Journal of neurotrauma最新文献

An acute subdural hematoma (ASDH) is the most common focal injury in traumatic brain injury (TBI) and a major cause of death and morbidity worldwide. The decision to perform neurosurgical evacuation of the ASDH is complex. The Brain Trauma Foundation (BTF) issued guidelines in 2006, recommending evacuation for ASDHs >1 cm or with >5 mm midline shift regardless of patients' Glasgow Coma Scale (GCS) score, and in cases of neurological deterioration, abnormal pupillary reaction, or high intracranial pressure (ICP). Despite their global recognition, the evidence supporting these guidelines is weak. This study assesses adherence to BTF guidelines in a European cohort and determines the effect on mortality and functional outcomes. Data from the prospective observational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were analyzed. Patients presenting after a TBI with an ASDH on the initial computed tomography scan across 65 trauma centers in Europe and Israel between 2014 and 2018 were included. Patients with concomitant epidural hematoma were excluded. Adherence to BTF guidelines for ASDH surgery and ICP monitoring was assessed, including subgroup analyses based on age and TBI severity. Multivariable logistic regression models examined the association between guideline adherence and outcomes, adjusting for prespecified confounders. Among 985 patients with traumatic ASDH, overall guideline adherence was 74% (n = 724), with higher adherence to conservative treatment (95% [n = 533]) compared with surgical recommendations (45% [n = 191]). Adherence varied by age and TBI severity, being lower in elderly and severely injured patients. ICP monitoring adherence in comatose patients was 63% (n = 240). Adherence to surgical ASDH guidelines was not significantly associated with in-hospital mortality (odds ratio [OR]: 0.72 [0.43-1.2]) or 6-month functional outcome (OR: 0.73 [0.47-1.1]). Overall adherence to BTF guidelines for surgical ASDH management was low. The current surgical thresholds do not align with clinical practice. Elderly patients and those with severe TBI were less likely to be treated per guidelines. Incorporating patient age, GCS and hematoma volume into the guidelines may enhance their relevance and adherence in clinical practice.

Chronic pain is among the most devastating and poorly understood symptoms after traumatic brain injury (TBI). Disruption of endogenous descending pain control pathways may contribute to chronic pain after TBI. In prior work, we found that TBI induces a two-stage pain dysregulation involving acute mechanical hindpaw hypersensitivity that resolves by 28 days post-injury (DPI), followed by chronic failure of descending control of nociception (DCN) lasting up to 180 DPI. However, the impact of sex on the dysfunction of endogenous pain control systems after TBI has not been explored. Using a lateral fluid percussion model of TBI in male and female rats, we assessed mechanical nociceptive responses using von Frey fibers and tested pharmacological interventions targeting established descending pain modulatory systems. We employed the selective noradrenergic (NA) reuptake inhibitor, reboxetine, the selective serotonin reuptake inhibitor, escitalopram, adrenoceptor antagonists' prazosin (α₁-adrenoceptors) and atipamezole (α₂-adrenoceptors), and the serotonin 5-HT₃ receptor antagonist, ondansetron. Findings revealed that acute hindlimb hypersensitivity involved enhanced descending serotonergic pain facilitation via the 5-HT₃ receptor in both sexes. In uninjured rats, pain control relies on descending NA inhibitory signaling via spinal α₂-adrenoceptors. Boosting noradrenaline in the acute phase after TBI with reboxetine reduced acute mechanical pain, but studies with selective adrenoceptor antagonists revealed a persistent switch from an α₂- to an α₁-adrenoceptor-driven antinociceptive pathway after TBI in both males and females. Acute phase mechanical pain resolved by 28 DPI, exposing a chronic phase of DCN failure up to 180 DPI. Reboxetine treatment restored the DCN response in female TBI rat via α₁-adrenoceptor but failed in male TBI rats. Restoration of the DCN response in male TBI rats was restored by enhancing serotonin signaling with escitalopram. These results demonstrate key differences in the susceptibility of endogenous pain modulatory pathways and the adaptations of those pathways between male and female rats after TBI. These findings suggest that sex needs to be considered when designing mechanism-based therapies for pain after TBI.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ]_1-40, Aβ_1-42, glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology (F(1, 147) = 5.781, 95% confidence interval (CI) = 0.0003-0.003, p = 0.035) as well as neurobehavioral dysregulation (F(1, 148) = 7.559, 95% CI = 0.001-0.009, p = 0.020), and functional dependence/dementia (F(1, 148) = 5.046, 95% CI = 0.0004-0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078-0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102-0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Traumatic brain injury (TBI) remains a global health challenge, with computed tomography serving as the primary diagnostic tool for initial evaluation. However, significant variability exists in repeat computed tomography (CT) scanning protocols, ranging from routine scheduled imaging to selective approaches based on clinical deterioration. This systematic review synthesized evidence from 1247 initially identified records, ultimately including 26 studies that met inclusion criteria, to determine optimal timing strategies for repeat CT scanning in patients with TBI. The analysis revealed dramatic heterogeneity in hemorrhagic progression rates (0.4-65%) and intervention requirements across studies, largely explained by differences in TBI severity. Patients with mild TBI (Glasgow Coma Scale [GCS] 13-15) demonstrated consistently lower progression rates (0.4-42%), intervention rates (0.13-0.9%), and mortality (0.13-1.2%) compared with moderate-severe TBI cohorts, which exhibited progression rates of 42.3-61%, intervention rates of 8.9-24%, and mortality of 13-18%. Critical temporal patterns emerged, with Fletcher-Sandersjöö demonstrating that 94% of hematomas ceased progressing within 24 h postinjury, establishing a crucial surveillance window. Multiple predictors of progression were identified, including concomitant intracranial lesions (subarachnoid hemorrhage odds ratio [OR] 3.28, subdural hemorrhage OR 4.35), advanced age, and antiplatelet therapy. Notably, patients undergoing initial CT scanning within 2-3 h postinjury showed higher rates of subsequent progression, suggesting that early scans warrant scheduled follow-up regardless of clinical status. These findings support severity-stratified approaches to repeat imaging, with routine protocols potentially justified in moderate-severe TBI, while selective strategies may be appropriate for patients with stable mild TBI. The evidence emphasizes balancing diagnostic yield against radiation exposure concerns, advocating for personalized protocols based on individual risk factors rather than universal approaches.

