Journal of neurotrauma最新文献

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.

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.

Respiratory failure is one of the greatest causes of morbidity and mortality after cervical lesions, the most common type of spinal cord injury (SCI). Fortunately, several pre-clinical and clinical studies have shown spontaneous, but limited, respiratory recovery after injury. However, there are still many unanswered questions about what is driving this recovery, so there is a growing need to further elucidate the neuroplastic potential of the phrenic network. Here, we investigated the structural plasticity of the right and left phrenic networks by analyzing perineuronal net (PNN) changes after a C2 hemisection (C2Hx) in mice. For this purpose, the right and left phrenic systems were traced with a pseudorabies virus, a trans-synaptic retrograde tracer applied to the diaphragm muscle, labeling the entire phrenic motor network. We found most PNN-bearing neurons within the ventral horn in naïve animals, specifically around phrenic motoneurons (PhMNs), but not phrenic spinal interneurons. Right, but not left, C2Hx resulted in a significant increase in PNNs and glutamatergic synapses around ipsilateral PhMNs, suggesting that the right C2Hx requires greater neuroplasticity to overcome respiratory dysfunction. The results from this study uncover profound anatomical and functional asymmetries in left- and right-sided phrenic networks, underlying the complex nature of the spinal respiratory system, and contribute to a more advanced understanding of how the phrenic network adapts to trauma. Overall, this work underscores the importance of studying neuroplasticity and how it holds the potential to help improve outcomes for individuals living with SCI.

Traumatic spinal cord injury (TSCI) is a debilitating disease that results in a heterogeneous set of symptoms. This includes secondary inflammatory mechanisms, which can perpetuate injury to the spinal cord, as well as negatively affect other organ systems. Standard prognostication, such as magnetic resonance imaging, is cumbersome and provides limited resolution; thus, the development of prognostic biofluid tests is of significant clinical importance. The current study systematically reviewed biomarker studies following acute (within 24 h) TSCI. Four databases were searched for this systematic review, PubMed/MEDLINE, Cochrane (OvidSP), Web of Science, and Scopus, resulting in 702 articles to be screened by two independent reviewers. Thirty-two studies met inclusion criteria and were included in the systemic review. About 116 total markers were examined, and 66.4% were found to be associated with TSCI with three major utilities: diagnostic, injury severity, and prognostics. Results generated from the current study highlight discrepancies between biofluids and recommend biomarkers for clinical utility. Future research should associate these acute biomarkers with long-term outcomes using predictive modeling, in addition to curating a clinical TSCI database for optimal prognostication. As TSCI outcomes are variable and impact many systems, the curation of preventative and interventional treatment strategies is crucial.

Spinal cord injury (SCI) can result in partial or full paralysis, depending on the level and completeness of injury. Locomotor function is often used as a measure of recovery and treatment outcomes. The Basso, Beattie, and Bresnahan scale and Basso Mouse Scale (BMS) are gold standards used in rodent SCI studies to evaluate changes in locomotor recovery. However, these scoring systems are observer-dependent measures that may be affected by the presence of an experimenter, particularly in studies where blinding is difficult. Observer-independent methods measure outcomes without an operator present, thus reducing bias and increasing reproducibility between research groups. Changes in locomotor recovery were evaluated after contusive SCI using the Advanced Dynamic Weight Bearing (ADWB) system, previously used successfully to assess acute and chronic pain. We observed a shift in body weight early after injury, with increased surface area and weight placement to the front paws and the trunk/tail region. Concurrently, there was a reduction in rear paw surface area and weight placement. As functional recovery occurred over time, there was a shift toward reduced weight placement on the front paws. As with locomotor recovery, these changes did not return to preinjury levels. We also found that the rate and degree to which mice shifted weight onto front paws depended on injury severity. Importantly, changes in weight distribution and surface area showed a strong correlation with BMS scores, suggesting that the observer-independent ADWB test is a viable measure to assess changes in locomotor function over time after SCI.

High-level spinal cord injury (SCI) often disrupts supraspinal control of sympathetic input to the heart. The resulting imbalance in the autonomic nervous system increases the risk of developing cardiac arrhythmias. It was previously demonstrated that passive hindlimb cycling (PHLC) effectively maintains or improves bodily function including cardiovascular performance following SCI. However, it remains unclear whether the exercise can affect cardiac electrical disorders. To address this specific question, we complemented a complete SCI at a high-thoracic level in rats and then performed PHLC for 5 or 10 weeks. Naive rats or those receiving injury alone served as controls. Subsequently, a telemetric transmitter was implanted to record blood pressure and electrocardiogram. In 24-h resting recordings, cycling training did not influence SCI-induced hypotension but significantly reduced the events of spontaneous autonomic dysreflexia. When colorectal distension was employed to artificially trigger autonomic dysreflexia, a fewer number of severe arrhythmias (e.g., atrioventricular block, premature ventricular contraction single, and sinus pause) were found in animals with 10-week PHLC compared with injury controls. As a stress test, a series of increasing concentrations of dobutamine was administered to stimulate cardiac sympathetic activity. Consequently, various types of arrhythmias occurred in animals with SCI alone, whereas very few were detected in animals obtaining exercise training for 10 weeks. Furthermore, pharmacological intervention disclosed that exercise appeared to reduce unopposed parasympathetic tone that arose post to injury. Thus, the results suggest that activity-based training for the long term improves autonomic balance to enhance tolerance of cardiac electrical conduction following SCI.