4 software was used for the meta-analysis. Compared with controls, the TREM1 inhibitor LP17 significantly reduced brain water content (standardized mean difference [SMD]: -1.36; 95% confidence interval [CI]: -1.77, -0.94; < 0.00001) and neurological deficit scores (SMD: -1.37; 95% CI: -1.76, -0.97; < 0.00001). It also decreased the expression of pro-inflammatory cytokines, including IL-1β (SMD: -1.88; 95% CI: -2.63, -1.13; < 0.00001) and TNF-α (SMD: -2.91; 95% CI: -3.89, -1.92; < 0.00001). LP17 mitigated blood-brain barrier (BBB) disruption (SMD: -1.58; 95% CI: -2.47, -0.68; = 0.0005) and enhanced ZO-1 expression (SMD: 2.77; 95% CI: 1.73, 3.80; < 0.00001). It also inhibited the activation of nuclear factor-κB (SMD: -1.70; 95% CI: -2.58, -0.83; = 0.0001), NLRP3 (SMD: -2.33; 95% CI: -3.27, -1.39; < 0.00001), and Caspase-1 (SMD: -2.03; 95% CI: -2.92, -1.14; < 0.00001). LP17 has neuroprotective effects in ABI animal models, likely through reducing neuroinflammation, preserving BBB integrity, and inhibiting apoptotic pathways. Further studies are needed to explore its mechanisms to better guide clinical use.
Diffusion Alterations at the Gray Matter/White Matter Boundary in Traumatic Encephalopathy Syndrome.
Wiegand TLT, Pankatz L, Arciniega H … +30 more , Jung LB, Tuz-Zahra F, Bouix S, Lubeck H, Rojczyk P, Schuhmacher LS, Buring J, Katz DI, Tripodis Y, Pasternak O, Cetin-Karayumak S, Rathi Y, Adler CH, McKee AC, Balcer LJ, Bernick C, Coleman MJ, Colasurdo EA, Lin AP, Peskind ER, Ashton NJ, Blennow K, Zetterberg H, Alosco ML, Cummings JL, Reiman EM, Stern RA, Shenton ME, Koerte IK, DIAGNOSE CTE Research Project
J Neurotrauma · 2026 Feb · PMID 41218808 · Full text
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cor...
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ], Aβ, glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology ((1, 147) = 5.781, 95% confidence interval (CI) = 0.0003-0.003, = 0.035) as well as neurobehavioral dysregulation ((1, 148) = 7.559, 95% CI = 0.001-0.009, = 0.020), and functional dependence/dementia ((1, 148) = 5.046, 95% CI = 0.0004-0.006, = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078-0.466, = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102-0.488, = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.
Parental and Family Functioning as Predictors of Longitudinal Trajectories of Postconcussive Symptoms Following Pediatric Mild Traumatic Brain Injury: An Advancing Concussion Assessment in Pediatrics Study.
Chadwick L, Madigan S, Callahan BL … +8 more , Beauchamp MH, Craig W, Doan Q, Freedman SB, Gravel J, Zemek R, Yeates KO, Pediatric Emergency Research Canada (PERC) A-CAP Study Team
J Neurotrauma · 2026 Apr · PMID 41218796 · Publisher ↗
The family environment plays an important role in children's recovery from traumatic brain injury (TBI); however, parental and family factors have not been examined in-depth in pediatric mild TBI (mTBI). Existing researc...
The family environment plays an important role in children's recovery from traumatic brain injury (TBI); however, parental and family factors have not been examined in-depth in pediatric mild TBI (mTBI). Existing research on postconcussive symptoms (PCS) typically employs conventional statistical analyses that assume that children with mTBI are a homogenous group. However, children may display distinct trajectories of PCS across time after mTBI. Group-based multitrajectory modeling can identify latent clusters of individuals following similar trajectories across multiple indicators of an outcome. This study sought to: (1) identify trajectories of PCS after mTBI in children, and (2) examine their association with parental and family functioning. Participants were 506 children and adolescents aged 8- to 16-years-old who were recruited during emergency department (ED) visits within 48 h of injury at five Pediatric Emergency Research Canada hospitals. Injury information was collected in the ED, and parental and family functioning was measured at approximately 7 days postinjury. Child and parent PCS ratings were obtained weekly to 3 months and biweekly to 6 months postinjury using the Health and Behavior Inventory. Parental and family functioning were assessed using validated measures of family functioning, parental adjustment, perceived social support from parents, and parental responses to children's symptom complaints. Group-based multitrajectory modeling was used to classify individual children into distinct trajectories of child- and parent-reported cognitive and somatic PCS over time and to examine predictors of those trajectories. Six distinct trajectories were identified: "low acute/resolved PCS" ( 98), "low acute/declining PCS" ( = 64), "moderate acute/elevated cognitive PCS" ( = 106), "moderate acute/declining PCS" ( = 118), "high acute/declining PCS" ( = 88), and "high acute/persisting PCS" ( = 32). Parental adjustment, protectiveness, and social support were independent predictors of trajectory membership after adjusting for demographic and injury characteristics. The identification of different symptom trajectories and specific aspects of parental and family functioning as predictors of these trajectories provides guidance for developing family-based treatments and targeting treatments to children at risk for poor recovery.
