Journal of neurotrauma最新文献

Traumatic brain injury (TBI) is the leading cause of death and neurological disabilities in young adults, representing a significant psychological and economic burden for patients, families, and society. Morbidity and mortality in TBI involve pathophysiological events such as rupture of the blood-brain barrier, neuronal death, and neuroinflammation triggered by the initial trauma and subsequent secondary injuries. A proper understanding of these pathophysiological events involved in TBI is essential to find new targets for the treatment of this disease. The purpose of this study was to analyze the signaling pathways involved in pericontusional brain tissue in severe human TBI. Twenty-two frozen pericontusional brain tissue samples from patients with severe TBI indicated for surgery were analyzed and compared against autopsy brain tissue samples from neurologically healthy donors. The transcriptome analysis by large-scale RNA sequencing (RNA-Seq) was performed in TBI and controls in the exploratory phase. The QuantSeq 3' mRNA-Seq RNASeq was performed to identify altered gene expression triggered by TBI. Signaling pathway enrichment analysis identified increased expression of gene sets involved in inflammation, angiogenesis, extracellular matrix remodeling, and wound healing pathways, while genes related to ion transport and synaptic transmission were downregulated in TBI relative to controls. Moreover, upregulation of signaling pathways involving TNFα, NFkB, IL6-JAK-STAT, cholesterol homeostasis, inflammatory response, TGFβ, epithelial-mesenchymal transition, coagulation, apoptosis, p53, and angiogenesis was detected with predominant downstream activation of six transcription factors: NFKB2, FOS, RELB, KLF4, ATF3, and EGR2. Specific brain cell compartment analysis based on gene expression profiles previously reported in single-cell transcriptomes confirmed the upregulation of genes related to microglia, immune cells, and endothelial cells, in contrast to the downregulation of genes related to neurons, astrocytes, and mature oligodendrocyte compartments. Notably, the expression of CCL2 was significant and uniquely correlated with SPHK1 expression, linking inflammatory response to angiogenesis. The transcriptome profile of TBI revealed several differentially expressed genes related to inflammatory response but also to concomitant activation of signaling pathways involved in tissue repair. More specifically, the CCL2-SPHK1 axis was validated at gene and protein expression levels in TBI. Further studies elucidating their role in angiogenesis and promotion of brain tissue repair, together with their potential applicability as therapeutic targets, are warranted.

Civilian gunshot wounds to the head (GSWH) carry high mortality yet lack standardized, imaging-based triage tools. Because initial noncontrast head computerized tomography (HCT) is universally obtained but not leveraged with validated, rapid, and reproducible methods, we developed and evaluated an interpretable, attention-based multiple-instance learning (MIL) model to predict in-hospital mortality from the initial HCT. In a retrospective cohort at a single level I trauma center (May 1, 2018-October 31, 2023), we included consecutive adults (≥16 years) with GSWH who underwent HCT, excluding those dead on arrival or without HCT. Of 222 patients, 106 (47.8%) survived to discharge and 116 (52.2%) died. We used a stratified random split to create a development set (n = 168, 75.7%) and an independent test set (n = 54, 24.3%); the development set was repeatedly partitioned 100 times into training and validation subsets to quantify performance uncertainty, and each of the 100 models was evaluated once on the test set. The MIL algorithm produced a prognostic severity score with case-level interpretability via attention maps. On the independent test set, discrimination for mortality was high (area under the curve: 0.92, 95% CI: 0.87-0.94) with sensitivity 0.88 (95% CI: 0.78-0.97) and specificity 0.87 (95% CI: 0.74-0.96) at the optimal operating point. Attention visualizations consistently highlighted brainstem, deep midline, and ventricular injury in high-mortality predictions, aligning with established high-risk neuroanatomy. These findings demonstrate that an interpretable, HCT-based MIL model can deliver objective, reproducible risk estimates and transparent case-level explanations, supporting early prognostication and imaging-first triage in penetrating brain injury.

