Background:Spinal cord injury (SCI) is frequently associated with orthostatic hypotension, defined by a sustained decrease in blood pressure upon assuming an upright posture due to impaired autonomic regulation. Cardiovascular spinal cord epidural stimulation (CV-scES) can regulate systolic blood pressure (SBP) in people with SCI, but stimulation paradigms are highly individualized. To make this treatment available to more patients, we developed an algorithm to tailor individualized CV-scES paradigms that closely mimic researcher-developed paradigms. Methods:We performed an offline analysis using datasets collected from eight individuals with SCI with epidural stimulators implanted over the lumbosacral spinal segments. During data collection, researchers modulated stimulation parameters with the goal of maintaining SBP between 110-120 mmHg. Each two-hour dataset included synchronized SBP and stimulation recordings. We ran optimization analyses offline to determine temporal requirements before modifying stimulation amplitude to mitigate out-of-range SBP. Results:The algorithm parameters that best matched researcher-selected stimulation changed relatively quickly during the first 12 min (one every ∼40 sec), and more slowly thereafter (one every ∼79 sec). Overall, algorithmic stimulation closely tracked researcher-controlled stimulation, with a mean correlation coefficient of 0.94. To evaluate online performance, we tested the algorithm in real time with a single participant. We found that a faster approach was needed to respond to changes in SBP caused by rapid, unpredictable events, such as postural changes. We implemented a sigmoid-based paradigm that determined the time to wait before changing stimulation as a function of the current SBP, with worse SBP values requiring faster responses. The new paradigm outperformed the original algorithm and researcher-controlled stimulation across measures of SBP stability, though recovery from a postural tilt maneuver remained slower than with researcher control. Conclusions:Our results indicate that algorithmic stimulation may minimize assistance required from researchers and participants, making CV-scES more feasible for clinical translation.

Spinal cord injury (SCI) disrupts the communication between the brain and the rest of the body, triggering widespread spinal and supraspinal changes resulting in a cascade of functional impairments. MRI has proved useful to investigate neural circuits reorganization, offering insights into the neuroplastic changes underlying specific impairments and deficits. However, it remains unclear whether different impairments are associated with differential patterns of structural and functional brain reorganization, a knowledge gap addressed in this study. Anatomical and resting-state functional MRI data from 12 participants with complete and incomplete chronic cervical SCI and 12 age- and sex-matched able-bodied individuals were acquired. SCI participants’ arm and hand sensory and motor functions were assessed using the Graded Redefined Assessment of Strength Sensibility and Prehension scale. Cortical thickness, gray matter volume and resting-state functional connectivity (rs-FC) were measured and compared between groups while also considering changes in clinical scores in SCI. Widespread structural and functional changes in various cortical and subcortical regions were highlighted in individuals with chronic cervical SCI as compared to the able-bodied controls. Specific alterations were seen in cortical thickness, gray matter volume and rs-FC of the sensorimotor, and visuospatial processing networks. Mainly rs-FC of sensorimotor cortical and subcortical areas showed changes differentially associated to only-motor versus sensory deficits in the SCI group. Motor and sensory impairments at the chronic stage appears associated with differential patterns of brain reorganization in individuals with chronic cervical SCI, prominently involving regions of the visual and visuospatial networks. Some of the regions with altered rs-FC, notably the thalamus and putamen, showed also changes in their anatomy in SCI. The findings confirm the value of multimodal brain MRI for characterizing neural correlates of specific impairments following SCI and informing personalized therapeutic strategies. Our results support the consideration of interventions that engage visual and visuospatial networks to promote function recovery after SCI.