N-Formylmethionine Is a Biologically Active Diagnostic Marker of Mild Traumatic Brain Injury.
Dash PK, Moore AN, Underwood E … +6 more , Gusdon AM, Badjatia N, Choi HA, Hergenroeder GW, Kobori N, Redell JB
J Neurotrauma · 2026 Mar · PMID 41213604 · Publisher ↗
Traumatic brain injury (TBI) is a major health problem worldwide. Approximately 2.8 million people in the United States sustain a TBI each year, the majority of which can be classified as mild TBI (mTBI) or concussive in...
Traumatic brain injury (TBI) is a major health problem worldwide. Approximately 2.8 million people in the United States sustain a TBI each year, the majority of which can be classified as mild TBI (mTBI) or concussive injuries. Although mTBI may not cause overt brain damage, it triggers many cellular and molecular changes in brain cells, resulting in neurological, cognitive, and behavioral impairments. Metabolites are released in response to mTBI and can serve as diagnostic markers, as well as potentially contributing to ongoing pathophysiological changes. N-formylmethionine (fMet) is used as the first amino acid for protein synthesis in mitochondria, bacteria, and chloroplasts. Both formylated peptides and free fMet have been detected in human plasma. While a number of studies have demonstrated that formylated peptides can activate the innate immune response, less is known about the role of free fMet in health and disease. In this study, we quantified the free fMet concentration in plasma samples obtained from persons who have sustained an mTBI and compared it with the plasma concentrations detected in healthy volunteers. Our results show that the plasma levels of fMet increased within 24 h of a documented mTBI in both males and females. Receiver operator characteristic (ROC) analysis indicated that the acute change in plasma fMet (<48 h after an injury) has an area under ROC (AUROC) of 0.82 in identifying an mTBI. Interestingly, when fMet was measured in plasma samples collected from these patients 3 months later, it remained elevated and had an AUROC of 0.88. The systemic administration of fMet to mTBI mice impaired brain mitochondrial function, suggesting that it may affect ongoing mTBI pathophysiology.
Three-Month Outcomes of Traumatic Brain Injury in the General Population: A Sunnybrook Traumatic Brain Injury Cohort Study.
Ure RJ, Kiss A, Mikolić A … +4 more , McLellan E, Silverberg ND, Feinstein A, Burke MJ
J Neurotrauma · 2026 Apr · PMID 41213600 · Publisher ↗
Traumatic brain injury (TBI) is common, disabling, and a growing public health concern. There are limited large-scale studies providing insight into factors associated with recovery in the general TBI population. Our aim...
Traumatic brain injury (TBI) is common, disabling, and a growing public health concern. There are limited large-scale studies providing insight into factors associated with recovery in the general TBI population. Our aim was to identify factors associated with concussion/TBI symptom severity and return-to-work. We performed a prospective cohort study of concussion/TBI (predominantly mild to moderate) patients with data collected over a 20-year period (1998-2018). This is the first study presenting data from the Sunnybrook TBI (SUNTBI) cohort. Primary outcome at approximately 3-month postinjury was the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), and secondary outcome was return-to-work. Outcomes were analyzed using multivariable linear regression and logistic regression models, respectively. There were 2924 TBI patients included in the study. General Health Questionnaire (GHQ), a screening measure of current psychiatric symptoms, and all its subscales (depression, anxiety, somatic, and social) ( < 0.0001), and active litigation ( < 0.001) were significantly associated with higher RPQ scores. Notably, factors related to injury characteristics and severity were not (e.g., injury mechanism, TBI severity, and neuroimaging abnormalities). For return-to-work, having a professional occupation ( < 0.001) was significantly positively associated with return, while abnormal CT scan ( = 0.001), admission to hospital ( < 0.001), and higher GHQ score ( < 0.001) were negatively associated. In one of the largest observational studies of general population concussion/TBI patients to date, we found that psychiatric symptoms and litigation status were significantly associated with symptoms at 3 months, while factors related to the injury severity were not. We also observed a decoupling of factors that impact symptom score outcomes from return-to-work outcomes. These results have important implications for the management of at-risk TBI subpopulations and wider public policy considerations.