Diffuse axonal injury (DAI) is a leading cause of traumatic brain injury (TBI) morbidity and has well-studied molecular pathobiology. Historically, white matter DAI studies indicated unmyelinated axons are more susceptible to injury than myelinated axons, with myelin posited to protect axons from diffuse TBI shear/tensile forces through unresolved mechanisms. Similarly, preclinical studies have also identified gray matter DAI localized to the perisomatic domain (i.e., the unmyelinated axon initial segment [AIS] and first one-to-two nodes of Ranvier). With these concepts in mind, we hypothesized unmyelinated segments are selectively vulnerable to TBI-mediated shear/tensile forces and serve as initiating sites for DAI pathobiology. Using murine midline fluid percussion injury, neocortical layer V pyramidal cell perisomatic domains at the gray-white matter interface were spatiotemporally examined for initiating pathology using antibodies to cytoskeletal proteins to demarcate unmyelinated segments and amyloid precursor protein (i.e., the gold-standard DAI marker) to identify injury. In cells expressing yellow fluorescent protein to enhance injury visualization, axonal swellings were observed simultaneously within perisomatic unmyelinated segments (e.g., AIS; nodes) as well as immediately adjacent myelinated segments, indicating concomitant reactive axonal changes. These data suggest non-selective axonal susceptibility and that myelin may not protect against diffuse injury forces. While expanding DAI topography to the gray-white matter junction, these findings also have implications for action potential initiation, axonal protein trafficking, and cortical circuit connectivity. Furthermore, studies are needed to determine if DAI pathological mechanisms are shared between white and gray matter axons, which have common and differentiating cytoarchitectural components.

Spinal cord injuries (SCI) are extremely difficult to treat due to the limited capacity for neural regeneration across the injury site. However, V2a interneurons have been a point of interest in SCI research over the last decade, as they have been shown to contribute to the promotion of neuroplasticity after injury. These excitatory interneurons contain either long or short projections that are effective at driving rhythmic motor firing. By possessing ipsilateral, contralateral, or propriospinal projections, subtypes of V2a interneurons expressing the visual system homeobox-2 (Vsx-2) gene have been shown to extend their projections past the site of injury and restore injured spinal circuits that contribute to the respiration and right-left coordination. Moreover, Vsx-2/Zfhx3-expressing V2a interneurons in the midthoracic region of the spinal cord are a point of interest due to their unique ability to extend long projections caudally past the injury site and into the lumbar region, which resulted in substantial improvement in hind limb function after SCI in mice. Here, we collectively summarize the origin, subtypes, and the role Vsx-2 V2a interneurons play after SCI. We further describe the various techniques utilized to promote the accumulation and growth of these interneurons across or around the site of injury, effectively rewiring motor networks to contribute to functional recovery.

Individuals experiencing severe polytrauma are typically transported to the highest level of care as soon as possible, including helicopter evacuation from remote and/or rural environments. However, several recent preclinical and clinical studies have suggested that aeromedical evacuation exacerbates central nervous system injury and inflammation, and potentially results in increased mortality, questioning the right time and conditions under which to fly. Twenty-four swine with moderate-to-severe rotational traumatic brain injury (TBI) and ∼40% blood loss were randomly assigned to standard (∼8500 feet), tactical (evasive maneuvering), or mock (stationary on ground) helicopter (U.S. Army Black Hawk; HH-60M model) evacuation 2 h post-injury, with standard recommended therapies initiated in-flight. Results indicated that tactical evacuation was associated with increased cerebral perfusion pressure and inflammation (IL-6) post-flight relative to the standard and mock evacuation profiles, even after statistically controlling for pre-flight trauma procedures. Although the overall mortality rate was ∼25%, indicating severe polytrauma, no differences in mortality were observed as a function of aeromedical evacuation scenarios. Primary biomarkers of hemorrhagic shock, traumatic brain injury, lung and kidney pathology were also negative for aeromedical evacuation effects. In summary, the medical benefits associated with immediate (i.e., within a few hours of injury) helicopter evacuation of severe polytrauma patients likely outweigh the few increased complications associated with flight, as the latter may only be present during more extreme helicopter evacuation scenarios. Additional studies are needed to address potential adjunctive therapies that can be administered pre-flight to minimize the potential adverse effects of tactical flight.

