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Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARC EX Therapy to improve arm and hand functions in people with chronic SCI. ARC EX Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARC EX Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARC EX Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARC EX Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472 . Externally applied electrical stimulation over the cervical spinal cord improves arm and hand functions in people with chronic tetraplegia due to spinal cord injury.

Neuromodulation of spinal networks can improve motor control after spinal cord injury (SCI). The objectives of this study were to (1) determine whether individuals with chronic paralysis can stand with the aid of non-invasive electrical spinal stimulation with their knees and hips extended without trainer assistance, and (2) investigate whether postural control can be further improved following repeated sessions of stand training. Using a double-blind, balanced, within-subject cross-over, and sham-controlled study design, 15 individuals with SCI of various severity received transcutaneous electrical spinal stimulation to regain self-assisted standing. The primary outcomes included qualitative comparison of need of external assistance for knee and hip extension provided by trainers during standing without and in the presence of stimulation in the same participants, as well as quantitative measures, such as the level of knee assistance and amount of time spent standing without trainer assistance. None of the participants could stand unassisted without stimulation or in the presence of sham stimulation. With stimulation all participants could maintain upright standing with minimum and some (n = 7) without external assistance applied to the knees or hips, using their hands for upper body balance as needed. Quality of balance control was practice-dependent, and improved with subsequent training. During self-initiated body-weight displacements in standing enabled by spinal stimulation, high levels of leg muscle activity emerged, and depended on the amount of muscle loading. Our findings indicate that the lumbosacral spinal networks can be modulated transcutaneously using electrical spinal stimulation to facilitate self-assisted standing after chronic motor and sensory complete paralysis.

Transcutaneous multisegmental spinal cord stimulation (tSCS) has shown superior efficacy in modulating spinal locomotor circuits compared to single-site stimulation in individuals with spinal cord injury (SCI). Building on these findings, we hypothesized that administering a single session of tSCS at multiple spinal segments may yield greater enhancements in muscle strength and gait function during stimulation compared to tSCS at only one or two segments. In our study, tSCS was applied at single segments (C5, L1, and Coc1), two segments (C5-L1, C5-Coc1, and L1-Coc1), or multisegments (C5-L1-Coc1) in a randomized order. We evaluated the 6-m walking test (6MWT) and maximum voluntary contraction (MVC) and assessed the Hmax/Mmax ratio during stimulation in ten individuals with incomplete motor SCI. Our findings indicate that multisegmental tSCS improved walking time and reduced spinal cord excitability, as measured by the Hmax/Mmax ratio, similar to some single or two-site tSCS interventions. However, only multisegmental tSCS resulted in increased tibialis anterior (TA) muscle strength. These results suggest that multisegmental tSCS holds promise for enhancing walking capacity, increasing muscle strength, and altering spinal cord excitability in individuals with incomplete SCI.

Decades of research have demonstrated that recovery from serious neurological injury will require synergistic therapeutic approaches. Rewiring spared neural circuits after injury is a long-standing goal of neurorehabilitation 1 , 2 . We hypothesized that combining intensive, progressive, task-focused training with real-time closed-loop vagus nerve stimulation (CLV) to enhance synaptic plasticity 3 could increase strength, expand range of motion and improve hand function in people with chronic, incomplete cervical spinal cord injury. Here we report the results from a prospective, double-blinded, sham-controlled, randomized study combining gamified physical therapy using force and motion sensors to deliver sham or active CLV (ClinicalTrials.gov identifier NCT04288245). After 12 weeks of therapy composed of a miniaturized implant selectively activating the vagus nerve on successful movements, 19 people exhibited a significant beneficial effect on arm and hand strength and the ability to perform activities of daily living. CLV represents a promising therapeutic avenue for people with chronic, incomplete cervical spinal cord injury. Following spinal cord injury, gamified physical therapy that incorporates closed-loop vagus nerve stimulation can aid restoration of arm and hand function.

There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥ 24 hours after injury) decompressive surgery after traumatic cervical SCI. We performed a multicenter, international, prospective cohort study (Surgical Timing In Acute Spinal Cord Injury Study: STASCIS) in adults aged 16-80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was ordinal change in ASIA Impairment Scale (AIS) grade at 6 months follow-up. Secondary outcomes included assessments of complications rates and mortality. A total of 313 patients with acute cervical SCI were enrolled. Of these, 182 underwent early surgery, at a mean of 14.2(± 5.4) hours, with the remaining 131 having late surgery, at a mean of 48.3(± 29.3) hours. Of the 222 patients with follow-up available at 6 months post injury, 19.8% of patients undergoing early surgery showed a ≥ 2 grade improvement in AIS compared to 8.8% in the late decompression group (OR = 2.57, 95% CI:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% CI:1.10,7.28). During the 30 day post injury period, there was 1 mortality in both of the surgical groups. Complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21). Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up.