Funding Distributions, Trends, Gaps, and Policy Implications for Spinal Cord Injury Research: A Systematic Analysis of U.S. Federal Funds.
Gillespie T, Buxton A, Kondiles BR … +32 more , Leal-Garcia M, Pacheco MR, Tran AV, Vo K, Abu L, Barr J, Barretto TA, Biundo J, Duenwald S, Evans A, Friedman TN, Gadaleta I, Ganesh S, Gottschall B, Green P, Lee G, Liu L, Malik RN, Nava EJ, Sorani C, Tandon V, Thomas H, Thomas K, Barr C, Burkhart I, McCreedy DA, Nowell P, Blackmon H, Rabchevsky AG, Rodreick M, Torres-Espín A, Dulin JN
J Neurotrauma · 2025 Nov · PMID 41204714 · Full text
Federal agencies including the National Institutes of Health (NIH), the Department of Defense (DoD) Congressionally Directed Medical Research Program (CDMRP) Spinal Cord Injury Research Program (SCIRP), and the Departmen...
Federal agencies including the National Institutes of Health (NIH), the Department of Defense (DoD) Congressionally Directed Medical Research Program (CDMRP) Spinal Cord Injury Research Program (SCIRP), and the Department of Veterans Affairs (VA) provide the majority of funding for spinal cord injury (SCI) research in the United States. However, systematic evaluation of how funding is distributed across research areas, therapeutic approaches, and translational stages has been limited. To understand the distribution of funds, we curated and classified 1,589 federally funded SCI research awards from the NIH (2008-2023), the CDMRP SCIRP (2009-2023), and the VA (2017-2025). Each award was annotated based on the biological system or problem studied, the therapeutic intervention or approach utilized, and its placement along the translational continuum. Our analysis revealed that the NIH predominantly supports basic and early-stage translational research, especially in areas of SCI pathology, regeneration, and motor functional recovery. In contrast, the CDMRP funding is more concentrated on applied and clinical research, particularly in the areas of pain, bladder function, and neuromodulatory device development. The VA predominantly invests in rehabilitation-focused studies and interventions aimed at improving musculoskeletal and functional health outcomes. While the complementary missions of these agencies collectively support a diverse SCI research ecosystem, we identified critical gaps in funding for high-priority areas such as bowel/gastrointestinal health, cardiovascular function, and mental health. Furthermore, the recent discontinuation of the CDMRP SCIRP and proposed NIH budget reductions are projected to lead to an approximate 50% decline in federal SCI research funding by 2026-posing a substantial risk to the field's progress and threatening the stability of this ecosystem. These findings underscore the urgent need for coordinated, data-driven funding strategies that align more closely with the needs and priorities of the SCI community. To that end, we propose the development of a publicly accessible "living dashboard" to enhance transparency, foster interdisciplinary collaboration, and guide strategic investment in SCI research moving forward.
Response to Verboon et al.: Integrating Somatosensory Evoked Potentials into EEG-Based Prognostication after TBI.
Machado C
J Neurotrauma · 2026 Mar · PMID 41203251 · Publisher ↗
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Linking Limbic-Prefrontal White Matter Microstructure to Behavioral Problems Following Pediatric Traumatic Brain Injury.
DeMaster D, Watson CG, Prasad MR … +3 more , Cox CS, Fischer JT, Ewing-Cobbs L
J Neurotrauma · 2026 Mar · PMID 41192919 · Publisher ↗
Diffusion tensor imaging studies in children suggest a link between abnormal white matter in limbic-prefrontal circuitry and behavioral problems. However, in children with traumatic injury, links between atypical limbic-...
