Neurological recovery following spinal cord injury (SCI) is commonly studied through changes in high-level descriptors of injury severity, such as the American Spinal Injury Association Impairment Scale (AIS) grade, or total upper and/or lower extremity motor scores. More recently, the analysis of segmental motor scores has attracted interest as it provides a more detailed understanding of the exact location and extent of changes occurring during recovery. We propose to augment the analysis of segmental motor recovery with a qualitative descriptor of local motor score patterns, which is defined for all upper and lower extremity myotomes below the neurological level of injury (NLI) and based on a categorization of the changes along the rostrocaudal motor score sequence. Our hypothesis is that recovery of segmental motor scores depends on the residual function as described by the newly proposed descriptors of local motor score patterns. Using data of 1385 patients from the European Multicenter Study about SCI, we analyze differences in recovery at approximately 6 months after injury between local motor score patterns and find an increased probability of full motor recovery for myotomes associated with increased motor scores in the caudal direction. We further use an aggregated descriptor of motor score patterns focusing on increases of motor scores in the caudal direction as an alternative or complementary feature to the AIS grade in prediction models for segmental motor scores at recovery. We observe equivalent predictive performance as measured by the root mean square error between actual and predicted motor scores below the NLI for models using the same set of features and additionally either the AIS grade (median = 0.79) or local pattern (median = 0.80). This is noteworthy as the definition of local motor score patterns requires only the examination of the 10 key muscles of the International Standards for Neurological Classification of SCI on each side of the body, while the AIS grade can only be reliably determined if extensive sensory testing is performed in addition. These results indicate the potential benefits of considering information inherent to the rostrocaudal sequence of motor scores for a better understanding of motor recovery. Furthermore, it supports the development and use of abbreviated sensorimotor examinations specifically in the early phase after SCI.
Invasive intracranial pressure (ICP) monitoring provides essential guidance for the treatment of patients with suspected head injuries; however, it remains incompatible with prehospital use. While several noninvasive ICP-measuring methods exist, previous studies have not adequately addressed their potential in a prehospital setting. In this systematic review and meta-analysis of diagnostic test accuracy, we explore the accuracy of existing noninvasive methods for ICP monitoring and assess their potential usefulness in prehospital screening for elevated ICP. This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Embase, Scopus, PubMed, CENTRAL, and Cochrane databases were sought for relevant articles on June 23, 2025. All studies evaluating minimally invasive and transportable methods for ICP assessment were included. Animal studies, in vitro studies, reviews, and meta-analyses were excluded. Study selection was performed by two independent reviewers, and conflicts were resolved by a third reviewer. Potential for prehospital use of each method was evaluated using four predetermined criteria. Summary receiver operator characteristic curves and summarized sensitivity and specificity were reported if multiple studies investigating the same method were eligible for meta-analysis. The applicability and risk of bias of the included studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool for diagnostic test accuracy studies. Fifty-five articles were included. Ultrasound of optic nerve sheath diameter (ONSD) was the method with the highest potential for prehospital use. We found a summarized sensitivity of 92.6% (95% confidence interval [CI]: 87.0; 95.9%) and a summarized specificity of 85.1% (95% CI: 74.1; 92.0%) for detecting increased ICP through ONSD measurement. Other methods for diagnosing elevated ICP diagnosis showed poor diagnostic accuracy or low potential for prehospital use. We found ultrasound estimation of the ONSD to show the highest potential for prehospital use. Prospective studies are needed to verify their diagnostic capability in the prehospital setting.
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], p < 0.001), lower rates of routine discharge disposition (OR = 0.17, p < 0.001), greater LOS (+50%, p < 0.001), and elevated costs (+49%, p < 0.001). SCI patients were more likely to have prepartum complications of venous thromboembolism (VTE) (OR = 4.01, p = 0.041) and genitourinary infections (OR = 4.26, p < 0.001). SCI patients were significantly less likely to be admitted electively (39.5% vs. 47.9%, p < 0.001) or for delivery (OR = 0.38, p < 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, p = 0.017) and stillbirth (OR = 0.05, p = 0.003). SCI patients had significantly higher odds of undergoing CS (OR = 1.88, p = 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.