Traumatic brain injury (TBI) initiates a series of pathogenic processes, including neuroinflammation, oxidative stress, and metabolic failure, that ultimately result in neurological damage. Plant-derived bioactive compounds have demonstrated promise as treatments to reduce TBI-associated neurodegeneration. However, most previous studies have investigated the efficacy of a single active ingredient, and many such compounds have poor permeability across the blood-brain barrier (BBB), limiting their therapeutic potential. Cells release vesicles containing various signaling factors, ions, and nutrients that are subsequently taken up by adjacent cells via endocytosis. The present study explored the therapeutic effects of extracellular vesicles derived from Salvia miltiorrhiza-derived extracellular vesicles (SalEVs) for the treatment of TBI in mice model via biochemical, histological, microfluorometric, behavioral, and omics analyses. Isolated SalEVs contain an array of bioactive compounds, including tanshinones and salvianolic acids, encapsulated within a unique bilayer lipid structure, as revealed by electron microscopy and chromatography. Membrane labeling indicated that these SalEVs readily crossed the BBB of TBI model mice and accumulated at the injury site. Systemic administration of SalEVs to TBI model mice suppressed microglial activation, infiltration at the injury site, and proinflammatory phenotype transition as well as astroglial activation, neuronal reactive oxygen species accumulation, and apoptotic neuronal cell death. In addition, SalEVs preserved the dendritic structure following TBI. Omics revealed changes in gene and metabolite expression consistent with these anti-inflammatory, antioxidant, and neuroprotective effects. Behavioral tests also revealed partial rescue of TBI-induced spatial memory deficits. Systemic SalEV administration may be an effective therapeutic strategy for TBI by simultaneously targeting multiple pathogenic pathways.

Mild traumatic brain injury (mTBI) is common in adolescents. Magnetoencephalography (MEG) studies (primarily reporting on adult males) have demonstrated abnormal resting-state (RS) brain activity in mTBI. The present study sought to identify RS abnormalities in male and female adolescents with mTBI (no previous Diagnostic and Statistical Manual of Mental Disorders - 5th Edition diagnosis) identified from an outpatient specialty care concussion program setting as a basis for evaluating potential clinical utility. Visit 1 MEG RS data were obtained from 46 adolescents with mTBI (mean age: 15.4 years, 25 females) within 4 months of a mTBI (mTBI acute to subacute period) as well as from 34 typically developing (TD) controls (mean age: 14.8 years; 17 females) identified from the local community. Visit 2 RS data (follow-up ∼4.3 months after Visit 1; mTBI subchronic period) were obtained from 36 mTBI (19 females) and 29 TD (14 females) of those participants. Source-space RS neural activity was examined from 4 to 56 Hz. Visit 1 t-tests showed that group differences were largest in the beta range (16-30 Hz; mTBI < TD), with whole-brain linear mixed model (LMM) analyses examining beta-band group differences as a function of Visit. A main effect of Group indicated Visits 1 and 2 beta-band group differences in midline superior frontal gyrus, right temporal pole, and right central sulcus (all mTBI < TD). The group effects were large (Cohen's d values 0.75 to 1.31). Of clinical significance in the mTBI group, a decrease in mTBI symptoms from Visit 1 to 2 was associated with an increase in beta power in 4 other brain regions. Present findings suggest that RS beta power has potential as a measure and perhaps as a mechanism of clinical recovery in adolescents with mTBI.

