Journal of neurotrauma最新文献

Acutely after traumatic spinal cord injury (SCI), the immune system responds with an inflammatory cascade that promotes secondary damage to the spinal cord and systemic inflammation, which promotes persistent medical consequences. Here, we combined clinical and research data to evaluate cellular and molecular changes in the systemic immune system of individuals with SCI (SCI, N = 36) within 0-4 days after injury compared to uninjured individuals (CTL, N = 36). Analyzing blood samples by bulk-RNA Seq, 4752 differentially expressed (DE) gene transcripts were identified in SCI compared with CTLs, including increased expression of genes associated with inflammation and innate immunity (e.g., Neutrophil degranulation, Toll-Like Receptor signaling). Most participants with SCI had complete blood count data available, of whom 36% had elevated white blood cell and neutrophil counts, 24% had elevated monocytes, and 36% had lymphopenia. Significantly reduced expression of canonical natural killer (NK) cell, T cell and dendritic cell (DC) genes were identified, consistent with reduced frequencies of these cell types, determined by flow cytometry. Some molecular changes appeared to be influenced by motor completeness of injury. C-reactive protein, a validated clinical biomarker of inflammation, was significantly elevated after SCI, with levels higher in motor complete compared to motor incomplete injuries. This was also apparent for several other proinflammatory cytokines (e.g., High Mobility Group Box 1 protein, IL-6, IL-8). These data confirm and extend prior observations of cellular and molecular immunological changes, that may serve as potential biomarkers of injury severity, or as future therapeutic targets to improve health.

Previous studies have shown that administration of high doses of morphine in the acute phase of spinal cord injury (SCI) significantly undermines locomotor recovery and increases symptoms of chronic pain in a rat spinal contusion model. Similarly, SCI patients treated with high doses of opioid for the first 24 h postinjury have increased symptoms of chronic pain 1 year later. Whether these adverse effects are driven by morphine only or all opioids compromise recovery after SCI, however, is unknown. Based on our previous findings we hypothesized that activation of the kappa opioid receptor (KOR) is key in the morphine-induced attenuation of locomotor recovery after SCI. Thus, we posited that opioids that engage KOR-mediated signaling pathways (morphine, oxycodone) would undermine recovery, and clinically relevant opioids with less KOR activity (fentanyl and buprenorphine) would not. To test this, we compared the effects of the clinically relevant opioids on locomotor recovery and pain in a male rat spinal contusion model. Rats were given a moderate spinal contusion injury followed by 7 days of intravenous morphine, oxycodone, fentanyl, buprenorphine, or saline, and recovery was assessed for 28 days. All opioids produced analgesia on tests of thermal, mechanical, and incremented shock reactivity. However, tolerance developed rapidly with buprenorphine administration, particularly with daily administrations of 5 morphine milligram equivalent (MME) buprenorphine. Opioid-induced hyperalgesia (OIH) also developed across days following administration of higher doses (10 MME, 20 MME) of morphine and oxycodone. Fentanyl and buprenorphine did not produce OIH. Contrary to our hypothesis, however, we found that high doses of all opioids reduced recovery of locomotor function. Unlike the other opioids, the effects of buprenorphine on locomotor recovery appeared transient, but it also produced chronic pain. Morphine, oxycodone, and buprenorphine decreased reactivity thresholds on tests of mechanical and incremented shock stimulation. In sum, all opioids undermined long-term recovery in the rat model. Further interrogation of the molecular mechanisms driving the adverse effects is essential. This study provides critical insight into pain management strategies in the acute phase of SCI and potential long-term consequences of early opioid administration.

