Journal of neurotrauma最新文献

Spinal cord injury (SCI) results in intramedullary microvasculature disruption and blood perfusion deficit at and remote from the injury site. However, the relationship between remote vascular impairment and functional recovery remains understudied. We characterized perfusion impairment in vivo, rostral to the injury, using magnetic resonance imaging (MRI), and investigated its association with lesion extent and impairment following SCI. Twenty-one patients with chronic cervical SCI and 39 healthy controls (HC) underwent a high-resolution MRI protocol, including intravoxel incoherent motion (IVIM) and T2*-weighted MRI covering C1-C3 cervical levels, as well as T2-weighted MRI to determine lesion volumes. IVIM matrices (i.e., blood volume fraction, velocity, flow indices, and diffusion) and cord structural characteristics were calculated to assess perfusion changes and cervical cord atrophy, respectively. Patients with SCI additionally underwent a standard clinical examination protocol to assess functional impairment. Correlation analysis was used to investigate associations between IVIM parameters with lesion volume and sensorimotor dysfunction. Cervical cord white and gray matter were atrophied (27.60% and 21.10%, p < 0.0001, respectively) above the cervical cord injury, accompanied by a lower blood volume fraction (-22.05%, p < 0.001) and a higher blood velocity-related index (+38.72%, p < 0.0001) in patients with SCI compared with HC. Crucially, gray matter remote perfusion deficit correlated with larger lesion volumes and clinical impairment. This study shows clinically eloquent perfusion deficit rostral to a SCI, its magnitude driven by injury severity. These findings indicate trauma-induced widespread microvascular alterations beyond the injury site. Perfusion MRI matrices in the spinal cord hold promise as biomarkers for monitoring treatment effects and dynamic changes in microvasculature integrity following SCI.

Cervical spinal cord injury usually leads to cardiorespiratory dysfunction due to interruptions of the supraspinal pathways innervating the phrenic motoneurons and thoracic sympathetic preganglionic neurons. Although clinical guidelines recommend maintaining the mean arterial pressure within 85-90 mmHg during the first week of injury, there is no pre-clinical evidence from animal models to prove the therapeutic efficacy of hemodynamic management. Accordingly, the present study was designed to investigate the therapeutic efficacy of hemodynamic management in rats with cervical spinal cord contusion. Adult male rats underwent cervical spinal cord contusion and the implantation of osmotic pumps filled with saline or norepinephrine (NE) (125 μg/(kg·h) for 1 week). The cardiorespiratory function of unanesthetized rats was examined using a non-invasive blood pressure analyzer and double-chamber plethysmography. Cervical spinal cord contusion caused a long-term reduction in the mean arterial pressure and tidal volume. This hypotensive response was significantly reversed in contused rats receiving NE (1 day: 88 ± 19 mmHg; 2 weeks: 96 ± 13 mmHg) compared with contused rats receiving saline (1 day: 72 ± 15 mmHg; 2 weeks: 82 ± 10 mmHg). NE also significantly improved the tidal volume 1 day post-injury (contused + NE: 0.7 ± 0.2 mL; contused + saline: 0.5 ± 0.1 mL). Immunofluorescence staining results revealed that injury-induced reductions of noradrenergic and glutamatergic fibers within the thoracic spinal cord were significantly improved by NE. These results provided the evidence demonstrating that hemodynamic management using NE significantly improves cardiorespiratory function by alleviating neural pathway damage after cervical spinal cord contusion.

Motorized cycling (MC) is utilized as an alternative to traditional exercise in individuals who are unable to perform voluntary movements post-spinal cord injury. Although rodent models of MC often show more positive outcomes when compared with clinical studies, the cause of this difference is unknown. We postulate that biomechanical differences between rats and humans may contribute to this discrepancy. To begin to test this theory, we examined pedal reaction forces and electromyography (EMG) of hindlimb muscles as a function of cycle phase and cadence in a rat model of MC. We found that higher cadences (≥30 RPM) increased EMG and force, with higher forces observed in animals with contusion injuries as compared with transections. To further investigate the forces, we developed a technique to separate rhythmic (developed with the motion of the pedals) from nonrhythmic forces. Rhythmic forces resulted from induced eccentric muscle contractions that increased (amplitude and prevalence) at higher cadences, whereas nonrhythmic forces showed the opposite pattern. Our results suggest that muscle activity during MC in rats depends on the stretch reflex, which, in turn, depends on the rate of muscle lengthening that is modulated by cadence. Additionally, we provide a framework for understanding MC that may help translate results from rat models to clinical use in the future.

