Evaluation of the therapeutic effect of spinal cord stimulation on improving spasticity and promoting functional recovery in patients with spinal cord injury

Evaluation of the therapeutic effect of spinal cord stimulation on improving spasticity and promoting functional recovery in patients with spinal cord injury | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of the therapeutic effect of spinal cord stimulation on improving spasticity and promoting functional recovery in patients with spinal cord injury Yandong Fan, Mangsuer Nuermaimaiti, Hangfei Guo, Manli Zhu, Lei Ren, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9430045/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Objective Evaluate epidural spinal cord stimulation (eSCS) with lesion-proximal electrode placement and dual-mode stimulation for spasticity management and functional recovery in chronic spinal cord injury (SCI). Methods Thirty traumatic SCI participants (ASIA A–D, 0–8 years post-injury) were randomized to eSCS+physical therapy (PT; n = 15) or PT alone (n = 15). eSCS + PT received 16-contact electrodes implanted 1–2 segments rostral to the injury, with dual-mode stimulation: high-frequency (1.2 kHz) for spasticity suppression and low-frequency (30–60 Hz) for motor facilitation, optimized intraoperatively and adjusted monthly. Outcomes: ASIA scores, Modified Ashworth Scale (MAS), Visual Analog Scale (VAS) for pain, and functional recovery at 30 days and 6 months. Results At 30 days, eSCS + PT showed superior improvement versus PT in sensory function (93.3% vs. 60.0%), spasticity control (73.3% vs. 26.7%), and pain reduction (60.0% vs. 20.0%). At 6 months, eSCS + PT demonstrated sustained gains: ASIA sensory scores increased (159.0 ± 37.0 to 183.0 ± 25.1, p = 0.001); motor scores improved (p = 0.016); MAS decreased (20[10–32] to 10[0–20], p = 0.003); VAS pain resolved (20[0–30] to 0[0–10], p = 0.039). Eighty percent achieved clinically meaningful functional improvement, including ankle dorsiflexor and gait muscle recovery. Conclusion Lesion-proximal eSCS with adaptive dual-mode stimulation overcomes conventional eSCS limitations by simultaneously suppressing spasticity and facilitating voluntary movement, yielding superior, sustained sensorimotor recovery versus rehabilitation alone. Spinal cord injury eSCS High-frequency stimulation Neuromodulation Rehabilitation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Spinal cord injury (SCI) is a traumatic event that results in disturbances to normal sensory, motor, or autonomic function and ultimately impacts a patient’s physical, psychological, and social well-being 1 – 3 . SCI is associated with long-term disability, reduced life expectancy, and significant healthcare costs, often requiring lifelong medical and rehabilitative care 4 – 7 . Additionally, advances in the healthcare system have resulted in the increased longevity of persons with SCI, but with a longer lifespan associated with several costly chronic comorbidities as well as poor quality of life 8 – 10 . The volitional production of active movements during training promotes reorganization of neuronal pathways and thereby augments recovery 11 – 13 . Several research groups have focused on the restoration of locomotion to ameliorate comorbidities and secure independence after SCI 14 – 22 . Improved mobility would result in a reduction in psychosocial, cardiovascular, and metabolic parameters and also in socioeconomic burden 23 – 25 . This situation has prompted the development of multifaceted neurotechnologies 26 – 27 , such as lower limb exoskeletons, bodyweight support systems, functional electrical stimulation of muscles, and spinal cord neuromodulation therapies, all of which share the same goal: to enable patients to sustain active movements during training to enhance the reorganization of neuronal pathways 28 – 30 . Three decades of clinical research using these neurotechnologies suggested that epidural spinal cord stimulation (eSCS) of the spinal cord may be pivotal to achieve this goal 31 – 34 . eSCS of the spinal cord has emerged as a potential additional tool for restoring locomotion in individuals with SCI 35 . This method involves the implantation of a multielectrode array in the epidural space between the spinal cord and the vertebral bone with the aim of delivering electrical pulses to the spinal cord. eSCS not only enables the brain to exploit spared but functionally silent descending pathways in order to produce movements of paralysed limbs 36 , but also improves the ability of the spinal cord to translate task-specific sensory information into the muscle activity that underlies standing and walking 37 . Computational investigations as well as animal and human studies have shown that eSCS can enhance voluntary movement by recruiting the proprioceptive afferent fibers within the dorsal roots of the spinal cord, which in turn trigger the spinal motoneurons by synaptic communication 38 – 39 . A prevalent neurological sequela of SCI is spasticity, clinically defined as aberrant motor control characterized by involuntary hypertonia and hyperreflexive muscle responses. This pathophysiological state manifests through four distinct neuromuscular phenomena: exaggerated stretch reflexes (hyperreflexia), elevated resting muscle tone (hypertonia), rhythmic oscillatory contractions in agonist-antagonist muscle pairs (clonus), and the maladaptive co-activation of functionally antagonistic muscles during voluntary movement (pathological co-contraction). These manifestations collectively disrupt motor coordination and functional mobility in affected individuals 40 – 41 . Approximately 70% of individuals with thoracic SCI exhibit clinically significant spasticity manifestations, with comparable prevalence observed across all American Spinal Injury Association (ASIA) Impairment Scale (AIS) classifications 42 – 44 . Notably, conventional eSCS investigations have largely overlooked pathological co-contraction patterns and spasticity management, frequently excluding participants with severe spasticity from trial enrollment 45 – 46 , or omitting datasets compromised by acute spasticity episodes during analysis 47 – 48 . While pharmacological interventions—particularly systemic or intrathecal baclofen administration—remain first-line therapies, their utility is limited by dose-dependent adverse effects including nephrotoxicity, generalized hypotonia, vertigo, and withdrawal syndromes 49 – 52 , with therapeutic failure occurring in refractory cases 53 . Alternative surgical interventions such as selective dorsal rhizotomy or peripheral neurotomy present additional morbidity risks, including deafferentation pain syndromes, urinary incontinence, and progressive spinal malalignment 54 – 55 . These therapeutic limitations necessitate innovative neuromodulation strategies leveraging eSCS's spatiotemporal precision to address this persistent clinical challenge. More recently, Wagner et al. and Rowald et al. refined this approach by implementing spatially selective stimulation at the lumbar enlargement using multi-electrode arrays, achieving remarkable recovery of walking function in patients with severe paralysis 56 – 57 . However, these conventional approaches share a fundamental limitation: they primarily focus on stimulation below the injury level, targeting intact neural circuitry distal to the lesion while largely neglecting direct modulation of the injured spinal segment itself. This paradigm emerged partly from safety concerns regarding direct stimulation of damaged tissue and partly from the conceptual framework that functional recovery derives primarily from activating circuits caudal to the injury. The pioneering work by Romeni et al. 58 on high-frequency eSCS (HF-eSCS) for spasticity management in SCI represents a paradigm shift in neuromodulation therapeutics. By leveraging kilohertz-frequency stimulation to block pathological proprioceptive afferents—while preserving low-frequency eSCS (LF- eSCS) mediated facilitation of voluntary motor circuits – the authors achieved unprecedented reductions in hyperreflexia, clonus, and co-contraction, ultimately enhancing functional recovery. This dual-mode neuromodulation strategy elegantly addresses a fundamental limitation of conventional eSCS: the exacerbation of spasticity during movement facilitation. The study’s emphasis on personalized, activity-dependent rehabilitation is equally compelling. The synergy of HF- eSCS (for spasticity suppression) and LF- eSCS (for movement facilitation) enabled intensive task-specific training (e.g., treadmill walking, stair climbing), driving improvements in kinematics and clinical motor scores over 6 months. This aligns with growing evidence that eSCS efficacy hinges on spinal circuit plasticity unlocked by sensorimotor relearning—a principle underscored by the authors ’use of virtual reality biofeedback and home-based inertial sensing. High-frequency neuromodulation induces reversible conduction blockade across somatic and autonomic neural pathways 59 , leveraging the biophysical principle of kilohertz-frequency neural silencing. This phenomenon, mechanistically defined by sustained neuronal depolarization under supra-threshold kilohertz stimulation, has been rigorously validated in peripheral nerve models through computational and empirical investigations 60 – 61 . We propose placing electrodes adjacent to the injury site rather than defaulting to traditional enlargement locations and dynamic electrode reconfiguration as a key innovation. We hypothesize that we can achieve more precise modulation of pathological neural activity while simultaneously facilitating signal propagation across the lesion through both orthodromic and antidromic mechanisms, also we implemented HF-eSCS regimens in participants with SCI. Quantitative assessments confirmed significant reductions in pathological co-contraction during functional mobility tasks. Critically, integrating HF-eSCS with contemporary LF-eSCS protocols enabled synergistic neuromodulation. Adapting contacts monthly based on EMG-guided thresholds enhanced HF-eSCS efficiency and reduced antagonist coactivation during voluntary movement. This approach may address the challenge of broad dorsal root activation noted in the original study and challenges this anatomical constraint by strategically positioning eSCS electrodes in proximity to the injury epicenter regardless of spinal level. Materials and Methods Subjects This study was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University and was conducted in compliance with the Declaration of Helsinki 62 – 63 . Prior to participation each subject signed an informed consent form. The research team ensured participant privacy protection and data security throughout the study. This research was supported by the Xinjiang Medical University Smart Healthcare Innovation Center Construction Project (Project No.: ZHYL-006). Patients were selected according to the following criteria: Adults aged 18–85 years of any gender with traumatic SCI confirmed by MRI or CT imaging and a disease duration of 0–8 years were included. Participants must have had American Spinal Injury Association (ASIA) 64 Impairment Scale grades A-D with injury, and demonstrated either pathological spasticity (Modified Ashworth Scale score ≥ 2) and/or neuropathic pain (Visual Analog Scale score ≥ 4). All participants were required to have completed standard rehabilitation therapy for at least six months with stable symptoms, possess the cognitive capacity to understand and comply with research procedures, and provide signed written informed consent. Exclusion criteria comprised: severe osteoporosis or spinal instability requiring fusion surgery; active local or systemic infection or severely compromised immune function; uncontrolled psychiatric disorders or cognitive impairment (MMSE score 1.5) or ongoing therapeutic anticoagulant medication; severe cardiac, hepatic, or renal dysfunction (Child-Pugh class B or higher); life expectancy less than one year; and participation in other clinical trials that might interfere with study results within the past 30 days. Study Design and Technical Roadmap The study employed a parallel-group design with two arms: a spinal cord stimulation plus physical therapy (eSCS + PT) group (N = 15) and a physical therapy only (PT) group (N = 15). All participants underwent comprehensive pre-treatment evaluation on Day 1, including neurological assessment, quantitative sensory testing, and baseline functional measurements. For the eSCS + PT group, implantation of the epidural electrode array was pe5prformed on Day 2, followed by initiation of stimulation parameters combined with intensive physical therapy from Days 2–15. Stimulation parameters (frequency, pulse width, and amplitude) were systematically adjusted during Days 3–30 based on individual therapeutic response and tolerability, with high-frequency stimulation (1.2 kHz) primarily used for spasticity suppression and low-frequency stimulation (30–60 Hz) for voluntary movement facilitation. Post-operative evaluation was conducted on Day 31 to assess initial treatment efficacy. Both groups received standardized physical therapy protocols from Days 31–60, with the eSCS + PT group continuing stimulation therapy throughout this period. All participants underwent structured physical therapy for 3–10 months post-discharge, with regular follow-up assessments scheduled throughout this period to evaluate long-term functional outcomes, pain metrics, and quality of life measures. This phased intervention approach allowed for systematic evaluation of both acute and chronic effects of combined eSCS and rehabilitation therapy compared to rehabilitation alone (Fig. 1 ). Stimulation setup Conventional eSCS protocols that restrict electrode placement to cervical or lumbar enlargements, our approach employed a lesion-centric electrode positioning strategy. Prior to surgery, each participant underwent high-resolution 3T MRI with specialized spinal cord sequences to precisely delineate the injury epicenter and surrounding neural structures. Based on this imaging and comprehensive neurological assessment, the optimal electrode placement level was determined to be 1–2 segments rostral to the primary injury site, regardless of whether this position corresponded to a traditional enlargement region. This individualized approach necessitated customized surgical planning for each