Post-traumatic headache (PTH) is one of the most disabling sequelae of mild traumatic brain injury (mTBI); however, its clinical determinants and long-term trajectories remain poorly defined. We conducted a large, multicenter, prospective follow-up study to characterize the phenotypic spectrum of persistent PTH, identify predictors of persistence, and explore the role of pre-existing migraine in shaping headache outcomes after mTBI. A total of 478 adults (52.1% male, mean age 40.5 ± 18.7 years) with mTBI were recruited and evaluated by experienced neurologists at two time points: immediately after mTBI and at 6 months post injury. Demographic data and detailed headache features were collected using clinical examination and standardized questionnaires, administered face-to-face during the first visit and either face-to-face or by phone at the 6-month follow-up by physicians. Headache-related disability, depression, and insomnia were assessed using the Headache Impact Test (HIT-6), Beck Depression Inventory (BDI), and Insomnia Severity Index (ISI), respectively. Statistical analyses included classification tree analysis to identify predictors of persistent PTH and K-means clustering to delineate phenotypic subgroups. Overall, 22.6% of patients developed persistent PTH at 6 months. Pre-existing headache (PH) was reported in 31.4% of participants, predominantly migraine (57.3%). Patients with pre-existing migraine more frequently exhibited migraine-like PTH features (throbbing quality, unilateral localization, longer headache attack duration, and associated symptoms such as nausea, photophobia, and phonophobia) and scored significantly higher on the HIT-6, numeric rating scale (NRS) for headache severity, ISI, and BDI, indicating greater disability, pain severity, insomnia, and depressive symptoms (p < 0.01 for all). Classification tree analysis revealed two robust predictors of persistent PTH: acute PTH lasting more than 30 consecutive days and an initial HIT-6 score greater than 45. Furthermore, cluster analysis of patients with persistent PTH identified two phenotypic groups. Cluster 1 (n = 47) comprised patients with ≥ 180 days of continuous headache, high disability, and poor sleep quality, whereas Cluster 2 (n = 60) included patients with shorter headache duration following mTBI (<180 days), lower disability, and infrequent, shorter headache attacks. This study demonstrates that nearly one in four patients with mTBI experiences persistent PTH. Early indicators of persistence, particularly prolonged continuous headache and higher disability, may help identify high-risk individuals who warrant early aggressive, targeted interventions. Recognition of distinct PTH clusters reflects the heterogeneity of this frequent but under-investigated disorder with high burden and highlights the need for early and tailored management strategies.
Impaired cerebral autoregulation is a contributor to secondary injury in traumatic brain injury (TBI) and is associated with worse outcomes. The mechanism of injury progression from impaired autoregulation is suggested to be related to triggering of spreading depolarization (SDs) events-massive waves of cellular dysfunction implicated in secondary injury. The most-studied continuous measurement of autoregulation is the pressure reactivity index (PRx), a rolling correlation between waveform level mean arterial pressure (MAP) and intracranial pressure. However, alternative indices using correlation of MAP with brain tissue oxygen tension (PbtO2), probe-derived cerebral blood flow (CBF), and regional brain oxygen saturation (rSO2) can also be performed and may have advantages. Our objective was to evaluate the predictive value of different multimodal autoregulation indices for 30-day mortality in TBI and to assess the relationship