Diffusion tensor imaging studies in children suggest a link between abnormal white matter in limbic-prefrontal circuitry and behavioral problems. However, in children with traumatic injury, links between atypical limbic-prefrontal circuitry and new behavioral problems remain largely unexamined. In a prospective longitudinal study of children ages 8-15 years, we examined white matter microstructure 7 weeks following a traumatic brain injury (TBI) or extracranial injury (EI) relative to typically developing children (TDC). Internalizing and externalizing behavioral problems were assessed via the Child Behavior Checklist; ratings estimated preinjury and 7-month postinjury status. Limbic-prefrontal white matter fiber tracts were estimated using seed-to-seed analysis originating in each amygdala and hippocampus; fractional anisotropy (FA) was calculated along with the tracts. Controlling for preinjury behavior problems, general linear models examined the effect of injury type on behavioral outcomes and pathway FA, including group (TBI+EI vs. TDC; TBI vs. EI), age, sex, and their interactions. Injured children had higher postinjury internalizing problem scores than TDC, and FA was lower in several pathways connecting hippocampi with nucleus accumbens and parahippocampal cingulate. Internalizing and/or externalizing problems were associated with FA of pathways connecting hippocampi to amygdalae, medial orbitalfrontal cortex, and parahippocampal cingulate, as well as pathways connecting amygdale to thalami. The relation between FA and behavioral problems was negative for the TBI group but neutral to positive for the EI and TDC groups. Together, these findings suggest disrupted microstructural organization of the limbic-prefrontal circuitry as a neurobiological predictor of behavioral problems following TBI.
Comment on Association Between Adherence to Guidelines and Patient Outcomes in Severe Pediatric Traumatic Brain Injury: A Scoping Review-Benefits of Management Protocolization .
Chesnut RM
J Neurotrauma · 2025 Oct · PMID 41189404 · Publisher ↗
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Multimodal Biomarkers of Consciousness in Acute Severe Traumatic Brain Injury.
Bodien YG, Fecchio M, Gilmore N … +8 more , Freeman HJ, Sanders WR, Meydan A, Lawrence PK, Atalay AS, Kirsch J, Healy BC, Edlow BL
J Neurotrauma · 2026 Mar · PMID 41182259 · Full text
Predicting outcome for patients with acute severe traumatic brain injury (TBI) is imprecise, relying on neurological examination, structural neuroimaging, and resting-state electroencephalography (EEG) to serve as proxie...
Predicting outcome for patients with acute severe traumatic brain injury (TBI) is imprecise, relying on neurological examination, structural neuroimaging, and resting-state electroencephalography (EEG) to serve as proxies for brain function. We implemented a multimodal assessment protocol to determine whether detection of consciousness using advanced tools, including standardized behavioral evaluation, advanced EEG, and functional magnetic resonance imaging (fMRI), is associated with functional outcome in patients with acute severe TBI admitted to the intensive care unit (ICU). We tested the association between 6-month Disability Rating Scale (DRS) scores and acute level of consciousness on the Coma Recovery Scale-Revised (CRS-R); responses to active-motor-imagery and passive-language EEG and fMRI; and resting-state fMRI default mode network (DMN) connectivity. We consecutively enrolled 55 patients with acute severe TBI. Six-month outcome was available in 45 (45.2 ± 20.7 years old, 70% male), of whom 10 died, all due to withdrawal of life-sustaining treatment (WLST). All deaths occurred in participants who were not behaviorally following commands. Lower (i.e., better) 6-month DRS scores were observed in participants who were younger (ρ = 0.401; 95% confidence interval [CI: 0.078, 0.649]; = 0.006]) and who were conscious (median DRS score difference [95% CI]: -11 [-20, -2]; = 0.003) or following commands (-9 [-20, -1]; = 0.011) on CRS-R assessment in the ICU. Evidence of command-following on EEG or fMRI did not strengthen this relationship. In participants without command-following on the CRS-R, we detected responses to active-motor-imagery (i.e., cognitive motor dissociation [CMD]) in 6/34 (18%) of participants on EEG and 8/24 (33%) participants on fMRI. We detected responses to passive-language stimuli (i.e., covert cortical processing [CCP]) in 30/33 (91%) of participants on EEG and 18/24 (75%) on fMRI. However, neither CMD nor CCP was associated with outcome on the DRS or several secondary outcome measures (e.g., dichotomous DRS, Glasgow Outcome Scale-Extended), an unexpected result that may reflect the modest sample size and high rate of WLST. In exploratory analyses, an intact DMN and the magnitude of DMN connectivity were associated with 6-month outcome on secondary outcome measures. Collectively, our results suggest that the level of consciousness in the ICU, assessed with a standardized behavioral measure, may predict recovery from severe TBI. Further research, conducted at multiple sites and with larger samples, is required to determine whether integrating behavioral, EEG, and fMRI biomarkers of consciousness is more predictive than behavioral assessment alone.
Guideline Adherence and Outcome in Neurosurgical Treatment of Traumatic Acute Subdural Hematoma.