Cavum septum pellucidum (CSP) is a common neuroimaging finding linked to repetitive head trauma, yet its relationship to blast exposure among the military population remains elusive. Here, we investigated whether lifetime exposure to different types of blast is associated with CSP morphology among Special Operations Forces (SOF) personnel. We retrospectively analyzed 323 SOF members from the Comprehensive Brain Health and Trauma Program at Home Base who completed high-resolution 3T MRI and the Blast Exposure Threshold Survey (BETS), which quantifies lifetime exposure to explosive weapons across five blast exposure count categories (BEC1-BEC5). CSP grade and length were assessed using validated criteria on coronal 3D T1-weighted Magnetization Prepared Rapid Gradient Echo scans. A CSP length-to-septum length ratio (CSP ratio) was calculated to adjust for anatomical variation. BEC1-BEC5 were log-transformed to correct skewness and are referred to as log-BEC1-5.Variance inflation factor analysis indicated low multicollinearity among predictors (log-BEC1-5 and age), and variable selection using Least Absolute Shrinkage and Selection Operator regression identified log-BEC5 (exposure to large explosives) as the only retained predictor. In fully adjusted models, only log-BEC5 remained significantly associated with CSP measures and was therefore the focus of subsequent analyses.Participants were stratified by BEC5 = 0 vs. BEC5 > 0, and associations with CSP measures were assessed using group comparisons, multivariable regression, and dose-response models.Among 323 participants (mean age 42.7 ± 8.8 years), 273 (84%) reported any BEC5 exposure. SOF members with BEC5 > 0 had significantly greater CSP presence (42.1% vs. 22.0%, p = 0.007) and longer CSP length (median 3 mm vs. 2 mm, p = 0.002). In age-adjusted models, BEC5 > 0 was associated with greater odds of CSP presence (OR = 2.58, 95% CI 1.26-5.25, p = 0.009) and a 1.45 mm increase in CSP length (p = 0.004). In continuous models, each one-unit increase in log-BEC5 was associated with a 0.31 mm increase in CSP length (p = 0.008) and a 0.0059 increase in CSP ratio (p = 0.008).These findings indicate a statistically significant association between cumulative exposure to heavy explosives and CSP enlargement, suggesting that CSP may serve as a potential imaging marker of blast-related neurotrauma.

In a cohort of children and adolescents with moderate and severe traumatic brain injury (TBI), we explored the location and burden of traumatic axonal injury (TAI) on early magnetic resonance imaging (MRI) and its associations with long-term outcomes at 1 and 5 years post-injury. Fifty-six patients (0-18 years) with moderate (n = 29) or severe (n = 27) TBI, where MRI was performed within 6 weeks, were prospectively included. TAI lesion locations (including grading), numbers, and volumes were registered on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging, and locations and numbers were registered on T2* gradient echo or susceptibility-weighted imaging. Long-term outcomes at 1 and 5 years post-injury were dichotomized into good outcome (Glasgow Outcome Scale Extended [GOSE] score 7-8) and disability (GOSE score ≤6). Logistic regression analyses, unadjusted and adjusted for the presence of TAI on the different MRI sequences, were performed. The median age was 14.3 years, 66% were boys, and the median number of days to MRI was 8. TAI was found in 89% of the patients with severe TBI and 72% of the patients with moderate TBI. The volumes of TAI on FLAIR were larger in the severe group than in the moderate group (p = 0.007). We found an increased risk of disability at 1-year post-injury with both more severe standard TAI grades (p = 0.005) and Trondheim TAI-MRI grades (p = 0.001). Similar results were found at 5 years post-injury. TAI bilaterally in the basal ganglia, thalami, mesencephalon, and/or pons was only observed in patients with severe TBI and disability. TAI had a high prevalence in our moderate-to-severe pediatric TBI cohort, and more severe grades of TAI were associated with an increased risk of disability at both 1 and 5 years post-injury. Assessing TAI on early MRI in pediatric TBI patients provides valuable prognostic insights and supports the optimization of rehabilitation strategies.