OBJECTIVE:Spinal cord transcutaneous stimulation (scTS) combined with activity-based training (ABT) has shown promise for improving upper limb function after cervical spinal cord injury (SCI). However, factors underlying variability in functional recovery remain unclear. This study examined the functional recovery and inter-individual variability in response to scTS + ABT in individuals with chronic cervical SCI. DESIGN AND SETTING:Preliminary multi-case study with pre- and post-intervention evaluations conducted in a rehabilitation laboratory. PARTICIPANTS:Five male adults with chronic cervical SCI (C3-C7; AIS A-D). INTERVENTIONS:All participants received scTS delivered over cervical/thoracic segments combined with upper limb ABT. Intervention dosage ranged from 16 to 54 sessions (60 min per session, 2-3 sessions per week). OUTCOME MEASURES:The Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP), handgrip and elbow flexion strength, Neuromuscular Recovery Scale (NRS), and Modified Functional Reach Test (MFRT). Spinally evoked potentials (SEP) were recorded in one participant to evaluate spinal excitability changes. RESULTS:All participants demonstrated improvements in at least one GRASSP subdomain, with the most consistent gains observed in strength. NRS and MFRT outcomes also improved, indicating enhanced trunk stability and upper limb control. Moderate-to-strong positive correlations (ρ = 0.67-1.0) were found between intervention dosage and functional gains, although confidence intervals were broad. SEP analysis revealed increased slope and reduced activation thresholds of recruitment curves, suggesting enhanced spinal excitability. CONCLUSION:scTS + ABT led to measurable functional improvements across participants; however, substantial variability was observed, likely influenced by injury characteristics and training dosage. Given the small sample size, participant heterogeneity, and lack of long-term follow-up, these findings should be interpreted as preliminary. Further controlled studies are warranted to evaluate the efficacy of individualized neuromodulation strategies for optimizing upper limb recovery after cervical SCI.

First-generation personal and home-use exoskeletal-assisted walking devices for individuals with spinal cord injury (SCI) require the use of forearm crutches or a walker and sufficient trunk control for balance and mobility, limiting their use among individuals with tetraplegia and high paraplegia. In addition, these devices typically permit only forward walking, which may restrict maneuverability in indoor environments. A self-balancing exoskeleton that provides trunk stability, enables standing and walking without an assistive walking device, permits hands-free activity, and allows forward, lateral, and backward stepping as well as bending and squatting was evaluated in individuals with tetraplegia and high paraplegia. A prospective, interventional, single-group, open-label study was conducted at two sites. Eligible participants with SCI and their companions who successfully completed screening evaluations were trained and evaluated as pairs. The protocol included participant screening, device fitting, four standardized training sessions, and competency evaluations. Training activities included device donning and doffing, standing and sitting, indoor and outdoor walking, ambulatory functions, activities of daily living, safety procedures, and device care and storage. Performance assessments included donning and doffing within 10 min, the timed-up-and-go (TUG) test within 3 min, and a distance of at least 40 m the 6-min walk test (6MWT). Among the first 16 participants who completed the protocol, all achieved the TUG and 6MWT performance goals, 15 achieved the donning goal after four training sessions, and all achieved the doffing goal. This article describes a standardized training protocol for individuals with tetraplegia and high paraplegia and their companions to safely operate a self-balancing exoskeleton for personal use.

Current evidence suggests that spinal cord epidural stimulation (scES) can promote aspects of motor recovery for standing, stepping and volitional lower limb movement in research participants with spinal cord injury (SCI), although the extent of such recovery varies among individuals. The goal of this retrospective cohort study was to assess (i) whether the early application of scES, prior to any training with scES, is sufficient to enhance standing ability; and (ii) which magnetic resonance imaging (MRI) biomarkers of spinal cord lesion, if any, are associated with early responsiveness to scES for standing. Twenty-nine non-ambulatory individuals with chronic, severe SCI (n = 27 clinically motor complete; n = 2 motor incomplete) underwent spinal cord MRI and were subsequently implanted with scES. Standing ability was assessed prior to epidural stimulator implant and after implant with scES parameters targeted to facilitate standing (Stand-scES). T2-weighted MRI was used to measure the following spinal cord lesion characteristics: lesion length, midsagittal tissue bridges, and estimates of spared tissue in the anterior, posterior, right, and left spinal cord regions. Early application of continuous Stand-scES significantly improved the ability to stand for longer periods (+ 17

