Traumatic brain injury (TBI) represents a significant global health challenge, but a systematic, severity-stratified analysis of its epidemiology and risk factors is lacking. Using data from the Global Burden of Disease (GBD) 2021 study, this study compares the burden of mild TBI (mTBI) and moderate-to-severe TBI (msTBI) from 1990 to 2021. We analyzed incidence, prevalence, and years lived with disability (YLDs) for TBI across 204 countries and territories and by sociodemographic index (SDI) quintiles. Analysis included the characterization of age and sex distributions, assessment of temporal trends, and evaluation of risk factor attributions for both mTBI and msTBI. The results revealed that while the global age-standardized incidence rate (ASIR) of TBI declined, low-SDI regions experienced rising prevalence and YLD rates despite falling incidence. The ASIR of mTBI decreased significantly (average annual percentage change [AAPC]: -0.587; 95% confidence interval [CI]: -1.211-0.059), whereas the ASIR of msTBI showed no statistically significant decline (AAPC: -0.483; 95% CI: -1.235-0.275). The absolute number of mTBI cases peaked among young and elderly males, while the ASIR of msTBI increased with age in both sexes but remained consistently higher in males. Falls and road injuries remained the leading causes; however, the absolute number of msTBI cases due to these causes continued to rise. Notably, violence-related factors-including conflict and terrorism as well as police conflict and executions-were among the most rapidly increasing risk factors for both TBI subtypes. In conclusion, the global TBI burden is characterized by a stagnant crisis of msTBI, underscoring an urgent need for severity-specific prevention strategies that target high-risk mechanisms and populations to mitigate the devastating impact of msTBI worldwide.
Traumatic spinal cord injury (SCI) increases the risk for skin complications, including the development of decubitus ulcers, that is, pressure sores. The mechanisms by which SCI adversely affects skin health are poorly understood. To better understand how SCI affects the normal progression of wound healing, two mouse models of cutaneous wound healing were used. Mice received a high-level (T3) SCI or sham injury (Lam) over the first week postinjury. Mice received standardized skin wounds on the dorsum below the injury level (punch biopsy or compression/ischemia wounds). Planimetric analysis revealed that wound closure was consistently delayed and impaired after SCI. Subsequent analyses of the expression of genes and proteins responsible for regulating cell migration and recruitment, particularly of neutrophils, were reduced in SCI mice as early as 1 day post-wounding. This impaired chemotactic signaling was associated with a corresponding decrease in neutrophil recruitment to the wounds of SCI mice. At later phases of healing, the expression of inflammatory genes and the accumulation of wound myeloid cells with an elevated capacity for arginine catabolism was enhanced in SCI mice relative to Lam. Overall, data in this report show that impaired wound closure in SCI mice is associated with early and prolonged disruption of the expression of genes and proteins needed to coordinate the sequential progression through all phases of wound healing. Consequently, skin wounds in SCI mice exhibit prolonged inflammation, characteristic of complicated wound healing. Thus, targeting signaling pathways during the inflammatory phase of healing of decubitus ulcers after SCI could improve wound closure and limit further complications.
Traumatic brain injury (TBI) is a leading cause of death and disability. While the Glasgow Coma Scale (GCS) guides initial assessment, single values miss evolving neurological change. In this multicenter ICU cohort integrating NSICU, MIMIC-IV, and eICU databases, we analyzed adults (≥18 years) with TBI who had ≥3 GCS measurements within the first 120 ICU hours. Using 12-hourly measures, latent class growth modeling identified four dynamic GCS trajectories (Stable High, Rapidly Improving, Persistently Moderate, Persistently Low), and we quantified cumulative neurological burden with a mean threshold-based area-under-the-curve (TBM-AUC) summarizing time above prespecified GCS thresholds. Among 3,132 patients, mortality increased monotonically across trajectories, highest in the Persistently Low group (adjusted hazard ratio [HR] 4.95, 95% confidence interval: 3.14-7.81 vs. Stable High). Lower TBM-AUC was strongly associated with mortality; most pronounced at threshold 13 (HR 0.34). Age-stratified analyses showed a trajectory-by-age interaction (p = 0.013), with Persistently Low conferring the greatest risk in both younger and older adults. Adding trajectory class to baseline predictors improved discrimination (AUC: 0.820-0.861, p < 0.001) with consistent gains in integrated discrimination improvement, net reclassification improvement, and median risk score across Boruta-, LASSO-, and best-subset-based models. Dynamic GCS trajectories and TBM-AUC provide prognostic information beyond conventional assessments and may enhance risk stratification and clinical decision-making in neurocritical care; prospective validation is warranted. [Figure: see text].