Following spinal cord injury (SCI), there is a short-lived recovery phase that ultimately plateaus. Understanding changes within the spinal cord over time may facilitate targeted approaches to prevent and/or reverse this plateau and allow for continued recovery. Untargeted metabolomics revealed distinct metabolic profiles within the injured cord during recovery (7 days postinjury [DPI]) and plateau (21 DPI) periods in a mouse model of severe contusion SCI. Alterations in lipid metabolites, particularly those involved in phospholipid (PL) metabolism, largely contributed to overall differences. PLs are hydrolyzed by phospholipases A2 (PLA2s), yielding lysophospholipids (LPLs) and fatty acids (FAs). PL metabolites decreased between 7 and 21 DPI, whereas LPLs increased at 21 DPI, suggesting amplified PL metabolism during the plateau phase. Expression of various PLA2s also differed between the two time points, further supporting dysregulation of PL metabolism during the two phases of injury. FAs, which can promote inflammation, mitochondrial dysfunction, and neuronal damage, were increased regardless of time point. Carnitine can bind with FAs to form acylcarnitines, lessening FA-induced toxicity. In contrast to FAs, carnitine and acylcarnitines were increased at 7 DPI, but decreased at 21 DPI, suggesting a loss of carnitine-mediated mitigation of FA toxicity at the later time point, which may contribute to the cessation of recovery post-SCI. Alterations in oxidative phosphorylation and tricarboxylic acid cycle metabolites were also observed, indicating persistent although dissimilar disruptions in mitochondrial function. These data aid in increasing our understanding of lipid metabolism following SCI and have the potential to lead to new biomarkers and/or therapeutic strategies.

Early activity-based therapy (E-ABT) has the potential to decrease complications and radically improve neurofunctional recovery following traumatic spinal cord injury (TSCI). Unfortunately, E-ABT after TSCI has never been attempted in humans due to practical obstacles and potential safety concerns. This study aims to report on the safety and feasibility outcomes of the Protocol for Rapid Onset of Mobilization in Patients with Traumatic SCI (PROMPT-SCI) trial: the first-ever trial of E-ABT in critically ill patients who suffered a severe TSCI. To do so, 45 patients with severe TSCI were recruited to participate in the PROMPT-SCI trial between April 2021 and August 2023. The intervention consisted of daily 30-min sessions of motor-assisted in-bed leg cycling for 14 days, starting within 48 h of early surgery (≈72 h from the initial trauma). Adverse events were closely monitored, and completion rates were evaluated. Out of the 45 participants, 36 (80%) completed a full and safe session within 48 h of surgery and all participants managed to achieve this outcome within 72 h of surgery. Over the full 14-day protocol, the average completion rate of sessions was 87.2 ± 22.7% (range: 7.1-100.0%). A total of three patients were mechanically ventilated during the protocol and all three had 100% completion of sessions. Frequent reasons for unattempted/incomplete sessions were scheduling conflicts with activities related to care (e.g., bronchoscopy) and fatigue/uncontrolled pain before initiating cycling. We also report no neurological deterioration caused by cycling and no major adverse event recorded during or between sessions. In conclusion, this study suggests that E-ABT can be safely initiated within 48-72 h after a severe TSCI with no major adverse event. In the form of daily passive in-bed leg cycling, E-ABT is also acceptable for target users, and feasible over the course of the first weeks after the initial trauma, as shown by our excellent rate of completed sessions (87%). The present results also suggest that improved collaboration with intensive care unit staff, including intensivists and nurses, could improve these rates even further.