between impaired autoregulation and SD. Autoregulation indices including PRx, oxygen reactivity index (ORx; from PbtO2), CBF reactivity (CBFRx; from thermal diffusion), and oxygen saturation reactivity index (OSRx; from rSO2) were obtained in a cohort of 218 patients with TBI requiring invasive monitoring. Associations between autoregulation indices and 30-day mortality were evaluated using multivariable logistic regression models, adjusting for age and admission Glasgow Coma Scale (GCS). A subset of postsurgical patients with SD monitoring was evaluated to assess for a potential relationship between SD and autoregulation. Within the first 24 h, univariable analysis demonstrated significant associations between 30-day mortality and ORx (p = 0.0078) or OSRx (p = 0.0014), but not other indices. In multivariable models adjusting for age and admission GCS, both ORx (p = 0.044) and OSRx (p = 0.027) remained significant predictors of 30-day mortality. In the overall monitoring time, only ORx (p = 0.008) and PRx from the parenchymal monitor (p = 0.027) were significantly associated with mortality. In patients with SD monitoring, we noted an inflection in the predicted probability of SD below MAP 85 mmHg, which may be supportive of the lower limit of autoregulation being a threshold for increased SD probability. We conclude that early (first 24 h) impairment in ORx and OSRx is associated with worse outcomes in TBI, while ORx and PRx are more strongly associated throughout the window of invasive monitoring. This effect may be mediated by increased SD with impaired autoregulation. OSRx can be derived from noninvasive near-infrared spectroscopy monitoring. This presents an opportunity to assess and optimize impaired autoregulation earlier in a patient's course without invasive monitoring. This could enhance outcome prediction and guide therapeutic strategies, particularly early after TBI.
The post-traumatic confusional state (PTCS) is a period of recovery that follows traumatic brain injury (TBI), characterized by post-traumatic amnesia (PTA), impairments in attention, and behavioral dysregulation, among other clinical symptoms. The pathophysiology of PTCS is unknown, contributing to the absence of neurobiologically based diagnostic criteria, prognostic models, and treatments. The workgroup conducted a scoping review of the literature in MEDLINE/PubMed database and manual searches of references to synthesize the existing knowledge on structural, functional, electroencephalographic (EEG), molecular, and genetic biomarkers underlying PTCS diagnosis and prognosis through five Population, Intervention, Comparison, and Outcome (PICO) questions. The search yielded 3,333 abstracts of which 69 were retained and included. Teams of two workgroup members independently reviewed abstracts and articles. Most articles addressed whether biomarkers differentiated patients with PTCS/PTA from those not in PTCS/PTA, and whether biomarkers were associated with severity or duration of PTCS/PTA. Our findings suggest that transition through PTCS/PTA from lower to higher states of consciousness involves increased thalamic function, restoration of default mode network dynamics, and normalizing of excessive slow wave activity on quantitative EEG. For patients with mild TBI, PTCS/PTA was associated with greater TBI lesion burden on structural imaging. PTCS/PTA severity and duration were associated with lesion burden, reduced white matter integrity, and electrophysiological signatures. Results across studies were variable with many finding no relationship between PTCS/PTA and biomarkers. In summary, while it is premature to include biomarkers in the definition of PTCS/PTA, our findings provide avenues for future research that is designed specifically to address the pathophysiology of this condition.