After a severe spinal cord injury (SCI), the human spinal circuitry receiving epidural stimulation can generate lower limb postural responses to sensory inputs associated with trunk perturbation. Here, we assessed the effects of different trunk perturbative forces on standing postural responses in six individuals with chronic, motor complete SCI receiving epidural stimulation to facilitate standing. The robotic upright stand trainer (RobUST) provided constant assistance for pelvic control and delivered precise trunk perturbations with different magnitudes (10 ± 4

The expanding application of spinal stimulation therapies in spinal cord injury (SCI) rehabilitation necessitates a critical reexamination of cardiovascular (CV) responses to these interventions. A key question arises: How should blood pressure (BP) responses to stimulation be interpreted, and does the conventional definition of autonomic dysreflexia (AD) adequately capture these phenomena? Researchers remain divided-some classify BP elevations during stimulation as AD, while others attribute them to intentional neuromodulation targeting sympathetic preganglionic neurons. This review scrutinizes the various AD definitions in the literature, including the conventional threshold (systolic BP increase >20 mmHg), revealing substantial limitations in research contexts. While symptomatic AD occurs in only 4-7% of stimulation study participants, asymptomatic BP increases are considerably more frequent. This established threshold lacks robust physiological rationale and creates significant interpretive challenges, particularly when evaluating interventions designed to modulate BP responses. The current limitations of guideline-based definitions of AD challenge research interpretation and clinical translation. Although several publications describe AD as "unregulated" or "uncontrolled," it has not yet been incorporated into formal guideline definitions. This review underscores the need for a collaborative effort to refine AD definitions in research, particularly in the context of spinal stimulation. Future consensus development should address whether uniform thresholds should apply across different contexts, how to integrate heart rate dynamics and absolute BP values alongside symptomatic status, and how to meaningfully distinguish therapeutic BP modulation from adverse autonomic responses. This is essential for standardizing research approaches, optimizing stimulation parameters, and ensuring efficacy and safety as spinal stimulation technologies advance clinically.

Background/Objectives: Cardiovascular (CV) dysfunction and, specifically, orthostatic hypotension, may significantly impact the quality of life of individuals with spinal cord injuries (SCIs) at T6 or above. While spinal cord transcutaneous stimulation (scTS) has shown immediate effects on blood pressure regulation, its long-term effects remain largely unexplored. Methods: This case study examines the sustained effects of scTS on blood pressure regulation and orthostatic tolerance in a 33-year-old female with cervical (C4) complete SCI sustained two years earlier. This individual underwent an initial baseline tilt test without stimulation, completed six 30 min scTS-CV sessions (cardiovascular-focused stimulation) over two weeks as the “training” phase, and then had repeated tilt tests without stimulation posttraining. Results: Following training, the participant demonstrated an improvement in orthostatic tolerance, maintaining a 70° tilt for 30 min, compared to only 3 min at baseline, in a tilt test (without stimulation) conducted one day posttraining. Self-reported reduction in orthostatic burden and decreased midodrine dependence were also observed for several weeks, with improvements diminishing by 6 weeks posttraining. Conclusions: These observations suggest that brief, repeated scTS-CV sessions may lead to sustained improvements in orthostatic tolerance beyond the immediate period of stimulation. Although the duration of these effects has yet to be established, this approach could offer a non-invasive alternative for managing CV dysfunction in SCIs.