Spinal cord injury (SCI) represents a major public health issue, as the consequences are often irreversible with no treatment currently available. This results in a growing population living with long-lasting motor, sensory, and/or autonomic impairments directly related to their SCI. Here, we have evaluated the therapeutic potential of a thrombospondin repeats peptide analogue, named NX210, in a mouse hemisection model of SCI. Adult female mice were subjected to a thoracic level 8 dorsal hemisection, and treated with intraperitoneal injections of NX210 starting at 4 h post-injury and then twice a week at 4, 8, or 16 mg/kg. Hind limb motor function was assessed once a week for 10 weeks post-injury using the Basso Mouse Scale (BMS) score and sub-score, the rotarod, and the activity chamber tests. Mice were then sacrificed, and the spinal cords were collected for immunohistochemistry. Interestingly, NX210 improved functional recovery (BMS score and sub-score, latency to fall from the rotarod, spontaneous locomotor activity) with rapid rises in function that were maintained throughout the 10-week study. This was accompanied by a reduction of nociceptive reactivity assessed by the tail flick test. NX210 treatment also increased myelin basic protein and reduced neuron/glial antigen 2 at the injury site 10 weeks post-injury while no significant effects were observed on lesion size, inflammation, and neuron survival. Overall, this study highlights a potential new therapeutic strategy to promote repair and decrease long-lasting functional impairments after SCI.

Acute traumatic cervical spinal cord injuries (TCSCI) are associated with significant mortality and morbidity, particularly when complicated by neurogenic respiratory failure. While upper cervical-level injuries are established risk factors for mechanical ventilation, patients with acute injuries below the fifth cervical level without significant chest trauma may also require ventilatory support. However, reliable early predictors remain unclear. This study aims to identify the primary predictors of early mechanical ventilation needs in patients with acute TCSCI. We conducted a retrospective analysis of 148 cases of TCSCI treated between 2019 and 2022. Among these, 27 cases (18.24%) required ventilatory support. Multivariate analysis revealed that a compression grade of 2 or higher, exceeding 25% on Computed Tomography (CT) (adjusted odds ratio [aOR]: 10.18; 95% CI: 2.03-50.94; p < 0.001), and a cord contusion length spanning at least two levels on Magnetic Resonance Imaging (MRI) (aOR: 2.11; 95% CI: 1.06-4.22; p = 0.03) were significant independent predictors. CT-based spinal cord compression measurements showed a strong correlation with MRI findings (linear regression coefficient = 0.88, 95% CI: 0.80-0.96; Spearman's rho = 0.90; both p < 0.001). The regression line was closely aligned with the equality line, indicating CT can reliably approximate MRI. Noninferiority testing revealed no significant difference in predicting mechanical ventilation risk between modalities (p = 0.21). Survival analyses stratified by compression grades demonstrated similar predictive performance, with higher compression grades (2-4) associated with increased risk of ventilation over time. These findings suggest that the degree of cord compression and cord contusion length are reliable, noninvasive predictors of the need for mechanical ventilation in TCSCI, emphasizing the importance of early recognition, cost-effective health care management, and prognostic counseling. The Subaxial Injury Classification and Severity Scale demonstrated borderline significance (sensitivity 81.5%, specificity 87.6%). The study found that patients with >25% cervical spinal cord compression had significantly poorer outcomes compared to those with ≤25% compression, including longer hospital stays, lower survival rates, worse pre-treatment neurological status, and higher complication rates. Surgical treatment, particularly the posterior approach, was more common in the >25% compression group; however, post-treatment neurological improvement was observed only in cases of grade 2 degree compression, not grades 3 and 4 in CT and MRI. In contrast, the ≤25% compression group demonstrated better outcomes, with greater post-treatment improvement. [Figure: see text].

Traumatic complete spinal cord injury (CSCI) leads to severe impairment of sensory-motor function, and patients often suffer from neuropsychological deficits such as anxiety, depression, and cognitive deficits, which involve different brain functional modules. However, the alterations in modular organization and the interactions between these modules in pediatric patients with CSCI remain unclear. In this study, a total of 70 participants, including 34 pediatric CSCI patients and 36 healthy controls (HCs) aged 6 to 12 years, underwent whole-brain resting-state functional MRI. The functional networks were analyzed via a graph theory approach based on the 90-region Automated Anatomical Labeling (AAL 90) atlas, generating a 90 × 90 correlation matrix. Metrics for nodal, global, and modular scales were calculated to evaluate alterations in the network's topology. Between-group comparisons and partial correlation analysis were performed. Compared to HCs, pediatric CSCI patients exhibited significant decreases in nodal metrics, particularly in subcortical networks (SN) like the bilateral thalamus. Besides, the distribution of core nodes changed, with five newly added core nodes primarily located in the regions of the default mode network (DMN). For modular interactions, patients group presented increased connectivity within the DMN and between the DMN and the attention network (AN) but reduced connectivity between DMN and SN, DMN and vision network (VN), and AN and SN. Notably, the participation coefficient (Pc) of the TPOmid.L (left temporal pole: middle temporal gyrus) was positively correlated with motor scores, suggesting its potential as an indicator for evaluating the motor function in pediatric CSCI patients. Additionally, the patients demonstrated a different modular structure with significantly lower modularity. These findings suggest that functional network and modular alterations chiefly occur in emotional cognition and vision-associated regions, emphasizing the importance to focus on their psychocognitive well-being and providing evidence for visual-feedback related rehabilitation strategies. [Figure: see text].