Veterans have an increased risk of developing Alzheimer disease and related dementia (ADRD) due to military exposures such as traumatic brain injury. There is a lack of information on home- and community-based services (HCBS) use among Veterans who served in the post-9/11 era and their caregivers. This study aims to (1) quantify HCBS use among post-9/11 Veterans with or at higher risk of ADRD, (2) identify facilitators, barriers, and preferences for HCBS among Veterans and family caregivers, and (3) prioritize HCBS interventions with input from Veterans and family caregivers. This study will include post-9/11 Veterans aged 65 years or younger with early-onset Alzheimer disease or frontotemporal dementia (current ADRD), and Veterans at elevated ADRD risk due to traumatic brain injury or cognitive dysfunction. Veterans' family caregivers will also be recruited. Secondary data will come from the Department of Veterans Affairs (VA), the Department of Defense, and a previous neurotrauma study. Using VA data augmented with Centers for Medicare and Medicaid Services data, we will characterize HCBS utilization. To address aim 1, we will calculate the crude and adjusted cumulative frequency of HCBS use and the proportion of Veterans using a service among Veterans with ADRD, and those at higher and lower risk for ADRD. We will compare groups using t tests for continuous measures (number of services) and chi-square tests for categorical measures (any service use). To address aim 2, we will interview Veterans and caregivers to identify facilitators and barriers to HCBS use. We will use descriptive content analysis, including rich descriptions, coding, and theme identification. Finally, to address aim 3, we will use a modified Delphi approach to identify and rank HCBS modifications that would increase use. Using the ranking data, we will consider items to have consensus on high importance if 70% or more respond "important" or "very important." Participants for primary data collection will be recruited from prior studies, VA health systems data, VA clinics, and Veteran- and caregiver-serving organizations. This study was reviewed by the institutional review boards of the University of Utah, Salt Lake City Veterans Affairs, and UT Health at San Antonio and classified as exempt. The 46,053 Veterans in the preliminary aim 1 cohort (903 with early-onset Alzheimer disease/frontotemporal dementia and 45,150 at-risk Veterans matched on age and index year) averaged 55 years old at the index date and were mostly male (38,842/46,053, 84%) and non-Hispanic White (28,016/46,053, 61%). This study will quantify current HCBS use and identify barriers and needs of Veterans with or at higher risk of ADRD and their caregivers. It will identify HCBS modifications that have consensus for needed changes, which will be shared with health system leaders.
Finite-element modeling and in vivo 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, in vivo 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 d; parcels or tracts with |d| ≥ 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, p < 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 in vivo evidence that joint diffusion MRI and MRE analysis sharpens mechanistic interpretations of gray matter microarchitecture and detects gray matter disruption across the mTBI timeline.
Triage of patients with mild traumatic brain injury (mTBI) and possible isolated epidural hematoma (iEDH) remains a clinical challenge. Blood-based biomarkers are being integrated into mTBI management, but their ability to identify patients with iEDH is uncertain. In this prospective, multicenter cohort study from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury study, which recruited between December 19, 2014, and December 17, 2017 (NCT02210221), we included 1,048 mTBI patients (Glasgow Coma Scale ≥ 13) with biomarker sampling and head computed tomography (CT) within 24 h of injury. We assessed six blood-based biomarkers-including glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1)-for their diagnostic performance in identifying patients with mTBI and iEDH. Patients with other traumatic intracranial findings potentially requiring surgery were excluded. Of 1,048 patients (median age 46 years; 64% male), 38 (3.6%) had iEDH and 982 (94%) had negative CT findings. GFAP showed the highest diagnostic accuracy for iEDH (area under the curve 0.77; 95% confidence interval 0.71-0.83) and yielded a negative predictive value of 1.0 at a threshold of 0.19 μg/L. The addition of UCH-L1 did not lead to a significant improvement in diagnostic performance. No significant correlation was found between EDH volume and biomarker levels. In this large multicenter study, GFAP was the only biomarker that could adequately distinguish patients with iEDH from CT-negative cases. These results suggest that GFAP may serve as a tool to rule out iEDH in patients with Glasgow Coma Scale ≥ 13, supporting its use in identifying individuals unlikely to require acute intervention for intracranial injury.