Singh RD, Corper SA, Vreeburg RJG … +5 more , van Dijck JTJM, den Boogert HF, de Ruiter GCW, Peul WC, van Essen TA
J Neurotrauma · 2026 Apr · PMID 41174921 · Publisher ↗
An acute subdural hematoma (ASDH) is the most common focal injury in traumatic brain injury (TBI) and a major cause of death and morbidity worldwide. The decision to perform neurosurgical evacuation of the ASDH is comple...
An acute subdural hematoma (ASDH) is the most common focal injury in traumatic brain injury (TBI) and a major cause of death and morbidity worldwide. The decision to perform neurosurgical evacuation of the ASDH is complex. The Brain Trauma Foundation (BTF) issued guidelines in 2006, recommending evacuation for ASDHs >1 cm or with >5 mm midline shift regardless of patients' Glasgow Coma Scale (GCS) score, and in cases of neurological deterioration, abnormal pupillary reaction, or high intracranial pressure (ICP). Despite their global recognition, the evidence supporting these guidelines is weak. This study assesses adherence to BTF guidelines in a European cohort and determines the effect on mortality and functional outcomes. Data from the prospective observational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed. Patients presenting after a TBI with an ASDH on the initial computed tomography scan across 65 trauma centers in Europe and Israel between 2014 and 2018 were included. Patients with concomitant epidural hematoma were excluded. Adherence to BTF guidelines for ASDH surgery and ICP monitoring was assessed, including subgroup analyses based on age and TBI severity. Multivariable logistic regression models examined the association between guideline adherence and outcomes, adjusting for prespecified confounders. Among 985 patients with traumatic ASDH, overall guideline adherence was 74% ( = 724), with higher adherence to conservative treatment (95% [ = 533]) compared with surgical recommendations (45% [ = 191]). Adherence varied by age and TBI severity, being lower in elderly and severely injured patients. ICP monitoring adherence in comatose patients was 63% ( = 240). Adherence to surgical ASDH guidelines was not significantly associated with in-hospital mortality (odds ratio [OR]: 0.72 [0.43-1.2]) or 6-month functional outcome (OR: 0.73 [0.47-1.1]). Overall adherence to BTF guidelines for surgical ASDH management was low. The current surgical thresholds do not align with clinical practice. Elderly patients and those with severe TBI were less likely to be treated per guidelines. Incorporating patient age, GCS and hematoma volume into the guidelines may enhance their relevance and adherence in clinical practice.
Traumatic Microbleeds in Mild Traumatic Brain Injury: Stability, Distribution, and Association with Other Injuries.
Junkkari A, Korvenoja A, Huovinen A … +3 more , Mäki K, Marinkovic I, Melkas S
J Neurotrauma · 2026 Mar · PMID 41173528 · Publisher ↗
This study aimed to investigate whether the amount of traumatic microbleeds (TMBs) detected on magnetic resonance imaging (MRI) changes in different brain regions after a 3-month follow-up in adult patients with mild tra...
This study aimed to investigate whether the amount of traumatic microbleeds (TMBs) detected on magnetic resonance imaging (MRI) changes in different brain regions after a 3-month follow-up in adult patients with mild traumatic brain injury (mTBI). A 3 T MRI of the brain was conducted at baseline (3-17 days after trauma) and at 3 months after patients were diagnosed with mTBI according to the World Health Organization criteria. The TMBs were evaluated, counted, and assigned locations by a neuroradiologist according to the Common Data Elements for Neuroimaging of Traumatic Brain Injury (CDE-TBI). At baseline, 22 out of 113 (19%) patients had at least one TMB. After initial imaging, 22 patients dropped out, resulting in 88 patients, of whom 21 (24%) had at least one TMB. Across these patients, a total of 129 TMB lesions were detected at baseline, all of which were visible at follow-up imaging. No new TMB lesions that were not detected at baseline were seen at follow-up imaging. The most common CDE-TBI regions for TMBs were the frontal (77/129, 60%), temporal (33/129, 26%), and parietal (8/129, 6%) subcortical white matter. For each patient, the TMB lesions were located in one region in 10% (9/88), two regions in 3% (3/88), three regions in 3% (3/88), and four or more regions in 7% (6/88) of the CDE-TBI regions. Twenty-five out of 88 (28%) patients also had other trauma-related intracranial abnormalities: 10/25 (40%) of which had at least one TMB, which was true only for 17% (11/63) for those without ( < 0.05). In conclusion, initial TMBs can still be reliably found with conventional MRI after 3 months in patients with mTBI: delayed imaging does not necessarily compromise the detection of these lesions. Other radiological abnormalities are linked with higher prevalence of TMBs, possibly suggesting increased injury burden within the mTBI population.