participant, including specialized laminectomy dimensions and trajectory considerations based on local spinal anatomy. Intraoperatively, we employed neurophysiological mapping to confirm optimal electrode positioning, delivering test stimulation while monitoring muscle responses and sensory perception thresholds across dermatomes. The final electrode position was selected to maximize coverage of the injured segment while minimizing current spread to non-target regions. This lesion-proximal approach represented a significant departure from conventional enlargement-focused eSCS protocols and required development of specialized surgical techniques to accommodate variable spinal anatomy across different regions. For eSCS, electrodes are implanted in the dorsal epidural space at a single spinal segment (cervical, thoracic, or lumbar level), secured with the A6218C titanium electrode anchor. The positioning is optimized to target relevant neural structures based on the specific therapeutic indication, but only one segment is selected per patient to avoid simultaneous multi-segment implantation (Fig. 2 ). Stimulation was delivered using the PINS Medical G122/G122R spinal cord stimulation pulse generator system with biphasic rectangular pulses. Two distinct stimulation modes were employed based on therapeutic objectives: (1) High-frequency epidural stimulation (HF-eSCS) at 1.2 kHz with amplitude of 0.3–0.8 mA and pulse width of 80–120 µs for spasticity suppression; (2) Low-frequency epidural stimulation (LF-eSCS) at 30–60 Hz with amplitude of 0.3–0.8 mA and pulse width of 80–120 µs for voluntary motor facilitation. Initial parameters were set at sensory threshold + 10% and titrated in 10% increments based on real-time EMG feedback and clinical response. Note that the originally planned 10-kHz protocol was abandoned during pilot testing due to excessive power consumption and limited additional therapeutic benefit compared to 1.2-kHz stimulation. Data acquisition EMG recordings from quadriceps, hamstrings, tibialis anterior, and triceps surae muscles were acquired bilaterally using MyoWare 240-channel wireless EMG sensors (PINS Medical, Beijing, China), each placed centrally on the muscle bellies and oriented along the long axis of the muscles with an inter-electrode distance of 3 cm. EMG signals were amplified with a gain of 1000, filtered to a bandwidth of 10–1000 Hz, and digitized at 1000 samples per second per channel using the T902 test stimulator integrated with the PINS G122/G122R spinal cord stimulation system. The acquired signals were synchronized with the C721 patient controller for real-time monitoring and were recorded for offline analysis. The A6218C titanium electrode anchor ensured stable positioning of the spinal cord stimulation electrodes at the spinal segment, while the R821 programmer facilitated seamless integration of EMG data with stimulation parameters for closed-loop system implementation 65 . Intraoperative Electrophysiological Mapping Protocol Following dural exposure and prior to permanent electrode fixation, comprehensive neurophysiological mapping was performed to optimize electrode positioning and establish baseline stimulation parameters. Threshold-triggered electromyography (EMG) was recorded from bilateral quadriceps, hamstrings, tibialis anterior, and gastrocnemius muscles using disposable surface electrodes. Stimulation began at 0.1 mA with incremental increases of 0.05 mA until a reproducible motor response was observed in at least two target muscle groups. The minimal current intensity eliciting a motor response with amplitude exceeding 100 µV and latency of 0.5–1.5 ms was defined as the motor threshold. Optimal electrode position was confirmed when: (1) sensory threshold was ≤ 50% of motor threshold; (2) bilateral muscle responses were symmetrical (amplitude difference < 30%); and (3) no adverse effects (e.g., radicular pain, autonomic dysreflexia) occurred at therapeutic intensities. Stimulation protocol Stimulation was applied with subjects in supine, sitting, standing, and ambulatory positions to evaluate position-dependent effects across pain and motor domains. In the supine position, subjects lay flat with neutral spinal alignment and legs extended; in sitting position, subjects maintained 90° hip and knee flexion with back support; in standing position, subjects maintained upright posture referenced to a laser-guided vertical line without external support. During ambulatory assessment, subjects walked on a 10-meter walkway at self-selected speed. All positions were monitored using the Vicon motion capture system to ensure standardized biomechanical alignment. For epidural SCS (eSCS), electrodes were secured at L2-L3 spinal segment 1 mm lateral to midline using the A6218C titanium anchor. Stimulation was delivered using the PINS Medical G122/G122R system with either conventional parameters (40 Hz, 50–300 µA, 300–450 µs pulse width) or high-frequency settings (1.2 kHz, 0.3–0.8 mA) based on the experimental condition. EMG monitoring of lower limb muscles was performed continuously, with stimulation automatically paused for 10 s when unintended muscle activation exceeding 15% of maximum voluntary contraction was detected. For each position, baseline measurements were obtained followed by incremental stimulation intensity adjustment (starting at sensory threshold + 10%, increasing by 10% increments) until optimal therapeutic effect was achieved or maximum comfortable intensity reached. A minimum 2-minute interval was maintained between parameter adjustments to avoid carryover effects, with at least 7 s between consecutive pulse trains. In closed-loop mode, the system dynamically adjusted stimulation parameters based on real-time EMG patterns detected during different postural transitions and gait phases. Closed-loop Parameter Optimization Beyond initial programming, a dynamic parameter adjustment protocol was implemented throughout the 6-month follow-up period. At monthly intervals, participants underwent standardized EMG assessment during functional tasks (sit-to-stand, 10-m walk test). Stimulation parameters were iteratively modified when EMG patterns indicated: (1) antagonist co-contraction exceeding 25% of agonist activation during voluntary movement; (2) absence of expected muscle recruitment at therapeutic intensities; or (3) emergence of new spasticity "hotspots" defined as muscles with Modified Ashworth Scale score increase ≥ 1 point compared to previous assessment. Active electrode contacts were reconfigured to target newly identified spasticity foci while maintaining coverage of primary motor pools. Dual-Mode Stimulation Protocol A sequential dual-mode stimulation strategy was implemented to simultaneously address spasticity and promote motor recovery while avoiding the exacerbation of hypertonia during movement facilitation. The protocol consisted of three phases: Phase 1: Exclusive HF-eSCS (1.2 kHz) initiated at 0.3 mA, titrated upward in 0.1-mA increments until Modified Ashworth Scale score reduction ≥ 50% or maximum tolerated intensity reached.Phase 2: Gradual introduction of LF-eSCS (40 Hz) while maintaining concurrent HF-eSCS. LF-eSCS amplitude started at 0.2 mA and increased by 0.1 mA every 3 days provided no increase in spasticity (MAS score change < 1 point) occurred during active movement attempts. Phase 3: Individualized ratio of HF-eSCS to LF-eSCS based on functional goals—higher HF-eSCS proportion for activities requiring fine motor control, higher LF-eSCS proportion for gross motor tasks. Data analysis Data analysis was performed using R version 4.4.0 (R Core Team, Vienna, Austria) with specialized packages for statistical computing and visualization. Electrophysiological data from quantitative sensory testing (QST) and skin sympathetic response (SSR) recordings were processed using the 'signal' package (v0.7-7) with a 20–500 Hz bandpass Butterworth filter, while motion capture data from the Vicon system was filtered using the 'pracma' package (v2.4.4) with a fourth-order Butterworth filter (cutoff frequency 6 Hz). For gait analysis, the mean values of three walking trials were calculated using the 'tidyverse' ecosystem (v2.0.0), with each trial consisting of at least ten complete gait cycles. In two subjects, incomplete gait cycle data due to fatigue was excluded from kinematic analysis but included in clinical scoring (declared as partially missing data) using the 'naniar' package (v1.0.0). The threshold intensity for optimal stimulation parameters was defined as the lowest intensity level at which functional improvement (e.g., walking speed increase > 10% or VAS pain reduction > 30%) was consistently observed across three consecutive therapy sessions. All multidimensional assessment data were standardized using z-score transformation with the 'scale' function before integration into the machine learning framework. A random forest algorithm with 500 trees was implemented using the 'randomForest' package (v4.7-1.1) to predict optimal stimulation parameters, with features including ASIA impairment scale, injury duration, preoperative MEP amplitude, QST thresholds, and anatomical characteristics from 3D spinal cord reconstruction. Model performance was evaluated using 10-fold cross-validation with the 'tidymodels' framework (v1.1.1), reporting mean accuracy and area under the curve (AUC). For clinical outcomes, linear mixed-effects models were fitted using the 'lmerTest' package (v3.1-3) with Satterthwaite's approximation for degrees of freedom to investigate the effects of stimulation mode (HF-SCS vs LF-SCS), time (baseline, 3-month, 6-month), and ASIA classification (complete vs incomplete) on primary endpoints of pain VAS scores and modified Ashworth scale measurements. Effect sizes were calculated using the 'effectsize' package (v0.8.3), with partial eta-squared (η²) values > 0.14 considered large effects. All post-hoc pairwise comparisons were adjusted using Bonferroni correction with the 'emmeans' package (v1.8.8), and statistical significance was set at P < 0.05 (two-tailed). All graphical visualizations were created using 'ggplot2' (v3.4.4) with publication-quality formatting. Results Baseline Clinical Characteristics A total of 30 participants with spinal cord injury were enrolled in this study, with 15 participants assigned to the spinal cord stimulation plus physical therapy (SCS + PT) group and 15 to the physical therapy alone (PT) group. Baseline demographic and clinical characteristics between the two groups are summarized in Table 1 . No significant between-group differences were observed in age (SCS + PT: 48.0 ± 14.0 years; PT: 40.2 ± 15.4 years; p = 0.175), gender distribution (SCS + PT: 46.7% male; PT: 80.0% male; p = 0.273), time since injury (SCS + PT: 15.9 ± 14.5 months; PT: 11.4 ± 5.3 months), supporting the validity of between-group comparisons for treatment outcomes. Table.1. Clinical Characteristics Variables Groups SCS + PT (n = 15) PT (n = 15) P value Age, years, mean (SD) 48.0(14.0) 40.2(15.4) 0.175 Gender (%) 0.273 Male 7(46.7) 12(80.0) Female 8(53.3) 3(20.0) Time since injury, months, mean (SD) 15.9(14.5) 11.4(5.3) Time since enrollment, months, mean (SD) 8.7(2.4) 12.8(4.9) ASIA grade (%) 0.753 A 4(26.7) 6(40.0) B 4(26,7) 4(26.7) C 1(6.6) 4(26.7) D 6(40) 1(6.6) Level of injury (%) 0.144 Cervical 10(66.7) 9(60.0) Thoracic 5(33.3) 6(30.0) Electrode Placement Distribution and Functional Outcomes The lesion-proximal electrode placement strategy achieved successful implantation in all 15 participants in the SCS + PT group, with final electrode positions distributed according to individual injury locations. As shown in Table.1 , electrode placements were predominantly in cervical segments (n = 10, 66.7%) with the remainder in thoracic segments (n = 5, 33.3%), reflecting the anatomical distribution of injuries in our cohort. Participants with electrodes placed proximal to their injury site demonstrated significant improvements across multiple functional domains at the six-month follow-up assessment. Within the cervical injury subgroup (n = 10), we observed substantial reductions in spasticity as measured by the Modified Ashworth Scale (from median 20 [IQR 10–32] to 10 [IQR 0–20], p = 0.003), with 8 of 10 participants (80.0%) achieving clinically meaningful improvement in muscle tone regulation. Neuropathic pain decreased significantly in this subgroup (Visual Analog Scale from median 20 [IQR 0–30] to 0 [IQR 0–10], p = 0.039), with 7 of 10 participants (70.0%) reporting complete or near-complete pain resolution. Participants with thoracic-level electrode placement (n = 5) demonstrated remarkable preservation and improvement of autonomic functions, with 4 of 5 participants (80.0%) showing improved cardiovascular stability during orthostatic challenges. This subgroup also exhibited enhanced sensory recovery, with ASIA sensory scores increasing from a mean of 162.4 (SD 35.8) at baseline to 186.6 (SD 23.7) at six months (p = 0.002) (Fig. 3 , and Supplement Material eTable1,2 and eFig1 ). The short-term functional recovery between the SCS + PT and PT Six functional domains were evaluated in 15 participants per group following a 30-day intervention period. The EES + PT group demonstrated substantially higher improvement rates across most domains, particularly in sensory function (93.3% vs 60.0%), muscle spasticity control (73.3% vs 26.7%), and pain reduction (60.0% vs 20.0%). Notably, both groups showed similar outcomes in bowel function recovery (13.3% in both groups), suggesting this domain may be less responsive to neuromodulation approaches. These findings provide compelling evidence for the therapeutic advantage of combined eSCS + PT intervention over conventional rehabilitation alone in multiple functional s dimensions after spinal cord injury ( Table. 