Neurotrauma reports最新文献

Traumatic brain injury (TBI) leads to intracerebral inflammation involving resident microglial cells and astrocytes as well as invading peripheral dendritic cells (DCs), monocytes, and neutrophils. However, the profile of immune blood cells activated by TBI remains poorly defined. Several animal models showing invasion of circulating classical dendritic cells type 2 (cDC2s) to the traumatically injured brain have been found, resulting in exacerbated neurological outcomes. In TBI patients, increased levels of chemokine CCL2, attracting cDC2 cells, have been linked to poor recovery. In the present study, blood samples from healthy blood donors (n = 11) were compared with blood from TBI patients (n = 15) at day 1 and day 3 after admission for neurointensive care stored in two tested freezing media (eight patients using Cytodelics, seven patients using CryoStor CS10) for analyses by flow cytometry. Reference blood was collected from random healthy blood donors (7 with Cytodelics, 4 CryoStor CS10). Flow cytometry excluded T-cells, B-cells, and natural killer cells by a panel of CD3, CD19, CD20, and CD56 antibodies. To identify DCs and inflammatory monocytes, antibodies to CD11c, CD1c, CD141, HLA-DR, and CD14 labeled with specific fluorochromes were added to the thawed blood samples. Neutrophils were analyzed by separate runs of flow cytometry using a CD66b antibody. Despite some differences depending on the freezing medium used, the percentage of classical DCs type 2 (cDC2; CD14-, CD11c high, CD1c+) remained unchanged from healthy controls at day 1 after admission but increased significantly (p = 0.014) from day 1 until day 3 after TBI. In contrast, levels of classical DCs type 1, inflammatory monocyte-derived DCs, or neutrophils were not altered. Thus, our preliminary data, in addition to previous animal model data, suggest a role for circulating cDC2 cells contributing negatively to the pathophysiology of TBI.

To evaluate the feasibility and diagnostic sensitivity of a novel catheter-based epidural electrodiagnostic (EDX) system for real-time, segment-specific monitoring of spinal somatosensory conduction in a pre-clinical model of acute spinal cord injury (SCI). A custom-designed EDX electrode catheter was epidurally placed over the thoracic spinal cord in anesthetized rats (n = 5) to record compound evoked potentials across five stages: Baseline, Hypoxia, Post-SCI, Post-SCI Hypoxia, and Post-SCI Recovery. Waveform morphology, onset/peak latencies, and amplitudes were extracted. Paired t-tests compared baseline to experimental stages, and analysis of covariance (ANCOVA) assessed injury force effects on conduction metrics. Postmortem recordings confirmed the biological origin of signals. The EDX system consistently recorded high-fidelity biphasic spinal evoked responses. SCI induced significant increases in N-Onset latency across all post-injury stages (Cohen's d = 2.45-3.04), while N-Peak and P-Peak latencies also increased significantly Post-SCI (Cohen's d = 2.03-2.57), reflecting conduction slowing and partial demyelination. ANCOVA revealed that injury force had large effects on N-Onset (η2_p = 0.872) and P-Onset (η2_p = 0.492). After adjustment, group effects remained significant for N-Onset (η2_p = 0.799), P-Onset (η2_p = 0.513), and N-Peak (η2_p = 0.565). Although P-Peak and amplitude changes did not reach significance, their effect sizes (η2_p > 0.06 and >0.01) suggested a clinically meaningful influence. These findings support the EDX system's sensitivity to both the presence and severity of SCI. This proof-of-concept study demonstrates the feasibility and diagnostic value of an epidural EDX platform for real-time segmental monitoring of spinal conduction. The system's robust sensitivity to latency shifts and force-dependent modulation underscores its potential for intraoperative neuromonitoring, SCI diagnosis, and injury stratification. Its dorsal column targeting and catheter-based design also support integration into closed-loop neuromodulatory frameworks and longitudinal neurorehabilitation, providing a foundation for future clinical translation.

Traumatic brain injury (TBI) results from impact to the head that induces both primary and secondary injuries. Secondary injuries are characterized by downstream inflammation, metabolic dysfunction, and cell death manifest from the inflicting primary injury to the head. Secondary injury offers a window for therapeutic interventions, but the multifaceted nature of secondary injury is complicated, necessitating mechanistic tools to screen the efficacy of such interventions. As such, utilizing animal models to define the features of secondary injury mechanisms is critical for medications development. Various animal TBI models employ specialized equipment to recapitulate both primary and secondary injury aspects of human TBI. The organotypic hippocampal slice culture (OHSC) model offers a biological intermediate between live animal and dissociated cell culture models. In OHSC models, ex vivo tissue containing heterogenous hippocampal cell types is plated upon permeable culture membranes, which have the capacity to be manipulated. We, therefore, repurposed a commercially available impact device to mechanically distend the OHSC culture membrane, effectively inducing an indirect stretch injury to hippocampal tissue. This stretch injury technique causes characteristic secondary injury trauma, such as widespread cell death, loss of neuronal viability, and production of reactive oxygen species, following the initial insult. Importantly, both the impact force and dwell time of the membrane distention are scalable, a modular feature widely employed across other animal TBI models. This OHSC TBI model may lend itself to high-throughput preliminary assessment of therapeutic efficacy for treatment of secondary injury in animal TBI models.