OBJECTIVE:Understanding motor neurophysiology is important for developing effective upper limb treatments for people with tetraplegia following cervical spinal cord injury (SCI). While literature has primarily focused on contralateral motor pathways, neurophysiology of ipsilateral pathways remains largely unexplored in tetraplegia. We aimed to investigate ipsilateral physiology and its relationship to upper limb function in individuals with tetraplegia. METHODS:Twenty-three individuals with tetraplegia and 24 age-matched controls underwent transcranial magnetic stimulation to assess ipsilateral and contralateral motor physiology in the biceps muscle of the weaker arm. We also evaluated upper limb function and spasticity in tetraplegia. RESULTS:There were no differences in ipsilateral motor evoked potential (iMEP) features (amplitudes, onsets, offsets, durations, and areas) between participants with tetraplegia and controls (all p > 0.05). However, participants with tetraplegia who had larger iMEP amplitudes also had larger contralateral MEP amplitudes (p = 0.008) and better proximal arm motor function (p = 0.031). CONCLUSION:Ipsilateral motor physiology is associated with contralateral physiology and proximal arm motor function in tetraplegia. SIGNIFICANCE:Ipsilateral pathways may play a role in proximal arm function in tetraplegia. However, injury-specific adaptations were missed due to preserved biceps strength in our sample. Future studies should investigate iMEPs in non-preserved muscles to establish injury-specific relevance for rehabilitation.

Individuals with a clinically complete spinal cord injury are unable to stand independently without external assistance. Studies have shown the combination of spinal cord epidural stimulation (scES) targeted for standing with activity-based recovery training (ABRT) can promote independence of standing in individuals with spinal cord injury. This cohort study aimed to assess the effects of stand-ABRT with scES in individuals with cervical chronic spinal cord injury. We evaluated the ability of these individuals to stand independently from physical assistance across multiple sessions. Thirty individuals participated in this study, all unable to stand independently at the start of the intervention. Individuals were participating in a randomized clinical trial and received stand-ABRT in addition to targeted cardiovascular scES or voluntary scES. During the standing intervention, participants were asked to stand 2 h a day, 5 days a week for 80 sessions (Groups 1 and 2) or 160 sessions (Groups 3 and 4). A total of 3,524 training days were considered for analysis. Group 1 had 507 days, group 2 with 578 days, and 1152 and 1269 days for groups 3 and 4 respectively. 71

Spinal cord injury (SCI) can severely impair motor and autonomic function, with long-term consequences for quality of life. Epidural stimulation has emerged as a promising intervention, offering partial recovery by activating neural circuits below the injury. To make this therapy effective in practice, precise placement of stimulation electrodes is essential — and that requires accurate segmentation of spinal cord structures in MRI data. We present a protocol for manual segmentation tailored to SCI anatomy, and evaluated a convolutional neural network deep learning approach using a U-Net architecture to automate this segmentation process. Our approach yields accurate, efficient segmentation that identifies potential electrode placement sites with high fidelity. Results demonstrate significantly improved electrode coverage ($p<0.001$) and reduced surgery time ($p= 0.013$) compared to conventional planning methods. However, automated segmentation of fine nerve structures remains challenging, with validation accuracy of 0.44 mIoU indicating room for improvement. Preliminary results suggest that this framework can accelerate SCI MRI analysis and improve planning for epidural stimulation, helping bridge the gap between advanced neurotechnologies and real-world clinical application with faster surgeries and more accurate electrode placement.

ABSTRACT Objectives Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive brain stimulation strategy with a demonstrated potential to reinforce the residual pathways after a spinal cord injury (SCI). A preclinically tested high‐frequency (15 Hz) rTMS (15 Hz rTMS) protocol was shown to induce corticospinal tract axon regeneration growth and sprouting, resulting in improved voluntary motor control and performance. In a translational perspective, we aimed to investigate the safety and feasibility of the 15 Hz rTMS paradigm as an adjunct therapeutic intervention in individuals with chronic SCI. Method We thus investigated the effects of a 15‐day repeated protocol consisting of 15 Hz rTMS followed by task‐specific hand motor training in 7 individuals with chronic cervical SCI. 15 Hz rTMS targeted the weaker wrist extensor muscle, based on participant‐ and day‐specific resting motor threshold, motor responses, and maximum tolerability. Safety, feasibility, neurophysiological, and clinical functional outcomes were measured at different times of the therapeutic protocol. Results The therapeutic stimulation protocol was delivered mostly as designed except with regard to stimulation intensity and duration and was overall tolerable without major serious effects. Preliminary neuroplastic and functional benefits revealed by corticospinal excitability and intracortical inhibition modulation and clinical improvements were noted and were still observable at follow‐up times. Interpretation This study confirms that an intervention combining 15 Hz rTMS and task‐specific motor training is feasible, tolerable, and has the potential to induce neuroplastic changes and improve function in individuals with chronic cervical SCI. This feasibility study, in parallel with previous reports in able‐bodied individuals, warrants further investigation of the adapted 15 Hz rTMS protocol in individuals at an earlier stage post‐injury and to confirm efficacy in a larger and controlled study trial.