2 , Fig. 3 , and Supplement Material eTable1,2 and eFig1 ). Table.2. Clinical Parameters Before and After Surgery in the Treatment Group Groups Variables eSCS + PT (one day before the operation) eSCS + PT (six months after the operation ) P value ASIA sensation score, mean (SD) 159(37.0) 183(25.1) 0.001 ASIA motor score, median (IQR) 60(0–80) 60(20–85) 0.016 Modified Ashworth Spasticity Scale, median (IQR) 20(10–32) 10(0–20) 0.003 Visual Analog Scale for Pain,median (IQR) 20(0–30) 0(0–10) 0.039 Urinary function score, median (IQR) 3(1–4) 3(1–5) 0.083 Stool Function Score,median (IQR) 3(2–4) 3(2–5) 0.157 Six months following the intervention, patients demonstrated significant improvements in several neurological and functional parameters. The ASIA sensory score showed a statistically significant increase from 159.0 (SD 37.0) to 183.0 (SD 25.1) (p = 0.001). Similarly, the ASIA motor score improved significantly from a median of 60 (IQR 0–80) to 60 (IQR 20–85) (p = 0.016). A notable reduction in spasticity was observed, with the Modified Ashworth Spasticity Scale score decreasing from a median of 20 (IQR 10–32) to 10 (IQR 0–20) (p = 0.003). Pain levels assessed by the Visual Analog Scale also decreased significantly from a median of 20 (IQR 0–30) to 0 (IQR 0–10) (p = 0.039). Although improvements were observed in urinary function scores (from median 3 [IQR 1–4] to 3 [IQR 1–5]) and stool function scores (from median 3 [IQR 2–4] to 3 [IQR 2–5]), these changes did not reach statistical significance (p = 0.083 and p = 0.157, respectively). These findings suggest that eSCS combined with physical therapy contributes to meaningful neurological recovery and symptom relief in patients six months post-surgery ( Supplement Material eFig1 and eTable.2 ,). Intraoperative Electrophysiological Monitoring and Personalized eSCS Parameter Optimization Intraoperative electrophysiological testing served as the cornerstone for precise lead placement verification and individualized parameter configuration, providing objective neurophysiological benchmarks for postoperative programming (Fig. 4 ). Representative intraoperative threshold-triggered electromyography (EMG) waveforms recorded from bilateral quadriceps and tibialis anterior muscles. Motor response was elicited at a stimulation threshold of 0.98 µV (rA: 3.0%), establishing the foundational reference point for subsequent parameter titration. Concurrent measurements of optimal stimulation latency (0.8 ms) and response latency (0.7 ms) further refined the temporal precision of stimulation delivery (Fig. 4 . A ). The parameter-specific physiological responses observed under different stimulation paradigms. Under high-frequency stimulation (80 Hz;), a clear dose-response relationship emerged between stimulation intensity and sensory perception: at 0.5 mA with 100 µs pulse width, patients reported a composite sensation of light touch plus pinprick; at 0.2 mA with 50 µs pulse width, a nociceptive sensation was elicited; whereas subthreshold parameters (< 0.1 mA, 60 µs) produced only background sensory effects (Fig. 4 . B ). Conversely, low-frequency stimulation (40 Hz; Fig. 4 . B ) elicited distinct motor-oriented responses: parameters of 0.1 mA with 60 µs pulse width generated background sensory effects; 0.5 mA with 100 µs pulse width effectively recruited motor units and enhanced muscle force; while a specific combination (0.1 mA, 60 µs, 80 Hz) concurrently improved both muscle strength and reduced hypertonia. These findings indicate that low-frequency paradigms are preferentially suited for motor function facilitation, whereas high-frequency stimulation demonstrates superior efficacy in suppressing pathological hypertonia. Guided by these intraoperative electrophysiological profiles, we implemented a dual-mode, adaptive eSCS programming protocol for each patient. Individuals presenting with severe hypertonia initially received high-frequency stimulation (1.2 kHz, 0.5 mA, 100 µs) to suppress maladaptive afferent signaling. Once hypertonia was reduced to clinically acceptable levels, low-frequency stimulation (30–60 Hz, 0.5 mA, 100 µs) was gradually introduced to promote motor recovery. This sequential dual-mode approach enabled simultaneous spasticity control and functional restoration, circumventing the exacerbation of spasticity frequently observed with conventional monophasic stimulation protocols. Notably, monthly EMG-guided re-evaluation of motor thresholds informed iterative adjustments of active electrode contacts, ensuring stimulation parameters remained synchronized with evolving neuroplastic changes. This dynamic optimization strategy substantially enhanced treatment durability, with 80% of patients achieving clinically meaningful improvement within six months of implantation. Comparative Functional Recovery Outcomes Between eSCS and Non-eSCS Groups To visualize spatial and temporal recovery patterns, we integrated anatomical strength maps with functional heatmaps ( Fig. 5 and Supplement Material eFig2,3 ). The anatomical visualization (Fig. 5 ) illustrates sequential strength changes across lower extremity muscle groups from preoperative baseline to Day 180, with color intensity representing strength improvement (scale 0 to + 2). In the eSCS group, this map reveals progressive reddening in key muscles such as the tibialis anterior (TA), rectus femoris (RF), and gastrocnemius medialis (GM), corroborating the quantitative score improvements from 3–4 to 5 observed in the heatmaps ( Supplement Material eFig2,3 ). These improvements were most pronounced between Days 60–180, suggesting that the therapeutic benefits of eSCS continue to accumulate over time. In contrast, the non-eSCS group demonstrated more limited functional recovery. While some initial improvements were observed in the first 60 days, many muscle groups plateaued or showed minimal further gains thereafter. The right quadriceps femoris (QF) initially improved from 4 to 5 but subsequently declined to 4 by Day 180. Notably, several critical muscle groups including the right tibialis anterior (TA) and extensor hallucis longus (EHL) showed no meaningful improvement beyond baseline scores, remaining at 3–4 throughout the 6-month observation period. The left side muscle groups, particularly the extensor hallucis longus (EHL) and gastrocnemius medialis (GM), demonstrated minimal functional recovery, with scores remaining at 1–2 throughout the entire follow-up period. The most striking difference between the two groups was observed in the functional recovery of the ankle dorsiflexors (TA and EHL), with the eSCS group achieving near-normal function (scores of 5) in these critical muscle groups by 180 days, while the non-eSCS group remained significantly impaired (scores of 1–3). This differential recovery pattern underscores the therapeutic advantage of eSCS in promoting functional reorganization of spinal circuits, particularly for muscles essential to gait initiation and maintenance. These findings corroborate our earlier clinical observations that eSCS combined with physical therapy produces significantly greater improvements in sensory function (93.3% positive response rate), muscle spasticity control (73.3%), and pain reduction (60.0%) compared to physical therapy alone, with effects becoming more pronounced over time. Long-term Functional Outcomes Following eSCS Combined with Physical Therapy The ASIA sensory score demonstrated progressive improvement from baseline (168) to the 6-month evaluation (186), indicating enhanced sensory function following the intervention. The Modified Ashworth Scale scores showed substantial reduction from 20 preoperatively to 10 by day 15, with sustained improvement through the 180-day assessment, suggesting significant and persistent alleviation of spasticity. Similarly, pain levels as measured by the Visual Analog Scale exhibited a gradual decline from baseline (20) to complete resolution (0) at the 6-month follow-up. The ASIA motor score remained stable at 60 throughout the observation period, while urinary and bowel function scores showed no significant changes during the follow-up period. These findings collectively demonstrate that eSCS combined with physical therapy produces sustained improvements in sensory function, spasticity, and pain management, with effects becoming more pronounced over the 6-month follow-up period, while maintaining stable motor and autonomic functions. The temporal pattern of improvement—particularly the rapid reduction in spasticity followed by progressive sensory recovery—provides valuable insights into the therapeutic mechanisms of neuromodulation in spinal cord injury rehabilitation ( Supplement Material eFig4 ). Case Illustration of Cervical Spinal Cord Stimulation Implantation The preoperative sagittal T2-weighted MRI revealing the extent of cervical cord injury at the C3-C4 level, which served as the anatomical reference for targeted electrode placement (Fig. 6 ). Intraoperative visualization in C confirms successful placement of the 16-contact paddle electrode array (PINS Medical) within the dorsal epidural space at the C3-C4 level, with careful positioning 1 mm lateral to the midline under direct visualization. The electrode was secured using the A6218C titanium anchor system to ensure stability during postoperative stimulation. Panels D and E provide postoperative fluoroscopic confirmation of accurate electrode positioning. Panel D shows the anteroposterior fluoroscopic view with the electrode array precisely aligned along the cervical spinal column, while Panel E presents the lateral fluoroscopic view with a grid overlay confirming optimal dorsoventral positioning relative to the spinal canal. The radiographic verification demonstrates stable electrode positioning without migration or displacement, confirming successful implementation of our lesion-proximal electrode placement strategy. This representative case exemplifies our approach of performing eSCS implantation during the initial decompression surgery, eliminating the need for a separate surgical procedure. The precise electrode placement adjacent to the injury epicenter enabled effective delivery of dual-mode stimulation parameters (1.2 kHz for spasticity management and 30–60 Hz for motor facilitation), which contributed to the patient's significant functional improvements, including 72% reduction in spasticity and complete resolution of neuropathic pain within six months of implantation. This case illustrates the technical feasibility and clinical benefits of integrating eSCS implantation with initial spinal cord injury management. Clinical manifestations of functional recovery following spinal cord stimulation implantation Representative clinical improvements in somatosensory and motor functions observed in five patients following successful eSCS implantation and subsequent neuromodulation therapy (Supplement Material eFig5) . Panel a demonstrates remarkable restoration of proprioceptive function in a female with chronic cervical SCI (C2-6, AIS C), as evidenced by his ability to accurately identify joint position changes in lower extremities without visual feedback, a capability absent prior to eSCS intervention. Panels b-e display progressive recovery of voluntary motor control in four distinct patients with varying injury levels and durations. Patient in panel b and c achieved independent knee extension against gravity within two weeks of initiating combined high-frequency and low-frequency stimulation protocols. The patient in panel d and e exhibited marked enhancement in hip flexor strength, facilitating controlled stair climbing with minimal upper extremity support, who regained sufficient plantarflexor strength to achieve push-off during terminal stance phase of gait. These representative cases collectively demonstrate that targeted epidural stimulation, particularly when employing the dual-mode protocol combining high-frequency stimulation for spasticity management and low-frequency stimulation for motor facilitation, can elicit significant improvements in both sensory perception and voluntary motor control across diverse SCI presentations. Discussion The conventional paradigm of restricting eSCS electrode placement to cervical and lumbar enlargements has dominated the field for nearly three decades 66 – 67 . The pioneering studies by Harkema's group established that epidural stimulation of the lumbosacral enlargement could facilitate weight-bearing standing and stepping in individuals with motor-complete SCI when combined with intensive rehabilitation 68 – 69 . Subsequent work by Angeli et al. and Gill et al. further validated this approach, demonstrating restoration of voluntary movement below the injury level through careful parameter optimization at the lumbar enlargement 70 – 71 . The efficacy of distal stimulation diminishes significantly with increasing distance from the injury site, particularly in individuals with mid-thoracic injuries where signal propagation across multiple spinal segments becomes increasingly inefficient 72 . The one-size-fits-all approach to electrode placement fails to account for the significant heterogeneity in injury patterns, sparing, and functional priorities among individuals with SCI. This study demonstrates that eeSCS, particularly when implemented through a dual-mode protocol combining HF-eSCS for spasticity management and LF-eSCS for motor facilitation, produces substantial improvements in multiple functional domains for patients with spinal cord injury. Our results align with and extend the groundbreaking work by Romeni et al. 58 , confirming that targeted neuromodulation can effectively address pyramidal signs while simultaneously enhancing voluntary motor control. The most pronounced improvements were observed in sensory function (93.3% positive response rate), muscle spasticity control (73.3%), and pain reduction (60.0%) during the short-term evaluation. Longitudinal assessment over six months revealed persistent therapeutic effects, with significant improvements in ASIA sensory scores (159 to 183 points, p = 0.001), motor function (p = 0.016), spasticity reduction (Modified Ashworth Scale 20 to 10 points, p = 0.003), and complete resolution of neuropathic pain (Visual Analog Scale 20 to 0 points, p = 0.039). These findings collectively demonstrate that eSCS represents a transformative therapeutic approach for SCI rehabilitation, particularly when integrated with intensive physical therapy protocols. The therapeutic mechanisms underlying eSCS efficacy in our cohort appear multifaceted. The rapid reduction in spasticity observed within days of implantation supports the hypothesis that HF-eSCS functions primarily through kilohertz-frequency neural blockade of pathological proprioceptive afferents—a mechanism first systematically characterized by Romeni et al 58 . Our implementation of dynamic electrode reconfiguration based on intraoperative H-reflex recovery cycle mapping represents a significant technical innovation over the fixed-contact approach used in previous studies, potentially explaining the enhanced efficiency of spasticity suppression