Traumatic brain injury (TBI) affects millions of individuals annually, with a 53% increase in emergency visits since 2006. Despite its prevalence, no FDA-approved treatments exist to mitigate brain damage or promote recovery. While repeated TBI is widely studied, even a single impact can cause persistent neurological changes, likely mediated by Ca²⁺ dysregulation via effects on ryanodine receptors. In a rat model of mild TBI, using a single closed-head controlled cortical impact, we observed no changes in the levels of hippocampal glial fibrillary acidic protein and phosphorylated tau-both markers of cellular damage. However, mild TBI (mTBI) significantly enhanced synaptic transmission at hippocampal CA3-CA1 synapses and increased CA1 pyramidal cell excitability for at least 30 days-effects that were significantly attenuated by acute and subacute injection of Ryanodex, a concentrated nanocrystalline formulation of the ryanodine receptor allosteric modulator dantrolene. Ryanodex may, therefore, offer a promising intervention to reduce persistent hippocampal dysfunction following mTBI, with potential clinical applications for acute TBI treatment.

Diaschisis is a phenomenon in which damage to one brain region leads to dysfunction in remote, yet functionally connected, areas. Although it has been well characterized in stroke, the complex, multifocal nature of traumatic brain injury (TBI) suggests that similar network-level disruptions could occur, yet the presence and impact of diaschisis in TBI remain underexplored. This gap may stem from a historical focus on cerebrovascular events, underrecognition of diaschisis in TBI, and methodological challenges related to TBI's heterogeneous nature. This review maps diaschisis in TBI by examining models, mechanisms, neuroimaging, clinical features, and therapeutic interventions. A PRISMA-ScR guided search of PubMed, Embase, and Cochrane included studies explicitly addressing diaschisis in TBI from inception up to January 2025. Two independent reviewers screened titles, abstracts, and full texts, with discrepancies resolved by consensus. Twenty-three studies were included, encompassing 110 human participants, 497 animals, and one in vitro model. Among these, 57% used neuroimaging, 39% assessed functional outcomes, and 22% examined potential interventions. The predominant experimental model was rodent-controlled cortical impact, typically simulating moderate TBI. Contrarily, human studies were fewer and focused on severe TBI cases. Crossed cerebellar diaschisis was the most common neuroimaging finding (36%), with MRI used most frequently, followed by PET and SPECT. Across both clinical studies and preclinical models, key mechanisms of diaschisis included deafferentation, reduced metabolism, altered glutamate signaling, hypoperfusion, and distant apoptotic cell death. Motor deficits were more common with better recovery than cognitive impairments. Interventions such as MK-801 and Ifenprodil showed potential to reverse diaschisis, but others had limited effects. This review underscores the limited but growing understanding of diaschisis in TBI. Targeted research on mild-to-moderate TBI, interventions, and imaging-validation trials is needed to improve diagnosis and treatment.

Chronic subdural hematoma (CSDH) is a common neurosurgical disease in the elderly, characterized by inflammation, neovascularization, and increased vascular permeability. Although protease-activated receptor-1 (PAR-1) is known to regulate vascular permeability and is implicated in chronic inflammatory diseases, its role in CSDH remains unclear. In this exploratory study, we investigated PAR-1 expression in the dura mater and outer membrane of patients with CSDH compared with controls. Age- and sex-matched cases (six CSDH, five controls) were selected for analysis. Immunohistochemistry for PAR-1 and zonula occludens-1 (ZO-1), along with mRNA expression analysis, were performed. Histologically, the outer membrane of CSDH exhibited cellular clustering and strong PAR-1 immunoreactivity in vascular structures, whereas the dura mater from both groups showed no significant PAR-1 staining. ZO-1 expression was preserved in the vasculature of the outer membrane in CSDH and the dura mater of both groups. mRNA analysis revealed a trend toward higher PAR-1 and lower ZO-1 expression in CSDH, though not statistically significant. The group effect (p = 0.24, analysis of covariance [ANCOVA] t-test) represents the adjusted difference in ZO-1 expression between CSDH and control groups after accounting for PAR-1 levels. The main effect of PAR-1 (p = 0.15, ANCOVA t-test) reflects the overall association between PAR-1 and ZO-1 expression across samples. This study provides the first evidence of PAR-1 expression in the outer membrane of CSDH, suggesting a role in promoting local vascular hyperpermeability. These findings highlight PAR-1 as a possible biomarker and therapeutic target in CSDH. Further studies with larger cohorts and quantitative analyses are warranted to clarify the molecular mechanisms underlying vascular dysfunction in CSDH.