A Modified Repetitive Closed Head Injury Model Inducing Persistent Neuroinflammation and Functional Deficits Without Extensive Cortical Tissue Destruction.
Fadon-Padilla L, Chu C, Liang Y … +4 more , Sarkar C, Lipinski MM, Janowski M, Walczak P
J Neurotrauma · 2026 Mar · PMID 41173520 · Publisher ↗
Traumatic brain injury (TBI) remains a significant clinical challenge, with limited treatment options and long-term neurological impairments. Mild to moderate TBI represents the most common form, making it a critical the...
Traumatic brain injury (TBI) remains a significant clinical challenge, with limited treatment options and long-term neurological impairments. Mild to moderate TBI represents the most common form, making it a critical therapeutic target. However, current animal models poorly reflect human TBI pathophysiology, necessitating improved preclinical paradigms. Here, we present a refined repetitive closed head injury (rCHI) model using consecutive controlled impacts within a single session, without craniotomy. We initially compared closed head injury (CCI) and rCHI models showing that the rCHI model enables precise impact application while preserving brain macrostructure. We evaluated the acute and chronic effects of increasing injury severity through 1, 3, or 5 consecutive impacts in adult C57BL6/J mice. MRI revealed severity-dependent blood-brain barrier (BBB) disruption, with significant gadolinium leakage in the 3- and 5-impact groups. Neuroinflammatory responses, assessed by immunofluorescence and qRT-PCR, demonstrated proliferation of microglia (IBA1) and astrocytes (GFAP), alongside increased inflammatory markers (, , , β, -α). Functional assessments (beam walk, CatWalk gait analysis, novel object recognition) confirmed sustained motor and cognitive deficits in the 5-impact group over 28 days. Diffusion MRI indicated persistent white matter alterations supporting progressive neurodegeneration. This rCHI model successfully replicates key TBI features-BBB dysfunction, chronic neuroinflammation, and functional impairments-without direct cortical destruction. It serves as a valuable platform for evaluating acute-phase interventions and investigating neuroprotective strategies targeting inflammation and BBB integrity. Our findings highlight the importance of injury severity in shaping TBI outcomes and reinforce the need for tailored therapeutic approaches.
Relationship Between Exercise Tolerance and Event-Related Potentials on Recovery in Adults with Postconcussion Syndrome.
Moser N, Popovic MR, Kalsi-Ryan S
J Neurotrauma · 2026 Mar · PMID 41167616 · Publisher ↗
From the diagnosis and management through to determining recovery, the clinical pathway for concussions and postconcussion syndrome (PCS) is reliant on symptom reporting. Under-reporting or over-reporting bias necessitat...
From the diagnosis and management through to determining recovery, the clinical pathway for concussions and postconcussion syndrome (PCS) is reliant on symptom reporting. Under-reporting or over-reporting bias necessitates the need for more objective measures. Exercise intolerance has shown to be a strong predictor of adolescent concussion patients likely to have protracted recoveries. Its role in predicting outcomes for adults is less clear. In addition to physiological measures, event-related potentials (ERPs) have demonstrated altered cognitive processing across the concussion recovery stages in various demographics. The aim of the present study was to assess the relationship between baseline exercise tolerance and ERPs on the degree of improvement in symptoms postrehabilitation in adults with persistent postconcussion symptoms (PPCS). Forty participants (mean age ± SD, 39 ± 13.5 years) with PPCS (mean duration ± SD, 5 ± 3 months) took part in this 6-week clinical trial. Participants were randomized at baseline to a customized rehabilitation (CR) program or standard, symptom-based care (SC). At baseline, participants underwent a standard exam inclusive of an exercise tolerance test and completed a quantitative electroencephalogram to examine three auditory ERPs (N100 for sensory processing, P300 for attention, and N400 for cognitive processing). To examine the association of exercise tolerance and ERPs on recovery, linear regression was done to compare participants' pre-post Rivermead Postconcussion Questionnaire scores (RPQ) with baseline delta heart rate (ΔHR), heart rate thresholds (HRt), and ERPs (amplitude and latency). The CR group showed significant and clinically meaningful improvements in reported symptoms (RPQ-3 and RPQ-13) and exercise tolerance (ΔHR, HRt). Notably, no baseline variables predicted outcomes in the CR group. Conversely, the SC group experienced no clinically meaningful symptom changes. For this group, baseline measures significantly correlated with symptom improvement. Exercise tolerance: Lower baseline ΔHR and HRt significantly correlated with less RPQ-3 (ΔHR: = 0.01, = 0.28, coefficient = 0.03 || HRt: = 0.006, = 0.36, coefficient = 0.04) and RPQ-13 improvement (ΔHR: = 0.03, = 0.24, coefficient = 0.15 || HRt: = 0.02, = 0.28, coefficient = 0.19). ERPs: Reduced N400 amplitude correlated with less improvement in RPQ-3 (RPQ-3: = 0.05, = 0.19, coefficient = 0.55). Baseline exercise tolerance and ERPs were significant prognostic indicators for symptom improvement in adults with PPCS undergoing standard, symptom-based care. Participants with lower baseline exercise tolerance showed less improvement in postconcussion symptoms (RPQ-3 and RPQ-13), while reduced N400 amplitude was associated with poorer symptom outcomes. These baseline measures did not predict outcomes for patients receiving the customized rehabilitation program, suggesting that a comprehensive program may overcome initial physiological and cognitive vulnerabilities, leading to more robust recovery regardless of baseline presentation.