Mild traumatic brain injury (mTBI), a common health burden among combat veterans, has been associated with alterations in brain structure. Moreover, post-traumatic stress disorder (PTSD), frequently comorbid with mTBI, is linked to smaller cerebellum volumes; however, little is known about whether mTBI (absent comorbid psychiatric symptoms) similarly affects cerebellar structure. The cerebellum may play a central role in common postconcussive symptoms due to its contributions to cognitive and emotional functions. In a sample of 122 combat veterans, we examined whether total cerebellum volumes differed among those with a remote history of mTBI with (n = 29) or without (n = 42) comorbid PTSD and healthy controls (n = 51). An automated cerebellum parcellation protocol was applied to T1-weighted anatomical scans to derive volumetric estimates of the cerebellum (and 28 subregions). Hierarchical regression analysis (adjusting for total intracranial volume, age, sex, and combat exposure) revealed that, compared with controls, participants with comorbid mTBI-PTSD had a significantly smaller volume of the total cerebellum (p = 0.010). There was no significant effect of mTBI-only on total cerebellum volume (p = 0.165). Follow-up exploratory analyses of subregional cerebellum volume differences suggested that volume differences in comorbid mTBI-PTSD were primarily localized to the posterior lobe (crus I, lobules VIIB, VIIIB). In sum, in a sample of combat veterans, mTBI was associated with a smaller volume of the cerebellum, but only when comorbid with PTSD. Consistent with recent work, exploratory subregional analyses indicated that volume differences were primarily attributable to regions of the cerebellum most prominently involved in cognition and emotion. These results underscore the profound effects of PTSD on brain health in military veterans and suggest that mTBI may not produce long-lasting structural damage to the cerebellum. Future work is needed, as it remains possible that subtle cerebellar volume changes may emerge in specific subgroups or as a function of injury-related factors (e.g., mechanism of injury, time since injury) not fully captured in the present study.
The aim of this study is to determine if there is a difference in tau and amyloid beta (Aβ) deposition on positron emission tomography (PET) scans between former players and controls, and if there is a differential association of the tau and Aβ deposition with concussion symptom burden. Participants completed the Rivermead Post-Concussion Questionnaire (RPQ) and PET imaging using Pittsburgh Compound B (PiB) and AV1451 ligands to identify uptake of Aβ and tau, respectively. Aβ standardized uptake value ratios (SUVR) and tau SUVR were compared between players and controls using a general linear model including age, race/ethnicity, years of education completed, and total number of prior sport-related traumatic brain injuries (TBIs) as covariates. A series of linear regression models were built to predict RPQ symptom scores including group status (player vs. control), Aβ SUVR and tau SUVR, and the interaction between group status and the Aβ SUVR and tau SUVR. Former players reported 4.9 ± 2.8 and control reported 1.4 ± 1.6 prior sport-related TBIs. Neither group reported any non-sport-related TBIs. Former players had higher RPQ symptom scores (13.3 ± 1.8) compared with controls (4.7 ± 1.8; p = 0.003). Controls had higher uptake for Aβ in the precuneus (1.22 ± 0.02) compared to players (1.14 ± 0.02; corrected p = 0.007). There were no differences between groups in uptake for Aβ in any other region of interest or tau in any region of interest. None of the regression models associating the interaction of group status and uptake with RPQ symptoms were significant. Aβ and tau PET scans may have limited utility for identifying potential neuropathological differences between participants with a career in professional football from controls who did not play football beyond high school. The PET tracer used for tau in the current study (AV1451) is well-suited for Alzheimer's disease-related tau pathology with limited binding for chronic traumatic encephalopathy-type tau proteins. A PET tracer for chronic traumatic encephalopathy-related tau deposition should remain a focus of future research.
Patients with traumatic brain injury (TBI) and Glasgow Coma Scale scores of 13-15 (historically called mild TBI [mTBI]) commonly experience changes in cognitive functioning, including processing speed, memory, and executive functioning. In a prospective sample (N = 523) of individuals of European descent who had been treated in a U.S. level 1 trauma center for mTBI, we examined the prognostic value of four polygenic risk scores (PRS) for cognitive outcomes at 6-months postinjury. To estimate the impact of mTBI on cognition, primary cognitive outcomes were scaled as z-scores reflecting changes in performance relative to predicted preinjury performance. The PRS examined were previously developed and validated to predict cognition-related outcomes of educational attainment (Education-PRS), intelligence (Intelligence-PRS), and Alzheimer's disease (AD-mild traumatic brain injury (APOE)-PRS and AD + APOE-PRS). Both the Education-PRS and Intelligence-PRS displayed bivariate associations with all four cognitive outcomes (β = 0.19-0.32), whereas neither Alzheimer's disease PRS was significantly associated with any outcome. After controlling for other factors known to predict cognitive outcomes of TBI (e.g., sex, education, mTBI severity defined by a combination of Glasgow Coma Scale scores and the presence/absence of acute intracranial findings on clinical neuroimaging), the Education-PRS and Intelligence-PRS remained independently predictive of verbal episodic memory (β = 0.10-0.16), whereas their associations with processing speed and executive functioning were mostly nonsignificant and were mediated through educational attainment. Looking across primary z-score and secondary raw score outcomes, cognitive outcomes 6 months post-mTBI were good on average, and PRS made small independent contributions to outcome prediction. The mediation model findings may support theories of cognitive reserve, which propose that individuals with stronger preinjury cognitive processing abilities (often estimated by educational history) can better compensate for TBI. Moreover, findings indicate that PRS may contribute modestly to multivariable models predicting cognitive function after TBI.