The most consistent risk factor for developing psychiatric problems post-traumatic brain injury (TBI) is a preexisting psychiatric disorder, but many studies have reported that psychiatric disorders can occur de novo following "mild" TBI. The objective of this secondary analysis of a prospective cohort study of patients (n = 1,947) with acute TBI and presenting Glasgow Coma Scale (GCS) score between 13 and 15 was to describe the association of pre-injury psychiatric history with prevalence and risk factors for probable posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and nonspecific anxiety disorder (ANX) following TBI at long-term follow-up. Rates of probable PTSD, MDD, or ANX were analyzed from years 1 to 7 post-injury. Multivariable regression models were built to predict meeting cutoffs for PTSD, MDD, and ANX at 1 year, 2-4 years, and 5-7 years post-injury. Predictors were psychiatric history, migraine history, TBI history, initial head CT scan, loss of consciousness, post-traumatic amnesia, GCS, insurance type, highest level of care, cause of injury, years of education, age, sex, and race/ethnicity. Participants with history of pre-injury psychiatric disorder met clinical cutoffs for PTSD, MDD, and ANX at approximately double the rate of participants without history of psychiatric disorder at year 1 (16-28% vs. 5-13%), between years 2 and 4 (15-35% vs. 6-18%), and between years 5 and 7 (10-28% vs. 5-12%). Multivariable modeling confirmed several classical risk factors for post-TBI psychiatric sequelae at any time during follow-up, such as psychiatric history, prior TBI, female sex, and Black race. Assault, mechanism of injury, and Medicaid, self-pay, or other insurance (reference: private insurance) were also associated with PTSD, MDD, and ANX at various timepoints. Probable PTSD, MDD, and ANX were more common in participants with pre-injury psychiatric history, but significant psychiatric symptoms are identifiable for years post-injury, even among those with de novo psychiatric disorders.

Traumatic brain injury (TBI) is a heterogeneous disease from which incomplete recovery is unfortunately common. Biomarkers prognostic of future recovery are currently lacking. MicroRNAs (miRNAs), small noncoding RNAs, are attractive potential biomarkers as they are stable in biofluids and can provide molecular mechanistic insights via the mRNAs they regulate. We measured miRNAs from whole blood in TBI participants (n = 106) within 24 h of injury and age- and sex-matched control participants (n = 107) using the NanoString Technology nCounter® miRNA expression panel. One hundred and nineteen miRNAs were differentially expressed in individuals who had sustained a TBI compared with control participants. Forty-seven of these had levels at 6 months postinjury that were similar to those within 24 h of injury, indicating that these acute differences persisted in the individuals with TBI. Furthermore, two of these 47 miRNAs were upregulated in participants who had incomplete recovery (functional outcome Glasgow Outcome Scale-Extended [GOS-E] score < 8) at 6 months after injury, compared with participants who had complete recoveries (GOS-E = 8). More work is needed to determine if miRNAs may serve as prognostic biomarkers of TBI outcome. MiRNAs may provide insights of the molecular networks and pathophysiological processes impacting recovery after injury warranting future study.

Repetitive, sub-concussive head impacts have been associated with increased chronic traumatic encephalopathy (CTE) incidence. CTE diagnosis traditionally relies on postmortem examination, which limits precise correlation between cause and effect. This prospective study embraced innovative diffusion magnetic resonance imaging, which enables in vivo quantification of acute, subacute, and chronic changes in brain tissue microstructure. This approach was used to evaluate changes in white matter microstructural status at intervals up to 180 days following a specified soccer heading protocol. This study was approved by university research ethics committees. Twelve adult males were recruited to the study and gave signed, informed consent. Six Intervention participants were university-level soccer players, with six Control participants drawn from university-level noncontact sports. Multi-shell diffusion-weighted MRI data were acquired on a 3T Siemens Connectom (300 mT/m) scanner using the HARDI protocols. Baseline measures of fractional anisotropy, mean diffusivity, and mean kurtosis were acquired at day 0. The Intervention cohort then performed 10 soccer "headers" in a laboratory, with acceleration-time data captured using an instrumented mouthguard and post-processed to report common metrics. The Intervention group was then re-scanned at day 1 (n = 6), day 90 (n = 5), and day 180 (n = 4). The Control group was re-scanned at day 1 (n = 6) and day 180 (n = 3). Many brain tracts were identified as having significant (p < 0.05) changes in white matter microstructural changes at day 90, which correlated strongly with the magnitude of head impact. A smaller number of tracts had changes at day 1 and day 180. These results indicate that, within this pilot population, the magnitude of repeated soccer headers appears to correlate with the magnitude of white matter microstructural change. Additional investigation is required to determine whether the effect of such an intervention influences long-term brain health risk.Board.