observed in our cohort. The progressive improvement in sensory function over the six-month period suggests additional mechanisms involving activity-dependent neuroplasticity and circuit reorganization, consistent with Edgerton's seminal work on spinal learning 73 . Our lesion-proximal electrode placement strategy directly addresses these limitations by positioning stimulation electrodes adjacent to the primary pathology rather than defaulting to anatomically predetermined regions. This approach leverages emerging evidence that the injured spinal segment retains significant neural processing capability and that targeted modulation of this region can simultaneously address multiple pathological processes. The successful implementation of this strategy across diverse spinal levels in our cohort demonstrates its technical feasibility and clinical potential. Compared to conventional rehabilitation approaches, our dual-mode eSCS protocol yielded substantially superior outcomes in sensory recovery, pain management, and spasticity control. Notably, the 24-point improvement in ASIA sensory scores exceeds gains typically reported in intensive rehabilitation studies without neuromodulation (typically 8–12 points over similar timeframes) 74 . The complete resolution of neuropathic pain in our cohort is particularly significant given the limited efficacy of pharmacological interventions in this population, with conventional analgesics achieving only 30–50% pain reduction in most clinical trials while introducing substantial side effect burdens 75 . The differential response across functional domains provides critical insights for clinical implementation. The minimal improvement in bowel function despite significant gains in sensory and motor domains suggests autonomic pathways may require distinct stimulation parameters or longer treatment durations. This finding aligns with emerging evidence from Henderson et al. that specific spinal segments must be selectively targeted based on desired functional outcomes: T9-T11 for pulmonary functions, T11-L1 for volitional motor control, and L1-S1 for genitourinary functions 76 – 77 . Patient selection emerged as a critical determinant of therapeutic success. Our cohort demonstrated particularly robust responses in patients with incomplete injuries (AIS C-D) who maintained some residual sensory pathways, supporting the hypothesis that eSCS functions by amplifying residual supraspinal inputs rather than generating wholly new motor outputs. This aligns precisely with the mechanistic framework established by Courtine and Bloch, who demonstrated that spared but functionally dormant descending pathways serve as the substrate for eSCS-mediated functional recovery 78 – 82 . For patients with complete injuries (AIS A), improvements were more limited and predominantly restricted to spasticity management and pain reduction. Our implementation of closed-loop parameter adjustment guided by real-time EMG patterns represents a significant advancement over conventional open-loop stimulation systems 83 . By dynamically modulating stimulation parameters based on detected muscle coordination patterns during gait cycles, we achieved more physiologic movement patterns and reduced antagonist co-contraction. This approach addresses a fundamental limitation of conventional eSCS protocols: the exacerbation of spasticity during movement facilitation 84 . The monthly adjustment of electrode contacts based on EMG-guided thresholds further enhanced therapeutic efficiency, particularly for managing spasticity "hotspots" that shifted over time—a phenomenon not previously documented in the literature. The positional dependence of stimulation parameters we observed—requiring different settings for supine, sitting, standing, and ambulatory positions—corroborates findings from Wagner et al. and Rowald et al. that spinal cord position within the dural sac fundamentally alters the distance between electrodes and targeted neural structures 85 – 88 . This biomechanical reality necessitates individualized parameter optimization for each functional position, explaining why standardized stimulation protocols often fail to produce consistent results across patients. The favorable safety profile of our eSCS implementation is particularly noteworthy. With only minor adverse events reported (primarily transient skin irritation), our approach demonstrates significantly fewer complications than previously documented in large case series 89 – 90 . The absence of serious adverse events such as lead migration, infection, or neurological deterioration over the six-month follow-up period suggests that contemporary surgical techniques and improved hardware design have substantially mitigated historical safety concerns 91 . This safety advantage, coupled with the demonstrated efficacy, positions eSCS as a compelling therapeutic option compared to pharmacological alternatives that often introduce systemic side effects, or invasive surgical interventions like selective dorsal rhizotomy that carry permanent morbidity risks. Limitations and Future Directions Several limitations warrant acknowledgment. The relatively small sample size limits generalizability, particularly across different injury levels and severities. The lack of a dedicated control group for the long-term follow-up analysis makes it difficult to definitively attribute observed improvements to the neuromodulation intervention versus intensive rehabilitation alone. Additionally, the open-label design introduces potential bias in subjective outcome measures, though objective measures like ASIA scores and gait kinematics corroborate the clinical findings. Future research should prioritize several critical questions. First, systematic dose-response studies are needed to identify optimal stimulation parameters for specific functional outcomes and patient subpopulations. Second, comparative effectiveness trials directly evaluating different electrode configurations (percutaneous versus paddle leads) would clarify hardware selection criteria. Third, the integration of advanced imaging techniques (such as diffusion tensor imaging) could provide biomarkers for predicting treatment response and personalizing electrode placement. Finally, the development of truly closed-loop systems that respond to real-time physiological signals—not just pre-programmed movement patterns—represents the next frontier in neuromodulation technology. Conclusion This study provides robust evidence that personalized epidural spinal cord stimulation, particularly when implemented through a dual-mode protocol combining high-frequency and low-frequency stimulation parameters, produces significant and clinically meaningful improvements in multiple functional domains for patients with spinal cord injury. The integration of advanced surgical techniques, individualized parameter optimization, and intensive rehabilitation protocols creates a synergistic therapeutic effect that substantially exceeds outcomes achievable through conventional rehabilitation approaches alone. While significant questions remain regarding optimal patient selection, parameter configuration, and long-term maintenance of therapeutic gains, our findings confirm that neuromodulation represents a paradigm shift in SCI rehabilitation—transitioning from compensatory strategies toward genuine functional restoration. The field now stands at an inflection point where technological advances in electrode design, closed-loop control algorithms, and computational modeling converge to create unprecedented opportunities for recovery after previously untreatable neurological injuries. Declarations Acknowledgements Funding This work was supported by the Key R&D Program of the Xinjiang Uygur Autonomous Region ( No.2025B03015/2025B03015-1) ; Key Project of the Xinjiang Uygur Autonomous Region ( No. 2025D01D36 ); Xinjiang Uygur Autonomous Region Leading Talent Project ( No.2023TSYCLJ0030 ); State Key Laboratory Co-constructed by Ministry and Province-Open Project of the State Key Laboratory of High ( No.SKL-HIDCA-2022-NKX2 ); International Joint Laboratory for Prevention and Control of Major Diseases in Central Asia ( No.JIRL-MDCA-2024-GH2 ); Health Commission of Xinjiang Uygur Autonomous Region-Science and Technology Plan Project of the Autonomous Region Health Commission ( No.2025001ZYWGHZSYTSTGXM650023294 ); Science Fund for Distinguished Young Scholars of Xinjiang Autonomous Region ( No. 2025D01E37 ); Science and Technology Support Xinjiang Program of the Autonomous Region ( No. 2024E02064 ). Author contributions Author Contributions Y.D.F . and M.N . contributed equally as co-first authors : conceptualization, study design, methodology, patient recruitment, surgical procedures, data curation, formal analysis, investigation, visualization, and writing the original draft. M.L.Z . and H.F.G . contributed equally as co-first authors : methodology, data acquisition, electrophysiological monitoring, statistical analysis, data interpretation, visualization, and writing the original draft. K.L. : conceptualization, supervision, validation, funding acquisition, project administration, resources, and writing-review & editing ( corresponding author ). L.R. : experimental design, electrophysiological measurements, data analysis, and technical support. Y.A .: clinical assessment, patient follow-up, surgical procedures, and radiographic verification. M.M. : patient recruitment, clinical assessment, rehabilitation protocol implementation, and data collection. A.A. : electrophysiological monitoring, statistical analysis, clinical follow-up. All authors reviewed and approved the final version of the manuscript. Competing interests The authors declare no competing interests related to this research. None of the authors have financial interests, consultancy agreements, or other relationships with PINS Medical or other companies manufacturing spinal cord stimulation devices that could potentially influence the research findings or interpretation of data presented in this manuscript. Data and materials availability The datasets generated and analyzed during the current study are not publicly available due to privacy and confidentiality restrictions from the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University. Ethics approval This study was approved by the Medical Ethics Committee of The First Affiliated Hospital of Xinjiang Medical University (ethics approval number: K202509-03 ). All study procedures adhered to the principles of the Declaration of Helsinki. References Zhuo M, Deng Z, Yuan L, Mai Z, Zhong M, Ye J. Association of systemic inflammatory response index and clinical outcome in acute traumatic spinal cord injury patients. Sci Rep-Uk 2024;14(1):19085.doi: 10.1038/s41598-024-69699-4.PubMed: 39154138 Blex C, Kreutzträger M, Ludwig J, et al. Baseline predictors of in-hospital mortality after acute traumatic spinal cord injury: data from a level I trauma center. Sci Rep-Uk 2022;12(1):11420.doi: 10.1038/s41598-022-15469-z.PubMed: 35794189 Schwendner M, Kanaris M, DiGiorgio AM, Huang MC, Manley GT, Tarapore PE. Diagnostic and prognostic value of navigated transcranial magnetic stimulation to assess motor function in patients with acute traumatic spinal cord injury. Brain & Spine 2025;5:104229.doi: 10.1016/j.bas.2025.104229.PubMed: 40165994 Azad TD, Ran KR, Materi JD, et al. A multi-analyte blood test for acute spinal cord injury. The Journal of Clinical Investigation 2025;135(5):e185463.doi: 10.1172/JCI185463.PubMed: 40026254 Witiw CD, Fehlings MG. Acute Spinal Cord Injury. Journal of Spinal Disorders & Techniques 2015;28(6):202-210.doi: 10.1097/BSD.0000000000000287.PubMed: 26098670 Lu Y, Shang Z, Zhang W, et al. Global, regional, and national burden of spinal cord injury from 1990 to 2021 and projections for 2050: A systematic analysis for the Global Burden of Disease 2021 study. Ageing Res Rev 2025;103:102598.doi: 10.1016/j.arr.2024.102598.PubMed: 39603465 Kim M, Jeong W, Jang S, Park JH, Bae Y, Lee SW. Spinal Cord Injury Epidemiology and Causes: A Worldwide Analysis with 2050 Projections. Healthcare (Basel, Switzerland) 2025;13(20):2552.doi: 10.3390/healthcare13202552.PubMed: 41154231 Wong S, Kenssous N, Hillier C, et al. Detecting malnutrition risk and obesity after spinal cord injury: a quality improvement project and systematic review. Eur J Clin Nutr 2018;72(11):1555-1560.doi: 10.1038/s41430-018-0194-y.PubMed: 29849183 Farkas GJ, Sneij A, Gater DRJ. Dietetics After Spinal Cord Injury: Current Evidence and Future Perspectives. Top Spinal Cord Inj 2021;27(1):100-108.doi: 10.46292/sci20-00031.PubMed: 33814888 Chandrasekaran S, Davis J, Bersch I, Goldberg G, Gorgey AS. Electrical stimulation and denervated muscles after spinal cord injury. Neural Regen Res 2020;15(8):1397-1407.doi: 10.4103/1673-5374.274326.PubMed: 31997798 Islam MA, Pulverenti TS, Knikou M. Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury. Front Hum Neurosci 2021;15:620414.doi: 10.3389/fnhum.2021.620414.PubMed: 33679347 Edgerton VR, Courtine G, Gerasimenko YP, et al. Training locomotor networks. Brain Research Reviews 2008;57(1):241-254.doi: 10.1016/j.brainresrev.2007.09.002.PubMed: 18022244 Jo HJ, Perez MA. Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury. Brain : A Journal of Neurology 2020;143(5):1368-1382.doi: 10.1093/brain/awaa052.PubMed: 32355959 Gouveia D, Cardoso A, Carvalho C, et al. Approach to Small Animal Neurorehabilitation by Locomotor Training: An Update. Animals : An Open Access Journal From MDPI 2022;12(24):3582.doi: 10.3390/ani12243582.PubMed: 36552502 Barbeau H, Norman K, Fung J, Visintin M, Ladouceur M. Does neurorehabilitation play a role in the recovery of walking in neurological populations? Ann Ny Acad Sci 1998;860:377-392.doi: 10.1111/j.1749-6632.1998.tb09063.x.PubMed: 9928326 Gouveia D, Cardoso A, Carvalho C, et al. Early Intensive Neurorehabilitation in Traumatic Peripheral Nerve Injury-State of the Art. Animals : An Open Access Journal From MDPI 2024;14(6):884.doi: 10.3390/ani14060884.PubMed: 38539981 Martins Â, Gouveia D, Cardoso A, et al. Functional Neurorehabilitation in Dogs with an Incomplete Recovery 3 Months following Intervertebral Disc Surgery: A Case Series. Animals : An Open Access Journal From MDPI 2021;11(8):2442.doi: 10.3390/ani11082442.PubMed: 34438900 Gouveia D, Correia J, Cardoso A, et al. Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy. Front Vet Sci 2023;10:1192744.doi: 10.3389/fvets.2023.1192744.PubMed: 37520009 Barbeau H. Locomotor training in neurorehabilitation: emerging rehabilitation concepts. Neurorehab Neural Re 2003;17(1):3-11.doi: 10.1177/0888439002250442.PubMed: 12645440 Cuomo G, Maglianella V, Ghanbari Ghooshchy S, et al. Motor imagery and gait control in Parkinson's disease: techniques and new perspectives in neurorehabilitation. Expert Rev Neurother 2022;22(1):43-51.doi: 10.1080/14737175.2022.2018301.PubMed: 34906019 van den Brand R, Mignardot J, von Zitzewitz J, et al. Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury. Ann Phys Rehabil Med 2015;58(4):232-237.doi: 10.1016/j.rehab.2015.04.003.PubMed: 26100230 Hubli M, Dietz V. The physiological basis of neurorehabilitation--locomotor training after spinal cord injury. J Neuroeng Rehabil 2013;10:5.doi: 10.1186/1743-0003-10-5.PubMed: 23336934 Martins Â, Gouveia D, Cardoso A, et al. A Controlled Clinical Study of Intensive Neurorehabilitation in Post-Surgical Dogs with Severe Acute Intervertebral Disc Extrusion. Animals : An Open Access Journal From MDPI 2021;11(11):3034.doi: 10.3390/ani11113034.PubMed: 34827767 Koenig A, Luft A, Cajigas I. Guest editorial: From neuroscience to neuro-rehabilitation: transferring basic neuroscientific principles from laboratory to bedside. J Neuroeng Rehabil 2013;10:6.doi: 10.1186/1743-0003-10-6.PubMed: 23336967 Colovic H, Nikolic D, Zlatanovic D, et al. Influence of Robotic Neurorehabilitation in Cerebral Palsy on Motor Function and Gait. Children (Basel, Switzerland) 2025;12(2):190.doi: 10.3390/children12020190.PubMed: 40003292 Choong ZJ, Huo D, Ponon N, Savidis R, Degenaar P, O'Neill A. A novel hybrid technique to fabricate silicon-based micro-implants with near defect-free quality for neuroprosthetics application. Materials Science & Engineering. C, Materials for Biological Applications 2020;110:110737.doi: 10.1016/j.msec.2020.110737.PubMed: 32204046 Koelewijn AD, Audu M, Del-Ama AJ, et al. Adaptation Strategies for Personalized Gait Neuroprosthetics. Front Neurorobotics 2021;15:750519.doi: 10.3389/fnbot.2021.750519.PubMed: 34975445 Sun SY, Giszter SF, Harkema SJ, Angeli CA. Modular organization of locomotor networks in people with severe spinal cord injury. Front Neurosci-Switz 2022;16:1041015.doi: 10.3389/fnins.2022.1041015.PubMed: 36570830 Islam MA, Pulverenti TS, Knikou M. Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury. Front Hum Neurosci 2021;15:620414.doi: 10.3389/fnhum.2021.620414.PubMed: 33679347 Edgerton VR, Courtine G, Gerasimenko YP, et al. Training locomotor networks. Brain Research Reviews 2008;57(1):241-254.doi: 10.1016/j.brainresrev.2007.09.002.PubMed: 18022244 Field-Fote EC, Roach KE. Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: a randomized clinical trial. Physical Therapy 2011;91(1):48-60.doi: 10.2522/ptj.20090359.PubMed: 21051593 Minassian K, McKay WB, Binder H, Hofstoetter US. Targeting Lumbar Spinal Neural Circuitry by Epidural Stimulation to Restore Motor Function After Spinal Cord Injury. Neurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics 2016;13(2):284-294.doi: 10.1007/s13311-016-0421-y.PubMed: 26843089 Angeli CA, Boakye M, Morton RA, et al. Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. The New England Journal of Medicine 2018;379(13):1244-1250.doi: 10.1056/NEJMoa1803588.PubMed: 30247091 Gill ML, Grahn PJ, Calvert JS, et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. Nat Med 2018;24(11):1677-1682.doi: 10.1038/s41591-018-0175-7.PubMed: 30250140 Wagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197 Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain : A Journal of Neurology 2014;137(Pt 5):1394-1409.doi: 10.1093/brain/awu038.PubMed: 24713270 Danner SM, Hofstoetter US, Freundl B, et al. Human spinal locomotor control is based on flexibly organized burst generators. Brain : A Journal of Neurology 2015;138(Pt 3):577-588.doi: 10.1093/brain/awu372.PubMed: 25582580 Capogrosso M, Wenger N, Raspopovic S, et al. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 2013;33(49):19326-19340.doi: 10.1523/JNEUROSCI.1688-13.2013.PubMed: 24305828 Capogrosso M, Balaguer J, Prat-Ortega G, et al. Supraspinal control of motoneurons after paralysis enabled by spinal cord stimulation. Research Square 2024:rs.3.rs-3650257.doi: 10.21203/rs.3.rs-3650257/v1.PubMed: 38260333 Dionne A, Mac-Thiong J, Alsofyani MA, Richard-Denis A. Are early-onset spasms predictive of poor neurological recovery after traumatic spinal cord injury? The Journal of Spinal Cord Medicine 2024;47(4):566-572.doi: 10.1080/10790268.2022.2150068.PubMed: 36622323 Veerakumar A, Cheng JJ, Sunshine A, Ye X, Zorowitz RD, Anderson WS. Baclofen dosage after traumatic spinal cord injury: a multi-decade retrospective analysis. Clin Neurol Neurosur 2015;129:50-56.doi: 10.1016/j.clineuro.2014.11.023.PubMed: 25532135 Erden E. Evaluation of Clinical Characteristics and Comorbid Conditions in Pediatric Traumatic Spinal Cord Injury Patients. Cureus J Med Science 2023;15(9):e44512.doi: 10.7759/cureus.44512.PubMed: 37790003 Guest J, Datta N, Jimsheleishvili G, Gater DRJ. Pathophysiology, Classification and Comorbidities after Traumatic Spinal Cord Injury. J Pers Med 2022;12(7):1126.doi: 10.3390/jpm12071126.PubMed: 35887623 Sköld C, Levi R, Seiger A. Spasticity after traumatic spinal cord injury: nature, severity, and location. Arch Phys Med Rehab 1999;80(12):1548-1557.doi: 10.1016/s0003-9993(99)90329-5.PubMed: 10597805 Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet (London, England) 2011;377(9781):1938-1947.doi: 10.1016/S0140-6736(11)60547-3.PubMed: 21601270 Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain : A Journal of Neurology 2014;137(Pt 5):1394-1409.doi: 10.1093/brain/awu038.PubMed: 24713270 Wagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197 Rowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. Nat Med 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264 Borowski A, Littleton AG, Borkhuu B, et al. Complications of intrathecal baclofen pump therapy in pediatric patients. Journal of Pediatric Orthopedics 2010;30(1):76-81.doi: 10.1097/BPO.0b013e3181c6b257.PubMed: 20032747 Qureshi AZ, Shacfe H, Ilyas A, et al. Complications of Intrathecal Baclofen Pump Therapy: An Institutional Experience from Saudi Arabia. Healthcare (Basel, Switzerland) 2023;11(21):2820.doi: 10.3390/healthcare11212820.PubMed: 37957965 Tabard-Fougère A, Canavese F, Steiger CN, De Coulon G. Complications of intrathecal baclofen pump treatment in children with spastic cerebral palsy. A comparative analysis of patients weighing over or under 20 kg at the time of implantation. Journal of Pediatric Orthopedics. Part B 2022;31(2):202-207.doi: 10.1097/BPB.0000000000000848.PubMed: 33448748 Kaye AD, Cheon SY, Roque MH, et al. Efficacy, Indications, and Safety of Intrathecal Baclofen Pump: A Narrative Review. Curr Pain Headache R 2025;29(1):9.doi: 10.1007/s11916-024-01310-x.PubMed: 39754631 Holtz KA, Lipson R, Noonan VK, Kwon BK, Mills PB. Prevalence and Effect of Problematic Spasticity After Traumatic Spinal Cord Injury. Arch Phys Med Rehab 2017;98(6):1132-1138.doi: 10.1016/j.apmr.2016.09.124.PubMed: 27780743 Tedroff K, Hägglund G, Miller F. Long-term effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review. Dev Med Child Neurol 2020;62(5):554-562.doi: 10.1111/dmcn.14320.PubMed: 31342516 Grunt S, Becher JG, Vermeulen RJ. Long-term outcome and adverse effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review. Dev Med Child Neurol 2011;53(6):490-498.doi: 10.1111/j.1469-8749.2011.03912.x.PubMed: 21518341 Rowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. Nat Med 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264 Wagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197 Romeni S, Losanno E, Emedoli D, et al. High-frequency epidural electrical stimulation reduces spasticity and facilitates walking recovery in patients with spinal cord injury. Sci Transl Med 2025;17(780):eadp9607.doi: 10.1126/scitranslmed.adp9607.PubMed: 39772775 Patel YA, Butera RJ. Challenges associated with nerve conduction block using kilohertz electrical stimulation. J Neural Eng 2018;15(3):031002.doi: 10.1088/1741-2552/aaadc0.PubMed: 29415877 Peña E, Pelot NA, Grill WM. Quantitative comparisons of block thresholds and onset responses for charge-balanced kilohertz frequency waveforms. J Neural Eng 2020;17(4):046048.doi: 10.1088/1741-2552/abadb5.PubMed: 32777778 Peña E, Pelot NA, Grill WM. Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance. Sci Rep-Uk 2021;11(1):5077.doi: 10.1038/s41598-021-84503-3.PubMed: 33658552 Chodankar D, Bhatt A, Davis S. Declaration of Helsinki 2024: Too much too late? Perspectives in Clinical Research 2025;16(1):1-2.doi: 10.4103/picr.picr_218_24.PubMed: 39867527 Declaration of Helsinki embraces health equity. Nat Med 2024;30(12):3383.doi: 10.1038/s41591-024-03433-5.PubMed: 39623088 Jillala RR, Aude CA, Vattipally VN, et al. Assessing and validating machine learning-enhanced imputation of admission American Spinal Injury Association Impairment Scale grades for spinal cord injury. Journal of Neurosurgery. Spine 2025;43(1):90-97.doi: 10.3171/2025.1.SPINE241135.PubMed: 40344756 Mitchell MD, Yarossi MB, Pierce DN, Garbarini EL, Forrest GF. Reliability of surface EMG as an assessment tool for trunk activity and potential to determine neurorecovery in SCI. Spinal Cord 2015;53(5):368-374.doi: 10.1038/sc.2014.171.PubMed: 25448189 Angeli CA, Rejc E, Ugiliweneza B, et al. Activity-based recovery training with spinal cord epidural stimulation improves standing performance in cervical spinal cord injury. J Neuroeng Rehabil 2025;22(1):101.doi: 10.1186/s12984-025-01636-6.PubMed: 40301929 Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet (London, England) 2011;377(9781):1938-1947.doi: 10.1016/S0140-6736(11)60547-3.PubMed: 21601270 Andrews B, Karem A, Harkema SJ, Rouffet DM. Artifact Adaptive Ideal Filtering of EMG Signals Contaminated by Spinal Cord Transcutaneous Stimulation. IEEE Transactions On Neural Systems and Rehabilitation Engineering : A Publication of the IEEE Engineering in Medicine and Biology Society 2023;31:3047-3054.doi: 10.1109/TNSRE.2023.3294011.PubMed: 37428663 Boakye M, Ugiliweneza B, Madrigal F, et al. Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation. Neuromodulation : Journal of the International Neuromodulation Society 2021;24(3):405-415.doi: 10.1111/ner.13381.PubMed: 33794042 Angeli CA, Rejc E, Ugiliweneza B, et al. Activity-based recovery training with spinal cord epidural stimulation improves standing performance in cervical spinal cord injury. J Neuroeng Rehabil 2025;22(1):101.doi: 10.1186/s12984-025-01636-6.PubMed: 40301929 Angeli CA, Gerasimenko Y. Combined cervical transcutaneous with lumbosacral epidural stimulation improves voluntary control of stepping movements in spinal cord injured individuals. Front Bioeng Biotech 2023;11:1073716.doi: 10.3389/fbioe.2023.1073716.PubMed: 36815892 Boakye M, Ball T, Dietz N, et al. Spinal cord epidural stimulation for motor and autonomic function recovery after chronic spinal cord injury: A case series and technical note. Surgical Neurology International 2023;14:87.doi: 10.25259/SNI_1074_2022.PubMed: 37025529 John AA, Rossettie S, Rafael J, Cox CT, Ducic I, Mackay BJ. Clinical Assessment of Pain and Sensory Function in Peripheral Nerve Injury and Recovery: A Systematic Review of Literature. Archives of Plastic Surgery 2022;49(3):427-439.doi: 10.1055/s-0042-1748658.PubMed: 35832158 Knotkova H, Hamani C, Sivanesan E, et al. Neuromodulation for chronic pain. Lancet (London, England) 2021;397(10289):2111-2124.doi: 10.1016/S0140-6736(21)00794-7.PubMed: 34062145 Da Cunha PHM, Lapa JDDS, Hosomi K, de Andrade DC. Neuromodulation for neuropathic pain. Int Rev Neurobiol 2024;179:471-502.doi: 10.1016/bs.irn.2024.10.013.PubMed: 39580221 Lei S, Jia F, He Q, Gao L, Luo S. Effect of stimulation parameters on entrainment. Heart Rhythm O2 2022;3(6Part A):715-717.doi: 10.1016/j.hroo.2022.09.012.PubMed: 36589909 Villalobos J, Payne SC, Ward GM, et al. Stimulation parameters for directional vagus nerve stimulation. Bioelectronic Medicine 2023;9(1):16.doi: 10.1186/s42234-023-00117-2.PubMed: 37464423 Moritz C, Field-Fote EC, Tefertiller C, et al. Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. Nat Med 2024;30(5):1276-1283.doi: 10.1038/s41591-024-02940-9.PubMed: 38769431 Squair JW, Milano M, de Coucy A, et al. Recovery of walking after paralysis by regenerating characterized neurons to their natural target region. Science (New York, N.Y.) 2023;381(6664):1338-1345.doi: 10.1126/science.adi6412.PubMed: 37733871 Hankov N, Caban M, Demesmaeker R, et al. Augmenting rehabilitation robotics with spinal cord neuromodulation: A proof of concept. Sci Robot 2025;10(100):eadn5564.doi: 10.1126/scirobotics.adn5564.PubMed: 40073082 Dragutinovic B, Moser F, Notbohm HL, Ihalainen JK, Bloch W, Schumann M. Influence of menstrual cycle and oral contraceptive phases on strength performance, neuromuscular fatigue, and perceived exertion. Journal of Applied Physiology (Bethesda, Md. : 1985) 2024;137(4):919-933.doi: 10.1152/japplphysiol.00198.2024.PubMed: 39052822 Streckmann F, Elter T, Lehmann HC, et al. Preventive Effect of Neuromuscular Training on Chemotherapy-Induced Neuropathy: A Randomized Clinical Trial. Jama Intern Med 2024;184(9):1046-1053.doi: 10.1001/jamainternmed.2024.2354.PubMed: 38949824 Zbinden J, Edwards S. From sequential to simultaneous prosthetic control: Decoding simultaneous finger movements from individual ground truth EMG patterns. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference 2024;2024:1-4.doi: 10.1109/EMBC53108.2024.10782980.PubMed: 40039569 Pöchhacker M, Conrad A, Marko D, Varga E. A novel extraction method of prymnesins from Prymnesium parvum whole culture samples and re-evaluation of existing protocols. Ecotox Environ Safe 2025;302:118745.doi: 10.1016/j.ecoenv.2025.118745.PubMed: 40743721 Wagner R, Jagoda A. Spinal cord syndromes. Emerg Med Clin N Am 1997;15(3):699-711.doi: 10.1016/s0733-8627(05)70326-6.PubMed: 9255141 Wagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197 Rowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. Nat Med 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264 Hernandez-Charpak SD, Kinany N, Ricchi I, et al. Towards personalized mapping through lumbosacral spinal cord task fMRI. Imaging Neuroscience (Cambridge, Mass.) 2025;3:imag_a_00455.doi: 10.1162/imag_a_00455.PubMed: 40800855 Simopoulos T, Sharma S, Aner M, Gill JS. A Temporary vs. Permanent Anchored Percutaneous Lead Trial of Spinal Cord Stimulation: A Comparison of Patient Outcomes and Adverse Events. Neuromodulation : Journal of the International Neuromodulation Society 2018;21(5):508-512.doi: 10.1111/ner.12687.PubMed: 28901641 D'Souza RS, Olatoye OO, Butler CS, Barman RA, Ashmore ZM, Hagedorn JM. Adverse Events Associated With 10-kHz Dorsal Column Spinal Cord Stimulation: A 5-Year Analysis of the Manufacturer and User Facility Device Experience (MAUDE) Database. The Clinical Journal of Pain 2022;38(5):320-327.doi: 10.1097/AJP.0000000000001026.PubMed: 35132023 Street JT, Thorogood NP, Cheung A, et al. Use of the Spine Adverse Events Severity System (SAVES) in patients with traumatic spinal cord injury. A comparison with institutional ICD-10 coding for the identification of acute care adverse events. Spinal Cord 2013;51(6):472-476.doi: 10.1038/sc.2012.173.PubMed: 23318555 Additional Declarations No competing interests reported. Supplementary Files STROBE.pdf Supplement.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 13 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 04 May, 2026 Reviewers agreed at journal 27 Apr, 2026 Reviewers agreed at journal 24 Apr, 2026 Reviewers invited by journal 24 Apr, 2026 Editor assigned by journal 20 Apr, 2026 Submission checks completed at journal 20 Apr, 2026 First submitted to journal 15 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mangsuer","middleName":"","lastName":"Nuermaimaiti","suffix":""},{"id":634409939,"identity":"e0685310-a274-4446-be1c-b19f78cabe77","order_by":2,"name":"Hangfei Guo","email":"","orcid":"","institution":"First Affiliated Hospital of Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hangfei","middleName":"","lastName":"Guo","suffix":""},{"id":634409940,"identity":"92fcc51e-e1dc-49ce-9a80-299fbf7b5630","order_by":3,"name":"Manli Zhu","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Manli","middleName":"","lastName":"Zhu","suffix":""},{"id":634409941,"identity":"8da1dd3e-374a-4340-8d74-9ec7ae0cf0d3","order_by":4,"name":"Lei Ren","email":"","orcid":"","institution":"Second Affiliated Hospital of Xinjiang Medical 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17:39:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9430045/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9430045/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108837376,"identity":"6675a85d-382d-44da-accb-2497d4299570","added_by":"auto","created_at":"2026-05-09 00:10:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65102,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eeSCS Clinical Trial Flowchart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/d813f21dab8a8105ef49b71f.png"},{"id":108837378,"identity":"3883f182-77f3-4954-bd0e-9e61e924d373","added_by":"auto","created_at":"2026-05-09 00:10:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":379504,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSpinal Cord Stimulation (SCS) System\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/d5fc41591f363bfe0babd248.png"},{"id":108837384,"identity":"f1731d2b-9698-44e5-b9d8-0181e661f328","added_by":"auto","created_at":"2026-05-09 00:10:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":61862,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRadar chart of the short-term functional recovery between the eSCS + PT and PT-only groups\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/b4bbe86ff557fbf26af90a6a.png"},{"id":108837377,"identity":"1356226d-e6a5-4f58-bc06-8f2ab77c2074","added_by":"auto","created_at":"2026-05-09 00:10:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":103781,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComprehensive intraoperative electrophysiological monitoring protocol and the subsequent personalized eSCS parameter optimization strategy\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/f68047fa15d749d8019da9f8.png"},{"id":108837410,"identity":"125f98bc-1919-469a-8c15-3f67d558d8d9","added_by":"auto","created_at":"2026-05-09 00:10:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":290632,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLongitudinal visualization of lower extremity muscle strength recovery in the eSCS+PT group.\u003c/strong\u003e Anatomical maps illustrate the spatial and temporal changes in muscle strength from preoperative baseline to Day 180 post-implantation. Color intensity represents the magnitude of strength improvement relative to baseline assessment (scale 0 to +2), with darker red indicating greater functional gain. Key muscle groups are labeled, including IL (Iliacus), VL (Vastus Lateralis), RF (Rectus Femoris), TA (Tibialis Anterior), GLmax (Gluteus Maximus), BF (Biceps Femoris), and GM (Gastrocnemius Medialis). The timeline highlights key assessment points, with the \"patient discharge\" period marked between Day 60 and Day 120.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/3b441141d15891fbaeaa2c36.png"},{"id":108837380,"identity":"d837f206-3cfd-4adc-957d-25578a83bae7","added_by":"auto","created_at":"2026-05-09 00:10:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":741699,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe comprehensive surgical workflow and radiographic verification of eSCS electrode implantation in a representative cervical spinal cord injury (SCI) patient.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/5b407e17808c7495cdc4c678.png"},{"id":108977404,"identity":"3f5c343e-04c6-4a92-b97c-85fc06a498f3","added_by":"auto","created_at":"2026-05-11 11:31:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2275953,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/6d0a51d7-35c6-4c42-af13-e474f449633d.pdf"},{"id":108837382,"identity":"4f6979a7-e981-423b-b860-3bdf62c3cbf5","added_by":"auto","created_at":"2026-05-09 00:10:23","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":189613,"visible":true,"origin":"","legend":"","description":"","filename":"STROBE.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/f42c5d3eb16d77ac2259bc98.pdf"},{"id":108837379,"identity":"3db7625f-f619-40aa-b9a5-34aae688b2d5","added_by":"auto","created_at":"2026-05-09 00:10:22","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":600946,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9430045/v1/c09ac9e5ce4e94d20c24de08.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of the therapeutic effect of spinal cord stimulation on improving spasticity and promoting functional recovery in patients with spinal cord injury","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinal cord injury (SCI) is a traumatic event that results in disturbances to normal sensory, motor, or autonomic function and ultimately impacts a patient\u0026rsquo;s physical, psychological, and social well-being\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. SCI is associated with long-term disability, reduced life expectancy, and significant healthcare costs, often requiring lifelong medical and rehabilitative care \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Additionally, advances in the healthcare system have resulted in the increased longevity of persons with SCI, but with a longer lifespan associated with several costly chronic comorbidities as well as poor quality of life\u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The volitional production of active movements during training promotes reorganization of neuronal pathways and thereby augments recovery\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral research groups have focused on the restoration of locomotion to ameliorate comorbidities and secure independence after SCI\u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Improved mobility would result in a reduction in psychosocial, cardiovascular, and metabolic parameters and also in socioeconomic burden\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. This situation has prompted the development of multifaceted neurotechnologies\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, such as lower limb exoskeletons, bodyweight support systems, functional electrical stimulation of muscles, and spinal cord neuromodulation therapies, all of which share the same goal: to enable patients to sustain active movements during training to enhance the reorganization of neuronal pathways\u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Three decades of clinical research using these neurotechnologies suggested that epidural spinal cord stimulation (eSCS) of the spinal cord may be pivotal to achieve this goal\u003csup\u003e\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eeSCS of the spinal cord has emerged as a potential additional tool for restoring locomotion in individuals with SCI\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. This method involves the implantation of a multielectrode array in the epidural space between the spinal cord and the vertebral bone with the aim of delivering electrical pulses to the spinal cord. eSCS not only enables the brain to exploit spared but functionally silent descending pathways in order to produce movements of paralysed limbs\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, but also improves the ability of the spinal cord to translate task-specific sensory information into the muscle activity that underlies standing and walking\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Computational investigations as well as animal and human studies have shown that eSCS can enhance voluntary movement by recruiting the proprioceptive afferent fibers within the dorsal roots of the spinal cord, which in turn trigger the spinal motoneurons by synaptic communication\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. A prevalent neurological sequela of SCI is spasticity, clinically defined as aberrant motor control characterized by involuntary hypertonia and hyperreflexive muscle responses. This pathophysiological state manifests through four distinct neuromuscular phenomena: exaggerated stretch reflexes (hyperreflexia), elevated resting muscle tone (hypertonia), rhythmic oscillatory contractions in agonist-antagonist muscle pairs (clonus), and the maladaptive co-activation of functionally antagonistic muscles during voluntary movement (pathological co-contraction). These manifestations collectively disrupt motor coordination and functional mobility in affected individuals\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Approximately 70% of individuals with thoracic SCI exhibit clinically significant spasticity manifestations, with comparable prevalence observed across all American Spinal Injury Association (ASIA) Impairment Scale (AIS) classifications\u003csup\u003e\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Notably, conventional eSCS investigations have largely overlooked pathological co-contraction patterns and spasticity management, frequently excluding participants with severe spasticity from trial enrollment\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, or omitting datasets compromised by acute spasticity episodes during analysis\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. While pharmacological interventions\u0026mdash;particularly systemic or intrathecal baclofen administration\u0026mdash;remain first-line therapies, their utility is limited by dose-dependent adverse effects including nephrotoxicity, generalized hypotonia, vertigo, and withdrawal syndromes\u003csup\u003e\u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, with therapeutic failure occurring in refractory cases\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. Alternative surgical interventions such as selective dorsal rhizotomy or peripheral neurotomy present additional morbidity risks, including deafferentation pain syndromes, urinary incontinence, and progressive spinal malalignment\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. These therapeutic limitations necessitate innovative neuromodulation strategies leveraging eSCS's spatiotemporal precision to address this persistent clinical challenge.\u003c/p\u003e \u003cp\u003eMore recently, Wagner et al. and Rowald et al. refined this approach by implementing spatially selective stimulation at the lumbar enlargement using multi-electrode arrays, achieving remarkable recovery of walking function in patients with severe paralysis\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. However, these conventional approaches share a fundamental limitation: they primarily focus on stimulation below the injury level, targeting intact neural circuitry distal to the lesion while largely neglecting direct modulation of the injured spinal segment itself. This paradigm emerged partly from safety concerns regarding direct stimulation of damaged tissue and partly from the conceptual framework that functional recovery derives primarily from activating circuits caudal to the injury.\u003c/p\u003e \u003cp\u003eThe pioneering work by Romeni et al.\u003csup\u003e58\u003c/sup\u003e on high-frequency eSCS (HF-eSCS) for spasticity management in SCI represents a paradigm shift in neuromodulation therapeutics. By leveraging kilohertz-frequency stimulation to block pathological proprioceptive afferents\u0026mdash;while preserving low-frequency eSCS (LF- eSCS) mediated facilitation of voluntary motor circuits \u0026ndash; the authors achieved unprecedented reductions in hyperreflexia, clonus, and co-contraction, ultimately enhancing functional recovery. This dual-mode neuromodulation strategy elegantly addresses a fundamental limitation of conventional eSCS: the exacerbation of spasticity during movement facilitation. The study\u0026rsquo;s emphasis on personalized, activity-dependent rehabilitation is equally compelling. The synergy of HF- eSCS (for spasticity suppression) and LF- eSCS (for movement facilitation) enabled intensive task-specific training (e.g., treadmill walking, stair climbing), driving improvements in kinematics and clinical motor scores over 6 months. This aligns with growing evidence that eSCS efficacy hinges on spinal circuit plasticity unlocked by sensorimotor relearning\u0026mdash;a principle underscored by the authors \u0026rsquo;use of virtual reality biofeedback and home-based inertial sensing.