Brain Injury Within Intimate Partner Violence: What Are the Cognitive Effects?
Makovec Knight J, Hannon O, Spitz G … +10 more , Astridge A, Copas C, Duarte Martins B, Rowse R, McDonald S, Padgett C, Meyer S, Shultz S, Symons GF, Ponsford J
J Neurotrauma · 2026 Feb · PMID 41164911 · Publisher ↗
Intimate partner violence (IPV) is a worldwide health concern with devastating implications for physical, mental, and cognitive health. IPV-associated brain injuries (IPV-BIs) induced through impacts to the head (e.g., m...
Intimate partner violence (IPV) is a worldwide health concern with devastating implications for physical, mental, and cognitive health. IPV-associated brain injuries (IPV-BIs) induced through impacts to the head (e.g., mild traumatic brain injury [mTBI]) and non-fatal strangulation (NFS; i.e., a hypoxic-ischemic injury) have long been overlooked among IPV victim-survivors. Identifying their presence and consequences is vital to inform interventions. Cross-sectional design with 3 groups including women with IPV-BI (1-6; >6) sustained through NFS and/or mTBI, women exposed to IPV without BI, and healthy age-matched controls. All participants completed medical history, biopsychosocial questionnaires, and cognitive tests of premorbid IQ, learning and memory, processing speed, and executive function. A total of 146 women aged 40.99 years ( = 13.97) were included: 46 with IPV-BI (27 1-6; 19 > 6), 42 with IPV alone, and 58 Healthy controls. IPV-BI was significantly associated with poorer performances on Rey Auditory Verbal Learning Test (RAVLT) Total Learning, Delayed Recall trials, and Trails Making Test B (TMT-B). Planned comparisons revealed that women with more than 6 IPV-BIs scored significantly lower on RAVLT Total Learning and Delayed Recall compared to other groups, with medium and large effect sizes. The association between IPV-BI and performances on the RAVLT remained significant after controlling for potential confounders, including age, premorbid functioning, post-traumatic stress disorder, depression, anxiety, substance use disorder, and other causes of BI. In contrast, the effect of IPV-BI on TMT-B performance was attenuated when anxiety was included in the model, rendering the IPV-BI group difference non-significant. There was evidence of impairments in memory and new learning among women with IPV-BI relative to the other groups beyond 6 months post-injury, with cumulative mTBI and NFS worsening outcomes. These findings highlight the need for IPV-BI screening, neuropsychological assessment, and targeted education and therapy for this underserved population.
Reassessing the Role of Machine Learning in Clinical Prediction: A Benchmark of Predicting Walking Function after Spinal Cord Injury.
Bugajska J, Lukas LP, Rupp R … +12 more , Weidner N, Schubert M, Röhrich F, Waldmann J, Kalke YB, Abel R, Maier D, Chhabra HS, Liebscher T, Curt A, Brüningk S, Jutzeler CR
J Neurotrauma · 2026 May · PMID 41163583 · Publisher ↗
In light of growing biomedical data, machine learning (ML) models offer tremendous potential for personalized prediction in medicine. However, the additional value provided by these computational tools should always be c...