Intimate partner violence (IPV) is a worldwide health concern with devastating implications for physical, mental, and cognitive health. IPV-associated brain injuries (IPV-BIs) induced through impacts to the head (e.g., mild traumatic brain injury [mTBI]) and non-fatal strangulation (NFS; i.e., a hypoxic-ischemic injury) have long been overlooked among IPV victim-survivors. Identifying their presence and consequences is vital to inform interventions. Cross-sectional design with 3 groups including women with IPV-BI (1-6; >6) sustained through NFS and/or mTBI, women exposed to IPV without BI, and healthy age-matched controls. All participants completed medical history, biopsychosocial questionnaires, and cognitive tests of premorbid IQ, learning and memory, processing speed, and executive function. A total of 146 women aged 40.99 years (SD = 13.97) were included: 46 with IPV-BI (27 1-6; 19 > 6), 42 with IPV alone, and 58 Healthy controls. IPV-BI was significantly associated with poorer performances on Rey Auditory Verbal Learning Test (RAVLT) Total Learning, Delayed Recall trials, and Trails Making Test B (TMT-B). Planned comparisons revealed that women with more than 6 IPV-BIs scored significantly lower on RAVLT Total Learning and Delayed Recall compared to other groups, with medium and large effect sizes. The association between IPV-BI and performances on the RAVLT remained significant after controlling for potential confounders, including age, premorbid functioning, post-traumatic stress disorder, depression, anxiety, substance use disorder, and other causes of BI. In contrast, the effect of IPV-BI on TMT-B performance was attenuated when anxiety was included in the model, rendering the IPV-BI group difference non-significant. There was evidence of impairments in memory and new learning among women with IPV-BI relative to the other groups beyond 6 months post-injury, with cumulative mTBI and NFS worsening outcomes. These findings highlight the need for IPV-BI screening, neuropsychological assessment, and targeted education and therapy for this underserved population.

At least 27% of women who report a history of intimate partner violence (IPV) also report experiencing IPV-related head trauma (IPV-HT) or probable brain injury (IPV-BI). Prior studies of non-IPV-related traumatic BI and IPV-BI suggest that adverse childhood experiences (ACEs) may be associated with the severity of common neurobehavioral symptoms after the injury, potentially due to their association with elevated post-traumatic stress disorder (PTSD) symptoms. This study sought to examine PTSD symptom severity as an intermediary of the relationship between ACEs and measures of symptoms commonly reported after HT among 121 women with exposure to IPV-HT. Linear regressions examined the association between ACEs and neurobehavioral symptoms assessed by the Rivermead Postconcussion Symptoms Questionnaire (RPQ), Headache Impact Test-6 (HIT-6), and Quality of Life in Neurological Disorders Cognitive Function-Version 2 (Neuro-QoL), while adjusting for other common influences on the severity of these symptoms: IPV-HT and other HT severity, time since most recent, worst IPV-HT (determined using the Brain Injury Screening Questionnaire), past year partner abuse frequency (determined using the Revised Conflict Tactics Scale), and age. Cross-sectional mediation analyses examined whether ACEs indirectly covaried with neurobehavioral symptoms via PTSD symptom severity (determined using the PTSD Checklist for DSM-5 [PCL-5]). ACE score was significantly associated with RPQ score (b = 1.65, p < 0.001) and Neuro-QoL T-score (b = -0.64, p = 0.03). The association between ACE score and RPQ score, and ACE score and Neuro-QoL T-score indirectly covaried by PCL-5 score (unstandardized indirect effect [bootstrapped 95% confidence interval]: RPQ: 0.680 [0.221,1.308]; Neuro-QoL: -0.658 [-1.255,-0.113]). The findings suggest that ACEs are associated with worse symptoms after IPV-HT, potentially by way of the association between ACEs and heightened PTSD symptom severity. Longitudinal studies are needed to determine the causality of these relationships. However, our findings suggest that ACEs and elevated PTSD symptoms may be important considerations for individuals reporting symptoms associated with IPV-HT. As such, providers of these individuals may want to consider whether childhood adversity may be impacting current symptom burden in conjunction with IPV, PTSD, and associated HT/BI.

Traumatic brain injury (TBI) induces severe neuropsychiatric complications. Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for microglial-mediated synaptic engulfment. This study aimed to clarify the unique role played by microglial TREM2 in memory dysfunction during the subacute phase of TBI. Behavior tests were conducted to assess post-TBI memory impairment in male Sprague-Dawley (SD) rats. The activity of microglia in different phases of TBI was observed via detecting Iba1 immunoreactivity by immunofluorescence and microglial markers by quantitative reverse transcription polymerase chain reaction. Pharmacological inhibition of microglia regulates its activity during the subacute phase. Additionally, we employed male Trem2 knockout mice in the C57BL/6J genetic background, as well as male wild-type C57BL/6J mice subjected to brain stereotaxic injection of TREM2 small interfering RNA. Rats subjected to TBI showed impaired memory retention in the Morris water maze test. Microglia activation and TREM2 expression peaked in the subacute phase, especially in Cornu Ammonis1 (CA1). Pharmacological inhibition of microglia in SD rats attenuated cell apoptosis and synaptic loss caused by TBI. Further studies demonstrated that selective knockdown of TREM2 in CA1 reduced microglia-mediated phagocytosis of synapses and enhanced synaptic plasticity, improving memory dysfunction associated with TBI. Our findings suggest that upregulation of TREM2 exacerbated TBI-induced memory dysfunction by promoting excessive microglial phagocytosis and synaptic loss in the subacute phase.