Physical therapy stretching remains one of the most prevalent therapies for patients with spinal cord injury (SCI); however, we have previously shown that daily hindlimb muscle stretching of rats following a T10 SCI significantly disrupts their hindlimb locomotor function, likely through maladaptive sprouting of nociceptive afferents and modulation of lumbar spinal circuitry. Despite these clinically significant findings, mid-thoracic contusion models do not represent a majority of clinical injuries and are not effective for modeling the loss of cardiovascular control and autonomic complications that patients with higher level SCI experience. Therefore, the objective of the current study was to examine the effects of hindlimb stretching on the locomotor and cardiovascular function of rats with a T2 SCI. Twenty-six female Sprague-Dawley rats received a moderate T2 contusion (25 g/cm) and were divided into SCI Control (n = 14) and Stretched (n = 12) groups. Our daily hindlimb stretching protocol was initiated at week 5 post-SCI and administered 5 days/week for 4 weeks before a portion of the animals from each group were euthanized. The remaining animals (Control: n = 8, Stretched: n = 6) recovered for 3 weeks before euthanasia. Locomotor function was assessed using the Basso, Beattie and Bresnahan Open Field Locomotor Scale and kinematic gait analysis. Additionally, cardiovascular indices were collected using echocardiography at baseline, pre-stretching, post-stretching, and post-recovery timepoints. Four weeks of daily stretching led to transient disruption of locomotor function as well as reduced overnight activity followed by robust improvements in locomotion once stretching was no longer administered. Although stretching did not appear to have a dramatic effect on cardiovascular indices, both groups displayed significant changes over time in cardiac output and stroke volume. Furthermore, immunohistochemistry staining revealed that stretching did not exacerbate Calcitonin Gene-Related Protein (CGRP⁺) nociceptor sprouting in the lumbar dorsal horn, contrary to the effects we have shown in T10 stretched animals. Overall, these results indicate that hindlimb stretching following a high-thoracic SCI does not appear to aberrantly modulate lumbar spinal circuitry as has been shown in low thoracic injuries. Additionally, stretching combined with a T2 SCI does not result in cardiovascular dysfunction, although future work must be conducted to determine whether stretching triggers autonomic events and maladaptive plasticity near the spinal lesion.

Bowel dysfunction, is a prevalent and life-impacting comorbidity of spinal cord injury (SCI) with no long-term treatment available. SCI-induced colon changes including motility and fibrosis are understudied as are strategies to address SCI bowel dysfunction. This need remains partly due to the lack of a mouse model that recapitulates the human condition. We hypothesized that a high thoracic spinal transection in mice would trigger bowel dysfunction with coincident colon pathology similar to humans and rats after SCI. We observed bowel dysfunction as increased fecal pellet numbers within the colon, smaller pellet size, and decreased motility. Fecal pellets numbers in the colon increased significantly in SCI animals versus sham (laminectomy only) injuries by 4 days postinjury (dpi) and persisted to 7 and 21 dpi. The number of pellets expelled (fecal output) significantly decreased in SCI versus sham animals at both 7 and 20 dpi. Pellet size was significantly decreased in SCI animals at 7 and 14 dpi, collectively indicative of decreased motility with SCI. SCI caused non-significant reductions in colonic motility (bead expulsion assay) at all three timepoints. Through ex vivo myograph analyses of live colon sections, we detected significant increase in the maximal contractility of the circular musculature from both the proximal and distal colon after SCI at 21 dpi. At the same time point, distal colons displayed significant collagen deposition in the musculature after SCI. Collectively, these findings demonstrate bowel dysfunction immediately after injury that continues in the distal colon over time. Establishing this mouse model enables further interrogation using transgenic models.