In light of growing biomedical data, machine learning (ML) models offer tremendous potential for personalized prediction in medicine. However, the additional value provided by these computational tools should always be critically evaluated. Using the example of predicting walking ability after spinal cord injury (SCI), we highlight a popular scenario in which data-driven predictions are feasible but not clinically meaningful, as the task can be performed equally well by humans. We asked 11 human observers from diverse backgrounds (five researchers without clinical training but proven knowledge of SCI and the International Standards for Neurological Classification of SCI [ISNCSCI], and six neurologists experienced in SCI) to predict walking ability following SCI based on acute phase neurological status assessed by the ISNCSCI motor and sensory scores (≤40 days after injury [DAI]). Following an established clinical prediction rule, walking ability was defined by a binary label derived from the indoor walking ability subitem of the Spinal Cord Independence Measure. We compared the performance of human observers with extreme gradient boosting and logistic regression-based models, which represent popular approaches in clinical literature on SCI. Using 794 patients from the European Multicenter Study about SCI, we show that all approaches provide similar, excellent performance at population level (area under the receiver operating characteristic 0.93-0.95; accuracy 0.88-0.90). Importantly, predictions combined from multiple neurologists (accuracy: 0.89) were comparable with model-based predictions (accuracy: 0.88-0.90), whereas individual neurologists (accuracy: 0.79 [0.01]; mean [standard deviation]) were marginally outperformed by computational approaches (accuracy: 0.88-0.90), particularly for more heterogeneous incomplete injuries. Individual SCI researchers performed equally well compared with neurologists (accuracy: 0.78 [0.02]). Our results show that prediction of walking function following SCI, if described through a binary label, does not benefit from ML, as ensembles of clinical experts and researchers each achieve performance similar to a range of ML models and an established clinical prediction rule. This highlights two key considerations in clinical applications of data-driven prediction models in SCI: first, the importance of carefully choosing clinical outcome measures to target in a prediction task to achieve a true benefit, and second, the necessity of benchmarking human performance on specific tasks to determine whether meaningful differences are present.
Netrin-1 Therapy Restores Partial Hindlimb Movement in a Rat Model of High-Severity Chronic Spinal Cord Injury.
Schmidt J, Uceda A, Sgariglia A … +2 more , Battagino R, Quintá HR
J Neurotrauma · 2026 May · PMID 41163574 · Publisher ↗
Spinal trauma caused by contusion or compression is the leading cause of spinal cord injury (SCI) worldwide. These injuries frequently progress to a chronic phase, especially in cases of severe damage. This process resul...
Spinal trauma caused by contusion or compression is the leading cause of spinal cord injury (SCI) worldwide. These injuries frequently progress to a chronic phase, especially in cases of severe damage. This process results in permanent impairment, affecting both physiological functions and voluntary motor control below the lesion level. At cellular level, the formation of a glial scar, which delineates the cystic cavity, interrupts the connectivity between the central nervous system (CNS) and muscles, as well as the neural communication between the peripheral and CNSs. This process, combined with the CNS inability to promote its self-repair to prevent the progression to a chronic phase, contributes to the exacerbation of spinal cord damage, resulting in a devastating pathology. Currently, there is no effective medical treatment to address the consequences of this condition, apart from physiotherapy, which has variable success depending on the type of injury and the degree of neural tissue preservation in the affected spinal cord. Considering this last, the development of new strategies to promote neuronal repair is essential for reversing this pathology in the future. Therefore, we propose Netrin-1-a developmental guidance molecule known to direct corticospinal tract (CST) growth during CNS development-as a potential therapeutic approach for enhancing neuronal repair in severe chronic SCI. Previously, we demonstrated in an acute phase model of transected SCI that this protein effectively promotes axonal regrowth, axonal reconnection, and recovery of locomotor activity. Based on these findings, we hypothesize that Netrin-1 may additionally act as a neuroreparative molecule in chronic SCI, promoting the recovery of hindlimb movement impaired by injury. To test the therapeutic potential of this molecule, we performed a rat model of chronic SCI with a high-severity lesion at Th10-Th11 thoracic level. We demonstrate that the delivery of Netrin-1 to the epicenter of the lesion promotes significant recovery of extensive movement in the three hindlimb joints, including full flexion and extension, previously impaired by chronic injury. Additionally, it restores functional abilities such as climbing and grasping to some extent. These functional findings correlate with anatomical and cellular observations, including regrowth, sprouting and remyelination of the CST; regrowth-reconnection of extrapyramidal tracts; regrowth-reconnection of serotonergic and dopaminergic axons; prevention of transsynaptic degeneration of lower motoneurons; and neuroprotection of both myelinated sciatic nerve fibers and ascending sensory pathways. In conclusion, this study extends the neuroreparative properties of Netrin-1 to chronic conditions. These findings support its use as potential therapeutic strategy in future human clinical trials.
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