Background While various body weight supported locomotor training (BWSLT) approaches are reported in the literature for individuals with spinal cord injury (SCI), none have evaluated outcomes in terms of gait quality. The purpose of this study was to compare changes in measures of gait quality associated with four different BWSLT approaches in individuals with chronic motor-incomplete SCI, and to identify how gait parameters differed from those of non-disabled (ND) individuals. Methods Data were analyzed from 51 subjects with SCI who had been randomized into one of four BWSLT groups: treadmill with manual assistance (TM), treadmill with electrical stimulation (TS), overground with electrical stimulation (OG), treadmill with locomotor robot (LR). Subjects with SCI performed a 10-meter kinematic walk test before and after 12 weeks of training. Ten ND subjects performed the test under three conditions: walking at preferred speed, at speed comparable to subjects with SCI, and with a walker at comparable speed. Six kinematic gait quality parameters were calculated including: cadence, step length, stride length, symmetry index, intralimb coordination, and timing of knee extension. Results In subjects with SCI, all training approaches were associated with improvements in gait quality. After training, subjects with SCI walked at higher cadence and had longer step and stride lengths. No significant differences were found among training groups, however there was an interaction effect indicating that step and stride length improved least in the LR group. Compared to when walking at preferred speed, gait quality of ND subjects was significantly different when walking at speeds comparable to those of the subjects with SCI (both with and without a walker). Post training, gait quality measures of subjects with SCI were more similar to those of ND subjects. Conclusion BWSLT leads to improvements in gait quality (values closer to ND subjects) regardless of training approach. We hypothesize that the smaller changes in the LR group were due to the passive settings used for the robotic device. Compared to walking at preferred speed, gait quality values of ND individuals walking at a slower speed and while using a walker were more similar to those of individuals with SCI.

We examined the combined effects of neuromuscular electrical stimulation-resistance training (NMES-RT) and functional electrical stimulation-lower extremity cycling (FES-LEC) compared to passive movement training (PMT) and FES-LEC on mitochondrial electron transport chain (ETC) complexes and citrate synthase (CS) in adults with SCI . Thirty-two participants with chronic SCI were randomized to 24 weeks of NMES-RT + FES [n = 16 (14 males and 2 females) with an age range of 20–54 years old] or PMT + FES [n = 16 (12 males and 4 females) with an age range of 21–61 years old]. The NMES-RT + FES group underwent 12 weeks of surface NMES-RT using ankle weights followed by an additional 12 weeks of FES-LEC. The PMT + FES performed 12 weeks of passive leg extension movements followed by an additional 12 weeks of FES-LEC. Using repeated measures design, muscle biopsies of the vastus lateralis were performed at baseline (BL), post-intervention 1 (P1) and post-intervention 2 (P2). Spectrophotometer was used to measure ETC complexes (I-III) and CS using aliquots of the homogenized muscle tissue. Magnetic resonance imaging was used to measure skeletal muscle CSAs. A time effect was noted on CS (P  =  0.001 ) with an interaction between both groups (P  =  0.01 ). 46% of the participants per group had zero activities of CI without any changes following both interventions. A time effect was noted in CII ( P  =  0.023 ) following both interventions. Finally, NMES-RT + FES increased CIII at P1 compared to BL ( P  = 0.023) without additional changes in P2 or following PMT + FES intervention. Skeletal muscle hypertrophy may potentially enhance mitochondrial bioenergetics after SCI. NMES-RT is likely to enhance the activities of complex III in sedentary persons with SCI. Clinical trials # NCT02660073.

Background Cervical traumatic spinal cord injuries (TSCIs) are the most prevalent type of traumatic spinal cord injury, marked by high disability rates, considerable medical expenses, and a poor prognosis for functional recovery. The clinical effectiveness of bony decompression in improving functional outcomes following TSCI remains limited, even when performed ultra-early (within 12 or 8 h), emphasizing the uncertainty and insufficient understanding of the extent of adequate decompression. The ISCUD trial aims (1) to evaluate the benefits and risks of combining expansive duroplasty with standard treatment compared to standard treatment alone; (2) to investigate whether spinal cord perfusion status, assessed by indocyanine green, is related to the development of spinal cord swelling as measured by intramedullary lesion length; and (3) to determine the necessity for additional expansive duroplasty based on these assessments. Methods This is a prospective, phase III, single-center, randomized controlled superiority trial. We aim to recruit 104 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is the change in motor score at 6 months compared to admission; while the secondary outcome assess the sensory score, the neurological outcome, the assessments of function (grasp, walking, urinary and anal sphincter control), quality of life at 6 months, the safety of duroplasty, the impact of mechanistic study on the patient’s recovery. The ISCUD trial aims to establish qualitative and quantitative selection criteria for cervical TSCIs patients who may experience additional benefits from receiving expansive duroplasty. Estimated study duration is 24 months (1 month set-up, 12 months recruitment, 12 months to complete follow-up, 2 months data analysis and reporting results). Discussion The current clinical management guidelines for spinal cord injury are fundamentally informed by principles derived from the management of traumatic brain injury. The ISCUD trial not only tests the hypothesis that additional duroplasty is beneficial to patients with cervical TSCIs but also incorporates mechanistic study results with clinical outcomes to provide qualitative and quantitative criteria for neurosurgeons to determine whether additional duroplasty should be performed. Trial registration Clinicaltrials.gov NCT06552507. Registered on 2024/08/14.