Bibliometric analysis. To analyze the global application of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and identify status and emerging trends in SCI research. Not applicable. Articles published between 2020 and 2023 were retrieved from the Web of Science Core Collection. Data on disciplines, ISNCSCI versions, research aims, journals, keywords, countries, authors, and collaboration patterns were manually extracted. Visualization and mapping analyses were performed using VOSviewer and CiteSpace. A total of 595 articles involving 3498 authors from 46 countries were included. Among them, 569 were ISNCSCI application studies and 26 were development or version-related studies. Within the application studies, the leading disciplines were neurology (507 articles), orthopedics (180), and rehabilitation (179). The 2011 ISNCSCI edition was the most frequently reported version (30.8%), although 56.2% of studies did not specify the version. The journals publishing the most articles were Spinal Cord, Journal of Neurotrauma, and Archives of Physical Medicine and Rehabilitation. The main research topics were SCI prognosis (15.8%), rehabilitation efficacy (15.4%), and SCI-related complications (15.4%). The United States, China, and Canada were the top publishing countries. Frequently emerging keywords in 2023 included "predictors," "cardiovascular disease," "features," and "disability." ISNCSCI is a widely accepted standardized tool in SCI research and clinical practice. The field is characterized by expanding international participation, stronger interdisciplinary collaboration, and increasingly diverse applications. Better reporting of ISNCSCI versions may improve consistency and comparability across future studies. None.
Traumatic brain injury (TBI) often leads to long-term disability, including persistent mental health issues and lower health-related quality of life (HRQoL). Early interventions can improve recovery, but because resources limit routine monitoring of all patients, trauma care remains largely symptom-driven. The combination of long-term disability and limited capacity for routine follow-up highlights the need for risk-stratified follow-up care and reliable evidence on early prognostic factors. However, the existing literature is sparse and methodologically heterogeneous, limiting the clinical applicability of findings. We therefore conducted a systematic review and meta-analysis to identify early risk factors for poorer long-term mental health and HRQoL outcomes. A systematic search of seven electronic databases identified studies of adult patients with TBI, with outcomes assessed at least 6 months postdischarge. Two authors independently screened the studies, assessed the risk of bias, and extracted the data. We pooled effect estimates using a random-effects meta-analysis and calculated 95% prediction intervals. A narrative synthesis was applied when meta-analysis was not feasible. The review was registered with PROSPERO (CRD42024576912) and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of the 8,104 articles screened, 64 studies met the inclusion criteria (n = 334,672). Most studies (58%) had a low risk of bias. Female sex, socioeconomic disadvantage, psychiatric history, assaultive-related injuries, and previous TBI were consistently associated with worse long-term outcomes. Across meta-analyses, assault-related injuries more than doubled the odds of post-traumatic stress disorder (odds ratio [OR] = 2.72; 95% confidence interval [CI]: 2.01-3.66, I2 = 0%). Higher odds were also observed among females (OR = 1.33; 95% CI: 1.11-1.59, I2 = 0%), individuals with prior TBI (OR = 1.56; 95% CI: 1.07-2.27, I2 = 0%), and those with psychiatric history (OR = 2.38; 95% CI: 1.83-3.10, I2 = 48%). We found that female sex (OR = 1.72; 95% CI: 1.38-2.16, I2 = 58%), prior TBI (OR = 1.52; 95% CI: 1.25-1.85, I2 = 0%), and psychiatric history (OR = 3.25; 95%CI: 1.86-5.69, I2 = 98%) were associated with higher odds of depression. Furthermore, higher pooled anxiety scores were observed in females and in individuals with a psychiatric history. The study identified several readily available factors present before or at discharge that are associated with poor long-term HRQoL and mental health outcomes. Leveraging these factors in follow-up protocols, prediction modeling, and clinical decision support systems may facilitate risk-stratified postdischarge care for TBI patients.