IntroductionPersons with non-ambulatory spinal cord injury (SCI) undergo immediate unloading of the skeleton and, as a result, have marked loss of bone mineral density below the level of lesion that is directly associated with increased risk of long-bone fractures. There is a paucity of research that has successfully implemented rehabilitation and/or exercise training interventions to mitigate bone loss after acute SCI or reverse bone loss that has already occurred in chronic SCI. This paper describes a research protocol to compare the effect of exoskeletal-assisted walking (EAW) alone versus EAW plus transcutaneous spinal cord stimulation (EAW+tSCS) on bone density, geometry and strength in a cohort of chronic SCI participants.Methods and analysisAfter meeting eligibility criteria and completing baseline testing, sixteen participants will be block randomised into the EAW alone group or the EAW+tSCS combined group (n=8 each group). Each group will receive a total of 108 overground training sessions (60 min sessions, 3 times a week, for 36 weeks) for the 9-month training period. Imaging for bone density and geometry by dual-energy X-ray absorptiometry and peripheral quantitative CT will be performed prior to starting the intervention (baseline), after 72 training sessions, and again after 108 sessions in each of the intervention arms. CT imaging of both lower extremities will be performed at baseline and at the 9-month time point in each of the intervention arms. Finite element models of bone loading will be generated based on three-dimensional (3D) reconstruction of bone architecture from CT imaging prior to and 9 months after the intervention.Ethics and disseminationThis study is currently approved by the Kessler Foundation and James J. Peters VA Medical Center Institutional Review Board. A member of the research team will review and explain the study consent form and will have all eligible participants sign prior to participation in the study. Results from this study will be disseminated to clinicians and researchers in the SCI community at national and international conferences.Trial registration numberNCT03096197.

Cervical spinal cord injury (SCI) results in significant sensorimotor impairments below the injury level, notably in the upper extremities (UEs), impacting daily activities and quality of life. Regaining UE function remains the top priority for individuals post-cervical SCI. Recent advances in understanding adaptive plasticity within the sensorimotor system have led to the development of novel non-invasive neurostimulation strategies, such as spinal cord transcutaneous stimulation (scTS), to facilitate UE motor recovery after SCI. This comprehensive review investigates the neuromotor control of UE, the typical recovery trajectories following SCI, and the therapeutic potential of scTS to enhance UE motor function in individuals with cervical SCI. Although limited in number with smaller sample sizes, the included research articles consistently suggest that scTS, when combined with task-specific training, improves voluntary control of arm and hand function and sensation. Further, the reported improvements translate to the recovery of various UE functional tasks and positively impact the quality of life in individuals with cervical SCI. Several methodological limitations, including stimulation site selection and parameters, training strategies, and sensitive outcome measures, require further advancements to allow successful translation of scTS from research to clinical settings. This review also summarizes the current literature and proposes future directions to support establishing approaches for scTS as a viable neuro-rehabilitative tool.