With the aging population, symptomatic chronic subdural hematoma (CSDH) is becoming increasingly prevalent in neurosurgical practice. While burr-hole drainage remains the mainstay treatment, the optimal drilling site remains controversial. This single-center, randomized controlled noninferiority trial aimed to compare frontal versus parietal burr-hole approaches in patients aged ≥18 years requiring surgical drainage for CSDH. Participants were randomized (1:1) via computer-generated allocation to frontal or parietal burr-hole groups, with blinding maintained for patients and staff except operating neurosurgeons. All patients received postoperative atorvastatin combination therapy. Primary outcomes included 6-month recurrence rates (noninferiority margin: 5.0%), with secondary outcomes assessing functional status (modified Rankin Scale [mRS] 4-6), mortality, and complications. From July 2020 to December 2022, 135 of 147 screened patients (92%) were enrolled (frontal: n = 67; parietal: n = 68), comprising 79% males (n = 107) and 21% females (n = 28). At 6-month follow-up (completed June 2023), recurrence rates were 1.5% (1/67) in the frontal group versus 4.4% (3/68) in the parietal group (difference: -2.9%; 95% confidence interval [CI]: -8.6 to 2.8; p = 0.31), meeting noninferiority criteria. Functional outcomes (mRS 4-6: 3.0% vs. 4.4%, p = 0.66) and mortality (3.0% vs. 1.5%, p = 0.55) showed no significant intergroup differences. Notably, postoperative pneumocephalus volume was significantly lower in the frontal group (11.6 ± 14.8 mL vs. 20.7 ± 20.4 mL; p = 0.038). Adverse event rates were comparable between groups, with pneumonia being most frequent (53.7% vs. 55.9%) and surgical complications similarly distributed (6.0% vs. 5.9%). These findings establish noninferiority of frontal burr-hole while demonstrating reduced postoperative pneumocephalus, supporting its clinical preference and warranting future superiority trials. (Trial registration: chictr.org.cn, ChiCTR2000033967).

Recent advancements in machine learning have increased studies predicting neurological outcomes following spinal cord injury (SCI). However, there is limited research on predictive models for bladder and bowel dysfunction outcomes postinjury. This study aims to develop predictive models for bladder and bowel dysfunction outcomes in patients with traumatic SCI and integrate the models into a web application. This study utilized data from 4181 patients with traumatic SCI, registered in the Japan Association of Rehabilitation Database between 1991 and 2015, to develop and validate predictive models. The explanatory variables were categorized into three groups: neurological findings at admission (such as American Spinal Injury Association scores and Functional Independence Measure scores), patient background (including demographics, comorbidities, and insurance status), and SCI pathology (including injury mechanism, vertebral fractures, surgical history, presence of ossification of the posterior longitudinal ligament/OLF, and time to admission). Feature selection was performed using Boruta, excluding features with more than 25% missing values. The target variables were the bladder and bowel functions at discharge, classified into a binary outcome of whether natural urination and defecation were possible. Machine learning models were implemented using PyCaret, and model performance was evaluated using the area under the curve (AUC). Shapley Additive Explanation (SHAP) values assessed the contribution of individual features. A total of 3,949 cases were analyzed, with an average age of 50.3 years. The model with the highest accuracy for predicting bladder function was the gradient boosting model, achieving an AUC of 0.9064 on the test data. For predicting bowel function, the gradient boosting model showed the highest accuracy with an AUC of 0.8714. The top three key predictive factors identified using SHAP values included L3 motor function, time from injury to admission, and the Functional Independence Measure bowel management score, which were common predictors for both bladder and bowel function. The web application of the predictive models can be found at https://takakikitamura-bladder-prediction.hf.space/ and https://takakikitamura-bowel-prediction.hf.space. In conclusion, we developed a predictive model for bladder and bowel dysfunction outcomes after traumatic SCI using machine learning, confirming its high predictive accuracy. Critical predictors included L3 motor function, time from injury to admission, and the degree of bowel dysfunction, all of which were relevant for predicting both bladder and bowel function. These models were made publicly available as a web application.