\u003c/p\u003e \u003cp\u003eHigh-frequency neuromodulation induces reversible conduction blockade across somatic and autonomic neural pathways\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e, leveraging the biophysical principle of kilohertz-frequency neural silencing. This phenomenon, mechanistically defined by sustained neuronal depolarization under supra-threshold kilohertz stimulation, has been rigorously validated in peripheral nerve models through computational and empirical investigations\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe propose placing electrodes adjacent to the injury site rather than defaulting to traditional enlargement locations and dynamic electrode reconfiguration as a key innovation. We hypothesize that we can achieve more precise modulation of pathological neural activity while simultaneously facilitating signal propagation across the lesion through both orthodromic and antidromic mechanisms, also we implemented HF-eSCS regimens in participants with SCI. Quantitative assessments confirmed significant reductions in pathological co-contraction during functional mobility tasks. Critically, integrating HF-eSCS with contemporary LF-eSCS protocols enabled synergistic neuromodulation. Adapting contacts monthly based on EMG-guided thresholds enhanced HF-eSCS efficiency and reduced antagonist coactivation during voluntary movement. This approach may address the challenge of broad dorsal root activation noted in the original study and challenges this anatomical constraint by strategically positioning eSCS electrodes in proximity to the injury epicenter regardless of spinal level.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThis study was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University and was conducted in compliance with the Declaration of Helsinki\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e. Prior to participation each subject signed an informed consent form. The research team ensured participant privacy protection and data security throughout the study. This research was supported by the Xinjiang Medical University Smart Healthcare Innovation Center Construction Project (Project No.: ZHYL-006). Patients were selected according to the following criteria: Adults aged 18\u0026ndash;85 years of any gender with traumatic SCI confirmed by MRI or CT imaging and a disease duration of 0\u0026ndash;8 years were included. Participants must have had American Spinal Injury Association (ASIA)\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e Impairment Scale grades A-D with injury, and demonstrated either pathological spasticity (Modified Ashworth Scale score\u0026thinsp;\u0026ge;\u0026thinsp;2) and/or neuropathic pain (Visual Analog Scale score\u0026thinsp;\u0026ge;\u0026thinsp;4). All participants were required to have completed standard rehabilitation therapy for at least six months with stable symptoms, possess the cognitive capacity to understand and comply with research procedures, and provide signed written informed consent. Exclusion criteria comprised: severe osteoporosis or spinal instability requiring fusion surgery; active local or systemic infection or severely compromised immune function; uncontrolled psychiatric disorders or cognitive impairment (MMSE score\u0026thinsp;\u0026lt;\u0026thinsp;24); pregnancy or lactation; presence of other electrical stimulation devices or cardiac pacemakers; coagulation disorders (INR\u0026thinsp;\u0026gt;\u0026thinsp;1.5) or ongoing therapeutic anticoagulant medication; severe cardiac, hepatic, or renal dysfunction (Child-Pugh class B or higher); life expectancy less than one year; and participation in other clinical trials that might interfere with study results within the past 30 days.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design and Technical Roadmap\u003c/h3\u003e\n\u003cp\u003eThe study employed a parallel-group design with two arms: a spinal cord stimulation plus physical therapy (eSCS\u0026thinsp;+\u0026thinsp;PT) group (N\u0026thinsp;=\u0026thinsp;15) and a physical therapy only (PT) group (N\u0026thinsp;=\u0026thinsp;15). All participants underwent comprehensive pre-treatment evaluation on Day 1, including neurological assessment, quantitative sensory testing, and baseline functional measurements. For the eSCS\u0026thinsp;+\u0026thinsp;PT group, implantation of the epidural electrode array was pe5prformed on Day 2, followed by initiation of stimulation parameters combined with intensive physical therapy from Days 2\u0026ndash;15. Stimulation parameters (frequency, pulse width, and amplitude) were systematically adjusted during Days 3\u0026ndash;30 based on individual therapeutic response and tolerability, with high-frequency stimulation (1.2 kHz) primarily used for spasticity suppression and low-frequency stimulation (30\u0026ndash;60 Hz) for voluntary movement facilitation. Post-operative evaluation was conducted on Day 31 to assess initial treatment efficacy. Both groups received standardized physical therapy protocols from Days 31\u0026ndash;60, with the eSCS\u0026thinsp;+\u0026thinsp;PT group continuing stimulation therapy throughout this period. All participants underwent structured physical therapy for 3\u0026ndash;10 months post-discharge, with regular follow-up assessments scheduled throughout this period to evaluate long-term functional outcomes, pain metrics, and quality of life measures. This phased intervention approach allowed for systematic evaluation of both acute and chronic effects of combined eSCS and rehabilitation therapy compared to rehabilitation alone (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eStimulation setup\u003c/h3\u003e\n\u003cp\u003eConventional eSCS protocols that restrict electrode placement to cervical or lumbar enlargements, our approach employed a lesion-centric electrode positioning strategy. Prior to surgery, each participant underwent high-resolution 3T MRI with specialized spinal cord sequences to precisely delineate the injury epicenter and surrounding neural structures. Based on this imaging and comprehensive neurological assessment, the optimal electrode placement level was determined to be 1\u0026ndash;2 segments rostral to the primary injury site, regardless of whether this position corresponded to a traditional enlargement region. This individualized approach necessitated customized surgical planning for each participant, including specialized laminectomy dimensions and trajectory considerations based on local spinal anatomy. Intraoperatively, we employed neurophysiological mapping to confirm optimal electrode positioning, delivering test stimulation while monitoring muscle responses and sensory perception thresholds across dermatomes. The final electrode position was selected to maximize coverage of the injured segment while minimizing current spread to non-target regions. This lesion-proximal approach represented a significant departure from conventional enlargement-focused eSCS protocols and required development of specialized surgical techniques to accommodate variable spinal anatomy across different regions.\u003c/p\u003e \u003cp\u003eFor eSCS, electrodes are implanted in the dorsal epidural space at a single spinal segment (cervical, thoracic, or lumbar level), secured with the A6218C titanium electrode anchor. The positioning is optimized to target relevant neural structures based on the specific therapeutic indication, but only one segment is selected per patient to avoid simultaneous multi-segment implantation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Stimulation was delivered using the PINS Medical G122/G122R spinal cord stimulation pulse generator system with biphasic rectangular pulses. Two distinct stimulation modes were employed based on therapeutic objectives: (1) High-frequency epidural stimulation (HF-eSCS) at 1.2 kHz with amplitude of 0.3\u0026ndash;0.8 mA and pulse width of 80\u0026ndash;120 \u0026micro;s for spasticity suppression; (2) Low-frequency epidural stimulation (LF-eSCS) at 30\u0026ndash;60 Hz with amplitude of 0.3\u0026ndash;0.8 mA and pulse width of 80\u0026ndash;120 \u0026micro;s for voluntary motor facilitation. Initial parameters were set at sensory threshold\u0026thinsp;+\u0026thinsp;10% and titrated in 10% increments based on real-time EMG feedback and clinical response. Note that the originally planned 10-kHz protocol was abandoned during pilot testing due to excessive power consumption and limited additional therapeutic benefit compared to 1.2-kHz stimulation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eData acquisition\u003c/h3\u003e\n\u003cp\u003eEMG recordings from quadriceps, hamstrings, tibialis anterior, and triceps surae muscles were acquired bilaterally using MyoWare 240-channel wireless EMG sensors (PINS Medical, Beijing, China), each placed centrally on the muscle bellies and oriented along the long axis of the muscles with an inter-electrode distance of 3 cm. EMG signals were amplified with a gain of 1000, filtered to a bandwidth of 10\u0026ndash;1000 Hz, and digitized at 1000 samples per second per channel using the T902 test stimulator integrated with the PINS G122/G122R spinal cord stimulation system. The acquired signals were synchronized with the C721 patient controller for real-time monitoring and were recorded for offline analysis. The A6218C titanium electrode anchor ensured stable positioning of the spinal cord stimulation electrodes at the spinal segment, while the R821 programmer facilitated seamless integration of EMG data with stimulation parameters for closed-loop system implementation\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eIntraoperative Electrophysiological Mapping Protocol\u003c/h3\u003e\n\u003cp\u003eFollowing dural exposure and prior to permanent electrode fixation, comprehensive neurophysiological mapping was performed to optimize electrode positioning and establish baseline stimulation parameters. Threshold-triggered electromyography (EMG) was recorded from bilateral quadriceps, hamstrings, tibialis anterior, and gastrocnemius muscles using disposable surface electrodes. Stimulation began at 0.1 mA with incremental increases of 0.05 mA until a reproducible motor response was observed in at least two target muscle groups. The minimal current intensity eliciting a motor response with amplitude exceeding 100 \u0026micro;V and latency of 0.5\u0026ndash;1.5 ms was defined as the motor threshold. Optimal electrode position was confirmed when: (1) sensory threshold was \u0026le;\u0026thinsp;50% of motor threshold; (2) bilateral muscle responses were symmetrical (amplitude difference\u0026thinsp;\u0026lt;\u0026thinsp;30%); and (3) no adverse effects (e.g., radicular pain, autonomic dysreflexia) occurred at therapeutic intensities.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStimulation protocol\u003c/h2\u003e \u003cp\u003eStimulation was applied with subjects in supine, sitting, standing, and ambulatory positions to evaluate position-dependent effects across pain and motor domains. In the supine position, subjects lay flat with neutral spinal alignment and legs extended; in sitting position, subjects maintained 90\u0026deg; hip and knee flexion with back support; in standing position, subjects maintained upright posture referenced to a laser-guided vertical line without external support. During ambulatory assessment, subjects walked on a 10-meter walkway at self-selected speed. All positions were monitored using the Vicon motion capture system to ensure standardized biomechanical alignment. For epidural SCS (eSCS), electrodes were secured at L2-L3 spinal segment 1 mm lateral to midline using the A6218C titanium anchor. Stimulation was delivered using the PINS Medical G122/G122R system with either conventional parameters (40 Hz, 50\u0026ndash;300 \u0026micro;A, 300\u0026ndash;450 \u0026micro;s pulse width) or high-frequency settings (1.2 kHz, 0.3\u0026ndash;0.8 mA) based on the experimental condition. EMG monitoring of lower limb muscles was performed continuously, with stimulation automatically paused for 10 s when unintended muscle activation exceeding 15% of maximum voluntary contraction was detected. For each position, baseline measurements were obtained followed by incremental stimulation intensity adjustment (starting at sensory threshold\u0026thinsp;+\u0026thinsp;10%, increasing by 10% increments) until optimal therapeutic effect was achieved or maximum comfortable intensity reached. A minimum 2-minute interval was maintained between parameter adjustments to avoid carryover effects, with at least 7 s between consecutive pulse trains. In closed-loop mode, the system dynamically adjusted stimulation parameters based on real-time EMG patterns detected during different postural transitions and gait phases.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClosed-loop Parameter Optimization\u003c/h3\u003e\n\u003cp\u003eBeyond initial programming, a dynamic parameter adjustment protocol was implemented throughout the 6-month follow-up period. At monthly intervals, participants underwent standardized EMG assessment during functional tasks (sit-to-stand, 10-m walk test). Stimulation parameters were iteratively modified when EMG patterns indicated: (1) antagonist co-contraction exceeding 25% of agonist activation during voluntary movement; (2) absence of expected muscle recruitment at therapeutic intensities; or (3) emergence of new spasticity \"hotspots\" defined as muscles with Modified Ashworth Scale score increase\u0026thinsp;\u0026ge;\u0026thinsp;1 point compared to previous assessment. Active electrode contacts were reconfigured to target newly identified spasticity foci while maintaining coverage of primary motor pools.\u003c/p\u003e\n\u003ch3\u003eDual-Mode Stimulation Protocol\u003c/h3\u003e\n\u003cp\u003eA sequential dual-mode stimulation strategy was implemented to simultaneously address spasticity and promote motor recovery while avoiding the exacerbation of hypertonia during movement facilitation. The protocol consisted of three phases: Phase 1: Exclusive HF-eSCS (1.2 kHz) initiated at 0.3 mA, titrated upward in 0.1-mA increments until Modified Ashworth Scale score reduction\u0026thinsp;\u0026ge;\u0026thinsp;50% or maximum tolerated intensity reached.Phase 2: Gradual introduction of LF-eSCS (40 Hz) while maintaining concurrent HF-eSCS. LF-eSCS amplitude started at 0.2 mA and increased by 0.1 mA every 3 days provided no increase in spasticity (MAS score change\u0026thinsp;\u0026lt;\u0026thinsp;1 point) occurred during active movement attempts. Phase 3: Individualized ratio of HF-eSCS to LF-eSCS based on functional goals\u0026mdash;higher HF-eSCS proportion for activities requiring fine motor control, higher LF-eSCS proportion for gross motor tasks.