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.
Traumatic brain injury (TBI) is both an acute health issue and a chronic disease. Cognitive impairments, particularly in learning and memory, cause significant distress for patients and their families. In this study, we innovatively implanted a photostimulation (PS) device into the injured brain tissue of a severe TBI mouse and performed intracranial PS therapy. Intracranial PS significantly improved learning and memory function in severe TBI mice, and the implantation process did not exacerbate the brain injury. Further investigation revealed that intracranial PS might enhance oxidative phosphorylation in the injured neurons, improving energy metabolism and thereby inhibiting neuronal apoptosis. This study provides a novel direction for clinical treatment of learning and memory deficits following TBI.
Pediatric traumatic brain injury (TBI) triggers biological changes that may differ from those observed in non-brain injuries. Brain-derived neurotrophic factor (BDNF) DNA methylation (DNAm) may serve as a novel, dynamic biomarker of the brain's response and help identify TBI-specific epigenetic patterns relevant to later recovery. Therefore, the purpose of this study was to examine whether BDNF DNAm differed between children with TBI and those with orthopedic injury (OI, comparison group) acutely and over time. Data were derived from the Epigenetic Effects on TBI Recovery study, a prospective, longitudinal cohort study conducted at UPMC Children's Hospital of Pittsburgh. Children aged 3-18 years hospitalized at a minimum of overnight for complicated mild-to-severe TBI or OI without head trauma were enrolled. Exclusion criteria included prior hospitalization for TBI, pre-existing neurological or psychiatric conditions, or sensory or motor impairments precluding study participation. Blood samples were collected during hospitalization (mean = 31.6 h post-injury) and at 6 (mean = 216.9 days) and 12 months (mean = 405.9 days) post-injury. The primary outcome variable was DNAm assessed via pyrosequencing at five quality-controlled CpG sites in the BDNF gene (chromosome 11, Genome Reference Consortium Human Build 38 positions 27722033, 27722036, 27722047, 27701612, and 27701614). The primary exposure was injury type (TBI vs. OI), with severity (measured via Glasgow Coma Scale [GCS]) examined as a secondary exposure within the TBI group. Primary covariates included age, sex, and race; secondary covariates included pubertal status, age-adjusted body mass index, non-head injury severity, socioeconomic status, and psychosocial adversity. The final analysis sample included n = 189 participants with TBI and n = 105 participants with OI. Participants were 66.3% male, 83.2% White, and had a mean age of 10.6 (±4.3) years at the time of enrollment. Acutely, children with TBI showed significantly lower DNAm at three of five sites (3.17-5.83% lower; p = 0.0044 to 6.48E-06) while controlling for age, sex, and race. One site remained significantly lower at 12 months (8.56% lower; p = 0.0045); no significant differences were observed at 6 months. Observed differences remained robust across sensitivity models adjusting for secondary covariates. GCS-measured TBI severity was not associated with DNAm at any time point. These findings suggest that BDNF DNAm differs between children with TBI and those with OI, particularly in the acute period. BDNF DNAm differences may reflect early biological responses that are specific to TBI.