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.
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.
Traumatic brain injury (TBI) accounts for approximately 2.5 million deaths yearly, with patients living in low- and middle-income countries disproportionally affected. Nonsurgical critical resuscitation interventions (nsCRIs) studied individually have been shown to improve outcomes in moderate-to-severe TBI (msTBI) patients. This cohort study primarily assesses the relationship between timeliness of delivery of grouped nsCRIs and all-cause 7-day mortality among blunt and/or penetrating isolated msTBI patients, with secondary objectives of 3- and 30-day mortality and discharge Glasgow Coma Scale (GCS). Adult trauma patients with isolated msTBI from January 2022 to December 2024 were enrolled from facilities in a trauma referral pathway in the Western Cape of South Africa. Cohort patients were categorized into treatment subgroups of those receiving nsCRI ≤1 h or nsCRI within 1-3 h; the reference group was receiving nsCRI >3 h from injury or missed nsCRIs. Inverse probability weighted Cox proportional hazard regression was used to model mortality outcome. Subgroup and sensitivity analyses were performed. Of the 507 patients within the cohort, 68.6% of patients had blunt injuries, and one-half had severe TBI. 21.7% of all msTBI patients died within 3 days, 27.6% deceased by 7 days, and 31.2% deceased within 30 days. There was a 26% (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.56, 0.98) 7-day mortality reduction among patients who received nsCRIs ≤1 h compared with the reference group. The subgroup of blunt and blunt with penetrating injured patients showed a 21% 7-day mortality benefit (HR = 0.79, 95% CI: 0.71, 0.88) and better discharge GCS categories among patients receiving timely nsCRIs (odds ratio = 1.79; 95% CI: 1.01, 3.19). Among severe TBI patients, there was a 29% 7-day mortality reduction in the nsCRI ≤1 h compared with >3 h or missed nsCRI (HR = 0.71, 95% CI: 0.5, 1.00). While those statistically significant subgroup findings should be interpreted with caution and several subgroup analyses did not show statistical significance, there was an overall trend towards survival benefit associated with nsCRIs at either ≤1 h and/or 1-3 h. Overall, in this cohort study of msTBI patients receiving care in a resource-limited trauma system, we found that nsCRIs delivered within 3 h were associated with improved 7-day mortality and neurological outcomes at discharge.
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 (n = 93), low (n = 136), medium (n = 71), and high (n = 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 (p = 0.002, ηp 2= 0.034) and GFAP (p = 0.035, ηp 2= 0.021), but not UCH-L1, tau, or p-tau. Post hoc comparisons with Bonferroni correction indicated NfL was higher in the No Blast group compared with the Low Blast (p = 0.004) group, but not the Medium Blast (p = 0.069) or High Blast (p = 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.
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], p = 0.607), 1 month (β = 3.81, 95% CI [-0.72, 8.3], p = 0.099), or 3 months (β = -3.18, 95% CI [-7.1, 0.70], p = 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.
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 (n = 2,984), among the four activity characterization options, activities were most frequently characterized as neither mentally nor physically demanding (n = 1,675, 44.3%), and most participants (n = 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.