Preclinical research in traumatic brain injury (TBI) continues to significantly increase knowledge and yield a large number of peer-reviewed studies, but translation of these results to the clinical setting has been minimal. Rigor and transparency factors such as concealment of group allocation (e.g., "blinding") or ensuring that reagents are identifiable are critical in ensuring that scientific studies are replicable and translatable. Yet, nearly all efforts aimed at measuring these factors have concluded that reporting practices are problematic and incomplete. One way to improve transparency of reporting practices is to require that authors address a set of transparency-related items in some way, such as a checklist or an article section. Recently, Journal of Neurotrauma, a leading publisher of preclinical TBI research, instituted a required rigor-related section, which is explained to authors via a set of transparency, rigor, and reproducibility (TRR) instructions (one example for each article type). These documents include specific transparency sections explaining blinding, power calculations, protocols, code, and data deposition. Experimental Neurology is a journal that is similar in size, impact, and topic, but the journal does not have explicit instructions to authors about transparency items. The purpose of this study was to assess the degree to which transparency reporting items were included in published articles comparing reporting practices in the Journal of Neurotrauma and Experimental Neurology. We used a commercial software, SciScore, which is an AI tool tuned to detect rigor/transparency sentences in published articles and count the number found (roughly dividing by the number expected) to obtain a score. Overall, SciScore found that in six of eight items that were explicitly asked for, such as power calculations, investigator blinding, inclusion criteria, attrition, and data, there were significant differences (more than 10%) compared to Experimental Neurology. However, in Journal of Neurotrauma articles with the extra rigor section, three of four rigor items that were not explicitly asked for in the template rigor documents, such as subject demographics or transparent antibody reporting, were not different from Experimental Neurology. One item, reporting of the sex of subjects, was significantly better in Experimental Neurology. This shows that the Journal of Neurotrauma's required rigor section is effective in improving reporting, but it would be far better if sex as a biological variable and transparent reporting of reagents (items present on major checklists, including NIH rigor criteria) would be included.
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.
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.
Traumatic brain injury (TBI) is frequently complicated by coagulopathy, characterized by a complex interaction between hypercoagulability and hyperfibrinolysis. TBI-induced coagulopathy is a critical factor in neurological deterioration, resulting in poor prognoses. Despite recent advances in the clinical management of TBI, few effective therapies are available for TBI-induced coagulopathy. Tranexamic acid (TXA) and various concentrates of coagulation factors are ineffective because these agents promote secondary rather than primary hemostasis. Currently, only platelet concentrates are involved in the formation of platelet clots for primary hemostasis. We aimed to develop H12-(adenosine 5'-diphosphate [ADP])-liposomes, a novel platelet substitute. This platelet-targeted hemostatic agent comprises liposomes with the H12 peptide, which selectively binds to activated platelets and encapsulates ADP to locally promote platelet activation and thrombus formation, subsequently halting bleeding. Similar to platelet concentrates, H12-(ADP)-liposomes can promote primary hemostasis. To elucidate the effects of H12-(ADP)-liposome treatment on TBI and TBI-induced coagulopathy, an appropriate animal model of TBI-induced coagulopathy is required. As only few reliable models are available, we established a novel rat model of TBI-induced coagulopathy induced by laser-induced shockwave (LISW) exposure. This model did not require surgical craniotomy and allowed us to focus on TBI-induced coagulopathy. In this model, expansion of the intracranial hematoma volume within 30 min of LISW exposure was the determining factor for mortality. The 24-h survival rate of LISW-exposed animals was 70.3% (26 of 37 rats). In this model, treatment with TXA showed a modest potential to rescue animals from TBI owing to its antifibrinolytic effects. However, TXA did not improve endothelial injury or prevent coagulopathy. In contrast, treatment with H12-(ADP)-liposomes after LISW exposure prevented endothelial injury and expansion of intracranial hematoma. H12-(ADP)-liposome treatment also prevented prolongation of the prothrombin time after 16 h of LISW exposure. Consequently, this treatment significantly improved the acute prognosis of LISW-exposed animals. These findings demonstrate that our LISW-based TBI model replicates the essential aspects of TBI-induced coagulopathy and that H12-(ADP)-liposomes have therapeutic potential for mitigating trauma-induced coagulopathy and improving TBI outcomes.
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.
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 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.
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.
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.
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.