Traumatic brain injury (TBI) is a neurological disease that seriously endangers human life and has a poor prognosis. In particular, neuroinflammation during secondary injury after TBI affects the course of TBI, and interleukin-33 (IL-33) plays an important regulatory role in neuroinflammation after TBI. Meanwhile, the Yes-associated protein (YAP) can influence the prognosis after TBI. In this study, we explored whether the upregulation of YAP in astrocytes can enhance the protective effect of IL-33 against neuroinflammation after TBI. In the current study, the markers of microglial proinflammatory/anti-inflammatory responses both in vivo and in vitro were assessed after the administration of exogenous IL-33. Adeno-associated virus targeting astrocytes in vivo and lentivirus transfecting astrocytes in vitro were used to overexpress YAP, and the expression and localization of proteins were evaluated by Western blotting and immunofluorescence staining. Chromatin immunoprecipitation-quantitative Polymerase Chain Reaction (qPCR) assays were performed to confirm that YAP transcriptionally regulates the IL33 gene by binding directly to its promoter region. Astegolimab was administered to block Growth Stimulation Express Gene 2 Protein (ST2) receptors in vivo and in vitro. Morris water maze and Y-maze tests were employed to assess cognitive function after TBI. The results demonstrated that the expression levels of both YAP and IL-33 were significantly decreased during the early phase of TBI. Concurrently, the anti-inflammatory marker CD206 in microglia was also markedly reduced in the acute stage post-TBI. Importantly, YAP was found to enhance IL-33 secretion by binding to its gene promoter, thereby activating the IL-33/ST2 signaling pathway. This activation promoted anti-inflammatory responses in microglia, which were mediated through the NF-κB signaling pathway, and ultimately led to improved cognitive function. These beneficial effects were effectively reversed by the administration of astegolimab, confirming the specificity of the YAP/IL-33/ST2 mechanism. Above all, we found that YAP produced by astrocytes regulates microglial anti-inflammatory responses through the IL-33/ST2 pathway, thereby improving cognitive function after TBI.
Given the heterogeneity of traumatic brain injury (TBI), the development of a therapeutic strategy has been difficult despite decades of research. To develop an accurate classification system to guide individualized treatment, new protein biomarkers of TBI have been studied. We explored if different subtypes of TBI have unique biomarker profiles and histological findings using four pig models of TBI: moderate rotational injury (100-110 r/s), mild rotational injury (85-95 r/s), moderate contusional injury (8-9 mm), and mild contusional injury (6-7 mm). Among these groups, we identified unique profile of plasma neurofilament light (NFL) and glial fibrillary acidic protein (GFAP): whereas moderate contusion animals had early peak of NFL (2-3 days) and GFAP (1 day), mild contusion animals had delayed peak of NFL (8 days) and GFAP (3 days). Diffusion tensor imaging analysis found reduced fractional anisotropy in corona radiata for contusional injured animals but rotational injured animals showed no significant changes compared to control animals. Histological analysis showed prominent vascular inflammation and axonal injury in the pericontusional cortex in contusional injured animals. In rotational injured animals, prominent axonal injury was found in perivascular white matter. Future studies for mechanistic underpinning of biomarker changes are needed to establish therapeutic targets, predict severity of injury, and determine clinical trial enrollment and therapeutic response.
Spinal cord injury (SCI) is a debilitating condition resulting in the loss of sensorimotor functioning at and below the site of injury. Despite advances in the treatment and management of SCI, there are no current approved pharmacological therapies to augment motor function and functional recovery. NX210c is a 12-amino acid peptide derived from thrombospondin type 1 (TSP1) repeat sequences from the subcommissural organ-spondin protein. TSPs are glycoproteins present in the extracellular matrix, mediating cell-cell and cell-matrix interactions and axon pathfinding. NX210c was previously shown to improve axonal regeneration and functional recovery in thoracic SCI. The aim of this study was to evaluate the ability of NX210c to promote functional recovery and tissue repair in a traumatic cervical SCI rat model. Adult female Wistar rats were subjected to a C6/C7 bilateral clip compression-contusion injury and treated once daily with intraperitoneal injections of NX210c (8 mg/kg) or its vehicle for 8 weeks, beginning 4 h or 8 h post-injury. Administration of NX210c beginning at 4 h post-injury increased forelimb grip strength post-injury and improved several static and dynamic aspects of locomotion, including interlimb coordination. When the first administration was undertaken at 8 h post-injury, NX210c promoted weight gain, improved trunk balance (inclined plane), trended toward accelerated bladder control recovery, and approached significance for skilled reaching at 8 weeks post-injury. Furthermore, for animals that were treated daily with NX210c starting 8 h post-injury, histological analysis demonstrated greater white and gray matter preservation and reduced cavity size, along with the upregulation of neuronal markers. To conclude, NX210c mitigates various aspects of SCI, including motor function and tissue preservation, with preferential results being obtained with the delayed initial administration of NX210c at 8 h post-injury.
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