Objective: Corticospinal inhibitory mechanisms are relevant to functional recovery but remain poorly understood after spinal cord injury (SCI). Post -injury characteristics of contralateral silent period (CSP), a measure of corticospinal inhibition evaluated using transcranial magnetic stimulation (TMS), is inconsistent in literature. We envisioned that investigating CSP across muscles with varying degrees of weakness may be a reasonable approach to resolve inconsistencies and elucidate the relevance of corticospinal inhibition for upper extremity function following SCI. Methods: We studied 27 adults with chronic C1 -C8 SCI (age 48.8 +/- 16.1 years, 3 females) and 16 ablebodied participants (age 33.2 +/- 11.8 years, 9 females). CSP characteristics were assessed across biceps (muscle power = 3-5) and triceps (muscle power = 1-3) representing stronger and weaker muscles, respectively. We assessed functional abilities using the Capabilities of the Upper Extremity Test (CUE -T). Results: Participants with chronic SCI had prolonged CSPs for biceps but delayed and diminished CSPs for triceps compared to able-bodied participants. Early -onset CSPs for biceps and longer, deeper CSPs for triceps correlated with better CUE -T scores. Conclusions: Corticospinal inhibition is pronounced for stronger biceps but diminished for weaker triceps muscle in SCI indicating innervation relative to the level of injury matters in the study of CSP. Significance: Nevertheless, corticospinal inhibition or CSP holds relevance for upper extremity function following SCI. (c) 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Spinal cord transcutaneous stimulation (scTS) offers a promising approach to enhance cardiovascular regulation in individuals with a high-level spinal cord injury (SCI), addressing the challenges of unstable blood pressure (BP) and the accompanying hypo- and hypertensive events. While scTS offers flexibility in stimulation locations, it also leads to significant variability and lack of validation in stimulation sites utilized by studies. Our study presents findings from a case series involving eight individuals with chronic cervical SCI, examining the hemodynamic effects of scTS applied in different vertebral locations, spanning from high cervical to sacral regions. Stimulation of the lumbosacral vertebrae region (L1/2, S1/2, and also including T11/12) significantly elevated BP, unlike cervical or upper thoracic stimulation. The observed trend, which remained consistent across different participants, highlights the promising role of lumbosacral stimulation in neuromodulating BP.

Following spinal cord injury (SCI), intact neural resources undergo widespread reorganization within the brain. Animal models reveal motor cortical representations devoted to spared muscles above injury expand at the expense of territories occupied by weaker muscles. In this study, we investigated whether motor representations are similarly reorganized between a relatively spared biceps muscle and a weakened triceps muscle in persons with chronic tetraplegia following traumatic cervical SCI in association with upper limb motor function. Twenty-four adults with cervical SCI and 15 able-bodied participants underwent motor mapping using transcranial magnetic stimulation. We determined following map characteristics: area, amplitude (maximal motor evoked potential and volume), and center of gravity. Maximal voluntary contraction (MVC) and motor function (Capabilities of the Upper Extremity Test or CUE-T) were also assessed. Findings reveal that participants with SCI had hyper-excitable biceps maps than triceps, and hyper-excitable biceps maps also compared to biceps maps in able-bodied participants. Higher amplitude of biceps and triceps maps was associated with better motor function (higher CUE-T) and more distal injury (i.e., more spared segments) in persons with SCI. Amplitudes of biceps but not the triceps maps were associated with higher muscle MVCs. In conclusion, over-excitable biceps than triceps map in SCI may represent deafferentation plasticity. For the first time, we demonstrate how map reorganization of spared and weaker muscles in persons with chronic cervical SCI is associated with upper limb motor status. Use-dependent mechanisms may shift neural balance in favor of spared muscles, supporting potential use as response biomarkers in rehabilitation studies. New & Noteworthy Our study reports evidence in humans with cervical SCI that motor representation for the relatively spared muscle becomes hyper-excitable compared to that for the weaker muscle to the extent that hyper-excitability is even higher compared to biceps maps in uninjured individuals. Use-dependent mechanisms likely favor such heightened excitability of spared maps. For the first time, we demonstrate clinical relevance of map excitability in humans with SCI, supporting potential use as a biomarker of recovery. ### Competing Interest Statement The authors have declared no competing interest.