The long-term sequelae of severe penetrating traumatic brain injury (TBI) include neurological and psychiatric disability, impaired cognitive function, and the development of post-traumatic epilepsy. The present study evaluated the therapeutic effects of intravenous immunoglobin (IVIg), a well-established immunomodulatory treatment, in a controlled cortical impact model of severe TBI in mice. The beneficial effects of IVIg treatment on acute neurological status, motor function, anxiety level, and spatial learning ability were demonstrated by reduced Neurological Severity Scores, increased Rotarod latency and cumulative movement durations in open-field tests, and improved active place avoidance performance. IVIg treatment also significantly reduced brain tissue loss, which was examined using Nissl staining at 16 weeks after TBI. Furthermore, brain microRNAs (miRNAs) were profiled to identify the biological pathways potentially associated with the actions of IVIg treatment using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. To identify potential peripheral biomarkers reflecting the changes in the brain, differentially expressed miRNAs in plasma and brain samples from the same animals were compared. Our immunostaining results showed that IVIg treatment significantly attenuated the upregulation of IL-1β and complement 3 (C3) and altered the activation of microglia and astrocytes. This proof-of-concept study provided strong evidence for the beneficial effects of IVIg treatment in severe penetrating TBI.
Neurogenic bowel (NB) affects roughly 60% of people with a spinal cord injury (SCI), and these patients present with slow colonic transit, constipation, and chronic abdominal pain. The mechanisms by which NB bowel develops are unclear, thereby limiting interventions to being primarily symptom-focused and ineffective. Therefore, the main goal of this study was to identify the mechanisms that initiate and maintain NB after SCI as a critical step to develop evidence-based, novel therapeutic options to prevent NB. In previous studies, the neurogenic inflammatory mediator calcitonin gene-related peptide (CGRP) was identified as a high-priority candidate gene. Therefore, in a midthoracic rodent spinal contusion model that presents with clinically translatable NB-like phenotypes, we conducted intrarectal antagonism of CGRP activity using CGRP8-37 (compared to vehicle administration) in mice with SCI. This was followed by histological, molecular, and functional (Ca2+ imaging) approaches to assess the prevention of previously reported phenotypes of NB. CGRP8-37 significantly prevented colonic dysmotility and structural defects of the colon (i.e., expanded lymphoid nodules). There was also a prevention of microbial invasion into the colon wall and neuronal hyperresponsiveness to autologous fecal supernatants. These data support the role of CGRP/CGRP as a candidate mechanism for NB after SCI and highlight the potential for novel therapeutic treatments for the prevention of NB.
Traumatic brain injury (TBI) remains a leading global cause of death and disability, disproportionately impacting low- and middle-income countries (LMICs), where neurosurgical resources are often limited. In these settings, foundational gaps in health system infrastructure-such as limited internet access, absence of electronic medical records (EMRs), and lack of standardized protocols-impede timely diagnosis, intervention, and continuity of care. This study evaluates the relationship between health system infrastructure and neurosurgical capacity, intervention delivery, and TBI outcomes across LMICs. We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across PubMed, Embase, and Scopus to identify studies examining TBI care and system infrastructure in LMIC institutions. Extracted data were categorized across two primary domains: (1) clinical management and patient outcomes, and (2) implementation of health system components, including EMRs, information and communication technology access, and standardized care protocols. Quantitative analysis incorporated descriptive statistics, chi-square testing, Kruskal-Wallis tests, Glasgow Coma Scale-adjusted linear regression models, and machine learning classifiers to examine associations. Of the LMIC institutions reviewed, only 41% reported the presence of neurosurgical capacity. Implementation of EMRs and standardized protocols was significantly associated with increased neurosurgical capacity (odds ratio [OR] = 1.1, p = 0.06; OR = 1.1, p = 0.03, respectively). Among facilities with operative capacity, the median neurosurgical intervention rate was 28% (interquartile range [IQR]: 3-33%). Policy implementation predicted reduced post-TBI mortality (B = -10.8, p = 0.06; R2 = 0.56), with a median institutional mortality rate of 19% (IQR: 8-17%). Machine learning models demonstrated strong discriminatory ability to predict TBI mortality based on neurosurgical capacity and infrastructure metrics (area under the curve = 0.76). These findings highlight the potential for health system infrastructure-particularly EMRs, internet access, and standardized clinical protocols-to improve neurosurgical readiness and reduce preventable mortality following TBI in LMICs. Strategic investment in digital health tools and policy standardization could be a high-yield, scalable approach to closing global neurosurgical care gaps and improving TBI outcomes in resource-limited settings.