Summary The goal of the work was to determine the effects of altering muscle quality (peak torque and muscle CSA) via NMES-RT on bone mineral density (BMD) following application of FES-lower extremity cycling. Components of muscle quality were altered and attenuated the decline in BMD after SCI. Introduction Spinal cord injury (SCI) negatively impacts muscle quality and bone health. Neuromuscular electrical stimulation-resistance training (NMES-RT) has been shown to enhance muscle quality. It is unclear whether adding NMES-RT to functional electrical stimulation (FES)-lower extremity cycling may further augment muscle quality and subsequently enhance bone mineral density (BMD). Methods Thirty-two participants were randomized into either 12 weeks of NMES-RT followed by 12 weeks of FES- lower extremity cycling (NMES-RT + FES; n  = 16) or 12 weeks of passive movement training (PMT) followed by 12 weeks of FES-lower extremity cycling (PMT + FES; n  = 16). Measurements were conducted at baseline (BL), post-interventions 1 and 2 (P1 and P2) separated evenly by 12 weeks. Left thigh muscle isometric and isokinetic torques were measured using an isokinetic dynamometer. Magnetic resonance imaging measured whole thigh and knee extensor (KE) muscle CSAs. Dual energy X-ray absorptiometry measured total and regional BMD. Results NMES-RT elicited a trend towards greater isometric torque at 80 Hz ( P  = 0.057) and isokinetic torque (60 deg/s; P  = 0.009 and 180 deg/s; P  = 0.003) compared to PMT. Muscle CSA was greater in left whole thigh (F (2,20) = 9.1; P  = 0.007) and KE (F (2,20) = 15.5; P  = 0.001) by 11.0 and 8.0 cm 2 respectively at P1 in the NMES-RT + FES compared to PMT + FES. In the NMES-RT + FES, ankle weights were positively associated with muscle CSA, isometric and isokinetic torques as well as muscle quality following P1. Compared to PMT + FES, NMES-RT + FES maintained BMD at the distal femur. Conclusion NMES-RT + FES enhanced muscle quality as measured by torque production and muscle CSA as result of increasing ankle weights. The addition of FES- lower extremity cycling to NMES-RT maintained but did not further augment muscle quality. Furthermore, NMES-RT + FES may help maintain BMD after SCI. Clinical trial registration Registered with clinicaltrials.gov: NCT02660073.

Background Exercise rehabilitation therapy has garnered widespread recognition for its beneficial effects on the restoration of locomotor function in individuals with spinal cord injury (SCI). Notably, resistance exercise has demonstrated significant improvements in muscle strength, coordination, and overall functional recovery. However, to optimize clinical management and mimic exercise-like effects, it is imperative to obtain a comprehensive understanding of the molecular alterations that underlie these positive effects. Methods We conducted a randomized controlled clinical trial investigating the effects of resistance exercise therapy for incomplete SCI. We integrated the analysis of plasma proteomics and peripheral blood mononuclear cells (PBMC) transcriptomics to explore the molecular and cellular changes induced by resistance exercise. Subsequently, we established a weight-loaded ladder-climbing mouse model to mimic the physiological effects of resistance exercise, and we analyzed the plasma proteome and metabolome, as well as the transcriptomes of PBMC and muscle tissue. Lastly, to confirm the transmissibility of the neuroprotective effects induced by resistance exercise, we intravenously injected plasma obtained from exercised male mice into SCI female mice during the non-acute phase. Results Plasma proteomic and PBMC transcriptomic profiling underscored the notable involvement of the complement pathways and humoral immune response in the process of restoring locomotor function following SCI in the human trial. Moreover, it was emphasized that resistance exercise interventions could effectively modulate these pathways. Through employing plasma proteomic profiling and transcriptomic profiling of PBMC and muscle tissues in mice, our study revealed immunomodulatory responses that parallel those observed in human trials. In addition, our analysis of plasma metabolomics revealed an enhancement in lipid metabolism following resistance exercise. We observed that resistance exercise plasma exhibited significant effects in ameliorating locomotor disability after SCI via reducing demyelination and inhibiting neuronal apoptosis. Conclusions Our investigation elucidates the molecular alterations associated with resistance exercise therapy promoting recovery of locomotor function following incomplete SCI. Moreover, we demonstrate the direct neuroprotective effects delivered via exercise plasma injection, which facilitates spinal cord repair. Mechanistically, the comprehensive multi-omics analysis involving both human and mice reveals that the principal constituents responsible for the observed neuroprotective effects within the plasma are predominantly immunoregulatory factors, warranting further experimental validation. Trial registration The study was retrospectively registered on 17 July, 2024, in Chinese Clinical Trial Registry (No.: ChiCTR2400087038) at https://www.chictr.org.cn/ .