Spinal cord injury (SCI) triggers a complex cascade of cellular and molecular events at the lesion site, driving progressive degeneration of the spinal cord. This increases the level of disability over time and also significantly diminishes the prospects of recovery. SCI also causes systemic changes that affect overall physiology and function. In this context, biomarkers detectable in body fluids-such as blood, urine, and cerebrospinal fluid-that reflect lesion-site events and correlate with recovery outcomes are critically important. Biomarker analysis can be leveraged for: a) research and drug discovery; b) confirming target engagement of therapies or drug delivery systems; c) optimizing dosage or dosing frequency to maximize outcomes; d) serving as early prognostic indicators; and e) enabling patient stratification and adaptive clinical trial design. Our comprehensive analyses of preclinical and clinical studies show that multiple biomarkers are common to both rodent models of SCI and humans with SCI. Notably, these biomarkers appear earlier and remain elevated for a shorter duration in rodents than in humans. Importantly, several of these biomarkers can predict injury severity and functional recovery. Artificial intelligence-driven analysis and interpretation of biomarker profiles can further transform early diagnosis and prediction of therapeutic outcomes. This review summarizes the current status, key challenges, and future prospects of biomarker-based approaches in SCI research and clinical trial design to accelerate therapeutic development.
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.
One of the most prevalent neurodegenerative diseases, Parkinson's disease (PD), is generally discussed in terms of aging, genetic predisposition, and environmental exposures. Nonetheless, there is growing evidence that both isolated severe traumatic events and repetitive mild traumatic brain injury may play a significant role in the development of parkinsonian features. This trauma-associated condition, known as Post-Traumatic Parkinsonism Syndrome (PTPS), is becoming more widely acknowledged as a clinically significant but underdiagnosed illness. The differences between PTPS and conditions like chronic traumatic encephalopathy (CTE) are often blurred because, in contrast to idiopathic PD, PTPS typically manifests after a specified latency period following head injury and is often accompanied by overlapping symptoms of cognitive, behavioral, and motor dysfunction. At the pathophysiological level, PTPS is defined by the combination of trauma-induced processes, such as neuroinflammation, axonal injury, and dysregulated acetylation pathways, with mechanisms known to be associated with PD, such as alpha-synuclein aggregation, dopaminergic neuronal loss, and impaired protein clearance. Today, experimental models demonstrate how trauma speeds up or even starts neurodegenerative cascades, providing a unique platform to investigate disease mechanisms outside of the traditional toxin-based paradigms of PD. The current understanding of PD, PTPS, and CTE is summarized in this review, with a focus on risk factors, comparative pathology, and experimental model translational insights. This review emphasizes the significance of acknowledging trauma as more than a trigger but rather as a potential contributor to long-term neurodegeneration and disability by presenting PTPS as a unique but related syndrome within the PD spectrum.
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) 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.
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.
Severe traumatic brain injury (TBI) during pregnancy is a rare but challenging condition. There is scarce evidence in this population, and severe TBI management during gestation remains empirical and extrapolated from data on non-pregnant women. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) collaborated to establish a multidisciplinary consensus panel of 115 physicians with vast expertise in the management of severe TBI, including cases of pregnant women. A modified Delphi approach was adopted. Two online questionnaires were conducted between February and June 2025. The list of statements (36) was distributed to the panelists to allow voting and to propose any comments and/or changes. The analysis of results was performed by an experienced non-voting methodologist. Statements were classified as strong suggestion, weak suggestion or no suggestion when >85%, 75-85% and <75% of votes were in favor, respectively. A consensus was reached, generating 36 strong suggestions regarding several important aspects in the care of isolated severe TBI during pregnancy. This consensus provides practical suggestions to support a clinician's decision-making in the management of severe isolated TBI during pregnancy in high-income countries. However, these statements are based mainly on expert opinion, and further evidence is required in this field.
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.
Acute brain injury (ABI), traumatic or nontraumatic, profoundly disrupts the gut microbiota (GM). To provide intensive care physicians with a clearer understanding of this phenomenon, we conducted a systematic review with qualitative synthesis. Due to significant heterogeneity in study designs, populations, and outcomes, a meta-analysis was not feasible. Instead, findings were synthesized thematically, focusing on study types, microbiota metrics, and clinical associations. Across studies, ABI is consistently associated with reduced microbial diversity, a decline in the relative abundance of several species, and increased interindividual variability in GM composition. Notably, phyla, such as Pseudomonadota, Bacteroidota, and Verrucomicrobiota, are frequently enriched, whereas Bacillota tends to be depleted. These patterns of dysbiosis appear largely consistent regardless of ABI etiologies. Furthermore, GM alterations can occur within a few hours postinjury and often return to baseline levels within months. The review highlights the metabolic, immune, and neuronal disruptions induced by ABI, which may contribute to gastrointestinal dysfunction and negatively influence patient prognosis. Moreover, standard intensive care unit (ICU) therapies may exacerbate GM disturbances. Importantly, dysbiosis has been linked to adverse clinical outcomes (delayed recovery, increased mortality). Emerging therapeutic strategies (metabolite supplementation, fecal microbiota transplantation) have shown potential to modulate the GM and support postinjury recovery. However, the underlying mechanisms of ABI-related dysbiosis and its consequences remain incompletely understood. Future research should aim to clarify the pathophysiological drivers of GM disruption, explore the potential prognostic value of GM dynamics, and assess how ICU therapies influence GM evolution. Developing GM-targeted interventions may offer novel opportunities to modulate ABI-related complications and improve patient outcomes.
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.