This study aims to quantify the change in time to surgery for treatment of complete traumatic cervical spinal cord injury (SCI) patients in American College of Surgeons accredited trauma centers across North America over the last decade (2010-2020). This multi-center retrospective observational cohort study used data from the Trauma Quality Improvement Program from 2010 to 2020. All surgically treated patients with complete traumatic cervical SCI were included. Primary outcome was time to spine surgery from treating hospital arrival in hours. Both descriptive statistics and a multi-variable Poisson regression model clustering standard of errors by each included trauma center were used to evaluate and quantify the annual change in time to surgical intervention. The study included 6855 complete traumatic cervical SCI patients managed across 484 trauma centers in North America. Median time to spine surgery was 14.6 h. A total of 4618 patients (67.3%) underwent surgical intervention within 24 h from hospital arrival. From 2010 to 2020, median time to surgery decreased by an average 0.6 h (±0.15) per year. A multi-variable adjusted model for time to surgery demonstrated a significant downward annual reduction of 5% in time to surgery between the years 2010 and 2020 (Incidence rate ratio = 0.95; 95% Confidence Interval: 0.93-0.96). This study provides compelling real-world based quantification of the change in time to surgical intervention following traumatic cervical SCI. A significant decreasing annual trend pertaining to surgical timing across trauma centers in North America over the past decade was demonstrated.

Visual feedback training (VFT) plays an important role in the motor rehabilitation of patients with spinal cord injury (SCI). However, the neural mechanisms are unclear. We aimed to investigate the changes in dynamic functional network connectivity (FNC) related to visual networks (VN) in patients with SCI and to reveal the neural mechanism of VFT promoting motor function rehabilitation. Dynamic FNC and the sliding window method were performed in 18 complete SCI (CSCI), 16 patients with incomplete SCI (ISCI), and 42 healthy controls (HCs). Then, k-mean clustering was implemented to identify discrete FNC states, and temporal properties were computed. The correlations between these dynamic features and neurological parameters in all patients with SCI were calculated. The majority of aberrant FNC was manifested between VN and executive control network (ECN). In addition, compared with HCs, temporal metrics derived from state transition vectors were decreased in patients with CSCI including the mean dwell time and the fraction of time spent in state 3. Furthermore, the disrupted FNC between salience network and ECN in state 2 and the number of transitions were all positively correlated with neurological scores in patients with SCI. Our findings indicated that SCI could result in VN-related FNC alterations, revealing the possible mechanism for VFT in rehabilitation of patients with SCI and increasing the training efficacy and promoting rehabilitation for SCI.

Following traumatic brain injury (TBI), inhibition of the Na⁺-K⁺-Cl^- cotransporter1 (NKCC1) has been observed to alleviate damage to the blood-brain barrier (BBB). However, the underlying mechanism for this effect remains unclear. This study aimed to investigate the mechanisms by which inhibiting the NKCC1 attenuates disruption of BBB integrity in TBI. The TBI model was induced in C57BL/6 mice through a controlled cortical impact device, and an in vitro BBB model was established using Transwell chambers. Western blot (WB) analysis was used to evaluate NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and nuclear factor-kappaB (NF-κB) pathway proteins. Flow cytometry and transendothelial electrical resistance (TEER) were employed to assess endothelial cell apoptosis levels and BBB integrity. ELISA was utilized to measure cytokines interleukin-1β (IL-1β) and matrix metalloproteinase-9 (MMP-9). Immunofluorescence techniques were used to evaluate protein levels and the nuclear translocation of the rela (p65) subunit. The Evans blue dye leakage assay and the brain wet-dry weight method were utilized to assess BBB integrity and brain swelling. Inhibition of NKCC1 reduced the level of NLRP3 inflammasome and the secretion of IL-1β and MMP-9 in microglia. Additionally, NKCC1 inhibition suppressed the activation of the NF-κB signaling pathway, which in turn decreased the level of NLRP3 inflammasome. The presence of NLRP3 inflammasome in BV2 cells led to compromised BBB integrity within an inflammatory milieu. Following TBI, an upregulation of NLRP3 inflammasome was observed in microglia, astrocytes, vascular endothelial cells, and neurons. Furthermore, inhibiting NKCC1 resulted in a decrease in the positive rate of NLRP3 inflammasome in microglia and the levels of inflammatory cytokines IL-1β and MMP-9 after TBI, which correlated with BBB damage and the development of cerebral edema. These findings demonstrate that the suppression of the NKCC1 cotransporter protein alleviates BBB disruption through the NF-κB/NLRP3 signaling pathway following TBI.