The Glasgow Outcome Scale-Extended (GOSE) is the most frequently used outcome measure for traumatic brain injury (TBI) clinical trials. The GOSE may be administered several ways, the choice depending on the purpose of the research. For example, the GOSE can be administered to reflect functional limitations attributed to the overall injury, including extracranial injuries (GOSE-All), or to discount limitations attributed to extracranial injuries (GOSE-TBI). In this investigation, we assessed the effect of using GOSE-All versus GOSE-TBI in clinical trial design. We estimated the impact of the differences in assessment strategy on sample size and power for a clinical trial of an intervention that affects only TBI-related limitations. Inclusion criteria based on TBI severity and extracranial injury severity were examined, as were primary assessments at 2 weeks or 3, 6, or 12 months after injury. Data from 2,288 participants in the prospective observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study were used to simulate the effects. If the trial were analyzed by a Mann-Whitney test comparing GOSE-All scores between treatment groups, sample size would need to increase 8-158% to account for the apparent decreased effect of a treatment that affects only the brain injury. If the sample size were not adjusted, power to detect a treatment effect would decrease from 80% to as low as 41%. If the outcome were dichotomized (favorable=GOSE 8 if including only patients with Glasgow Coma Scale [GCS]=13-15, GOSE 5-8 if GCS = 3-12), the sample size would need to increase 6-165%. The ratios of sample size are largest when the trial population consists of people with milder brain injuries and decrease with time since injury in those with GCS 13-15. It is crucial for researchers, given the aims of their studies, to decide in advance whether the classification of the GOSE should be based on effects attributed to the brain injury, despite the fact that extracranial injuries may not have allowed one to experience the extent of limitation due to the TBI, or all injuries, including extracranial injuries, and to power their studies accordingly. Instructions to the respondent and outcomes examiner need to be clear about what causes of disability are to be included. The assessment method should be accounted for in the power and sample size calculations, clearly indicated in the protocol and publications and documentation accompanying shared data, and emphasized in the training of the outcome examiners so all are collecting the desired information.
Neuroimaging technologies such as computed tomography and magnetic resonance imaging (MRI) have been widely adopted in the clinical diagnosis and management of traumatic brain injury (TBI), particularly at the more acute and severe levels of injury. Additionally, a number of advanced applications of MRI have been employed in TBI-related clinical research with great promise, and researchers have used these techniques to better understand the underlying mechanisms, progression of secondary injury and tissue perturbation over time, and relation of focal and diffuse injury to outcome. However, the acquisition and analysis time, the cost of these and other imaging modalities, and the need for specialized expertise have represented historical barriers in extending these tools in clinical practice. While group studies are important in detecting patterns, heterogeneity among patient presentation and limited sample sizes from which to compare individual-level data to well-developed normative data have also played a role in the limited translatability of imaging to wider clinical application. Fortunately, the field of TBI has benefited from increased public and scientific awareness of the prevalence and impact of TBI, particularly related to recent military conflicts and sport-related concussion. This awareness parallels an increase in federal funding in the United States and other countries allocated to investigation in these areas. In 2025, funding for TBI research in the United States is less certain due to the changing administrative priorities, so we hope this article can highlight the incredible productivity of the TBI neuroimaging research community. In this article, we summarize funding and publication trends since the mainstream adoption of imaging in TBI to elucidate evolving trends and priorities in the application of different techniques and patient populations. A total of 4872 articles over 82 years are categorized. We also review recent and ongoing efforts to advance the field through promoting reproducibility, data sharing, big data analytic methods, and team science. Finally, we discuss international collaborative efforts to combine and harmonize neuroimaging, cognitive, and clinical data, both prospectively and retrospectively. Each of these represents unique, but related, efforts that facilitate closing gaps between the use of advanced imaging solely as a research tool and the use of it in clinical diagnosis, prognosis, and treatment planning and monitoring.
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