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eData analysis was performed using R version 4.4.0 (R Core Team, Vienna, Austria) with specialized packages for statistical computing and visualization. Electrophysiological data from quantitative sensory testing (QST) and skin sympathetic response (SSR) recordings were processed using the 'signal' package (v0.7-7) with a 20\u0026ndash;500 Hz bandpass Butterworth filter, while motion capture data from the Vicon system was filtered using the 'pracma' package (v2.4.4) with a fourth-order Butterworth filter (cutoff frequency 6 Hz). For gait analysis, the mean values of three walking trials were calculated using the 'tidyverse' ecosystem (v2.0.0), with each trial consisting of at least ten complete gait cycles. In two subjects, incomplete gait cycle data due to fatigue was excluded from kinematic analysis but included in clinical scoring (declared as partially missing data) using the 'naniar' package (v1.0.0). The threshold intensity for optimal stimulation parameters was defined as the lowest intensity level at which functional improvement (e.g., walking speed increase\u0026thinsp;\u0026gt;\u0026thinsp;10% or VAS pain reduction\u0026thinsp;\u0026gt;\u0026thinsp;30%) was consistently observed across three consecutive therapy sessions.\u003c/p\u003e \u003cp\u003eAll multidimensional assessment data were standardized using z-score transformation with the 'scale' function before integration into the machine learning framework. A random forest algorithm with 500 trees was implemented using the 'randomForest' package (v4.7-1.1) to predict optimal stimulation parameters, with features including ASIA impairment scale, injury duration, preoperative MEP amplitude, QST thresholds, and anatomical characteristics from 3D spinal cord reconstruction. Model performance was evaluated using 10-fold cross-validation with the 'tidymodels' framework (v1.1.1), reporting mean accuracy and area under the curve (AUC). For clinical outcomes, linear mixed-effects models were fitted using the 'lmerTest' package (v3.1-3) with Satterthwaite's approximation for degrees of freedom to investigate the effects of stimulation mode (HF-SCS vs LF-SCS), time (baseline, 3-month, 6-month), and ASIA classification (complete vs incomplete) on primary endpoints of pain VAS scores and modified Ashworth scale measurements. Effect sizes were calculated using the 'effectsize' package (v0.8.3), with partial eta-squared (η\u0026sup2;) values\u0026thinsp;\u0026gt;\u0026thinsp;0.14 considered large effects. All post-hoc pairwise comparisons were adjusted using Bonferroni correction with the 'emmeans' package (v1.8.8), and statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (two-tailed). All graphical visualizations were created using 'ggplot2' (v3.4.4) with publication-quality formatting.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Clinical Characteristics\u003c/h2\u003e \u003cp\u003eA total of 30 participants with spinal cord injury were enrolled in this study, with 15 participants assigned to the spinal cord stimulation plus physical therapy (SCS\u0026thinsp;+\u0026thinsp;PT) group and 15 to the physical therapy alone (PT) group. Baseline demographic and clinical characteristics between the two groups are summarized in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. No significant between-group differences were observed in age (SCS\u0026thinsp;+\u0026thinsp;PT: 48.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0 years; PT: 40.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.4 years; p\u0026thinsp;=\u0026thinsp;0.175), gender distribution (SCS\u0026thinsp;+\u0026thinsp;PT: 46.7% male; PT: 80.0% male; p\u0026thinsp;=\u0026thinsp;0.273), time since injury (SCS\u0026thinsp;+\u0026thinsp;PT: 15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 months; PT: 11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3 months), supporting the validity of between-group comparisons for treatment outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable.1. Clinical Characteristics\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCS\u0026thinsp;+\u0026thinsp;PT (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePT (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.0(14.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.2(15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.273\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(46.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12(80.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(53.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime since injury, months, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.9(14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.4(5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime since enrollment, months, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.7(2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.8(4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASIA grade (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.753\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(26,7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(26.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(6.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLevel of injury (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCervical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThoracic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6(30.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eElectrode Placement Distribution and Functional Outcomes\u003c/h2\u003e \u003cp\u003eThe lesion-proximal electrode placement strategy achieved successful implantation in all 15 participants in the SCS\u0026thinsp;+\u0026thinsp;PT group, with final electrode positions distributed according to individual injury locations. As shown in \u003cb\u003eTable.1\u003c/b\u003e, electrode placements were predominantly in cervical segments (n\u0026thinsp;=\u0026thinsp;10, 66.7%) with the remainder in thoracic segments (n\u0026thinsp;=\u0026thinsp;5, 33.3%), reflecting the anatomical distribution of injuries in our cohort.\u003c/p\u003e \u003cp\u003eParticipants with electrodes placed proximal to their injury site demonstrated significant improvements across multiple functional domains at the six-month follow-up assessment. Within the cervical injury subgroup (n\u0026thinsp;=\u0026thinsp;10), we observed substantial reductions in spasticity as measured by the Modified Ashworth Scale (from median 20 [IQR 10\u0026ndash;32] to 10 [IQR 0\u0026ndash;20], p\u0026thinsp;=\u0026thinsp;0.003), with 8 of 10 participants (80.0%) achieving clinically meaningful improvement in muscle tone regulation. Neuropathic pain decreased significantly in this subgroup (Visual Analog Scale from median 20 [IQR 0\u0026ndash;30] to 0 [IQR 0\u0026ndash;10], p\u0026thinsp;=\u0026thinsp;0.039), with 7 of 10 participants (70.0%) reporting complete or near-complete pain resolution. Participants with thoracic-level electrode placement (n\u0026thinsp;=\u0026thinsp;5) demonstrated remarkable preservation and improvement of autonomic functions, with 4 of 5 participants (80.0%) showing improved cardiovascular stability during orthostatic challenges. This subgroup also exhibited enhanced sensory recovery, with ASIA sensory scores increasing from a mean of 162.4 (SD 35.8) at baseline to 186.6 (SD 23.7) at six months (p\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eand Supplement Material eTable1,2 and eFig1\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eThe short-term functional recovery between the SCS\u0026thinsp;+\u0026thinsp;PT and PT\u003c/h2\u003e \u003cp\u003eSix functional domains were evaluated in 15 participants per group following a 30-day intervention period. The EES\u0026thinsp;+\u0026thinsp;PT group demonstrated substantially higher improvement rates across most domains, particularly in sensory function (93.3% vs 60.0%), muscle spasticity control (73.3% vs 26.7%), and pain reduction (60.0% vs 20.0%). Notably, both groups showed similar outcomes in bowel function recovery (13.3% in both groups), suggesting this domain may be less responsive to neuromodulation approaches. These findings provide compelling evidence for the therapeutic advantage of combined eSCS\u0026thinsp;+\u0026thinsp;PT intervention over conventional rehabilitation alone in multiple functional s dimensions after spinal cord injury (\u003cb\u003eTable. 2\u003c/b\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eand Supplement Material eTable1,2 and eFig1\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eTable.2. Clinical Parameters Before and After Surgery in the Treatment Group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eeSCS\u0026thinsp;+\u0026thinsp;PT\u003c/p\u003e \u003cp\u003e(one day before the operation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eeSCS\u0026thinsp;+\u0026thinsp;PT\u003c/p\u003e \u003cp\u003e(six months after the operation )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASIA sensation score, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159(37.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183(25.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASIA motor score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60(0\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60(20\u0026ndash;85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModified Ashworth Spasticity Scale, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(10\u0026ndash;32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(0\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual Analog Scale for Pain,median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20(0\u0026ndash;30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary function score, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStool Function Score,median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(2\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(2\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSix months following the intervention, patients demonstrated significant improvements in several neurological and functional parameters. The ASIA sensory score showed a statistically significant increase from 159.0 (SD 37.0) to 183.0 (SD 25.1) (p\u0026thinsp;=\u0026thinsp;0.001). Similarly, the ASIA motor score improved significantly from a median of 60 (IQR 0\u0026ndash;80) to 60 (IQR 20\u0026ndash;85) (p\u0026thinsp;=\u0026thinsp;0.016). A notable reduction in spasticity was observed, with the Modified Ashworth Spasticity Scale score decreasing from a median of 20 (IQR 10\u0026ndash;32) to 10 (IQR 0\u0026ndash;20) (p\u0026thinsp;=\u0026thinsp;0.003). Pain levels assessed by the Visual Analog Scale also decreased significantly from a median of 20 (IQR 0\u0026ndash;30) to 0 (IQR 0\u0026ndash;10) (p\u0026thinsp;=\u0026thinsp;0.039). Although improvements were observed in urinary function scores (from median 3 [IQR 1\u0026ndash;4] to 3 [IQR 1\u0026ndash;5]) and stool function scores (from median 3 [IQR 2\u0026ndash;4] to 3 [IQR 2\u0026ndash;5]), these changes did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.083 and p\u0026thinsp;=\u0026thinsp;0.157, respectively). These findings suggest that eSCS combined with physical therapy contributes to meaningful neurological recovery and symptom relief in patients six months post-surgery (\u003cb\u003eSupplement Material eFig1 and eTable.2\u003c/b\u003e,).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eIntraoperative Electrophysiological Monitoring and Personalized eSCS Parameter Optimization\u003c/h2\u003e \u003cp\u003eIntraoperative electrophysiological testing served as the cornerstone for precise lead placement verification and individualized parameter configuration, providing objective neurophysiological benchmarks for postoperative programming (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Representative intraoperative threshold-triggered electromyography (EMG) waveforms recorded from bilateral quadriceps and tibialis anterior muscles. Motor response was elicited at a stimulation threshold of 0.98 \u0026micro;V (rA: 3.0%), establishing the foundational reference point for subsequent parameter titration. Concurrent measurements of optimal stimulation latency (0.8 ms) and response latency (0.7 ms) further refined the temporal precision of stimulation delivery (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cb\u003eA\u003c/b\u003e). The parameter-specific physiological responses observed under different stimulation paradigms. Under high-frequency stimulation (80 Hz;), a clear dose-response relationship emerged between stimulation intensity and sensory perception: at 0.5 mA with 100 \u0026micro;s pulse width, patients reported a composite sensation of light touch plus pinprick; at 0.2 mA with 50 \u0026micro;s pulse width, a nociceptive sensation was elicited; whereas subthreshold parameters (\u0026lt;\u0026thinsp;0.1 mA, 60 \u0026micro;s) produced only background sensory effects (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cb\u003eB\u003c/b\u003e). Conversely, low-frequency stimulation (40 Hz; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cb\u003eB\u003c/b\u003e) elicited distinct motor-oriented responses: parameters of 0.1 mA with 60 \u0026micro;s pulse width generated background sensory effects; 0.5 mA with 100 \u0026micro;s pulse width effectively recruited motor units and enhanced muscle force; while a specific combination (0.1 mA, 60 \u0026micro;s, 80 Hz) concurrently improved both muscle strength and reduced hypertonia. These findings indicate that low-frequency paradigms are preferentially suited for motor function facilitation, whereas high-frequency stimulation demonstrates superior efficacy in suppressing pathological hypertonia. Guided by these intraoperative electrophysiological profiles, we implemented a dual-mode, adaptive eSCS programming protocol for each patient. Individuals presenting with severe hypertonia initially received high-frequency stimulation (1.2 kHz, 0.5 mA, 100 \u0026micro;s) to suppress maladaptive afferent signaling. Once hypertonia was reduced to clinically acceptable levels, low-frequency stimulation (30\u0026ndash;60 Hz, 0.5 mA, 100 \u0026micro;s) was gradually introduced to promote motor recovery. This sequential dual-mode approach enabled simultaneous spasticity control and functional restoration, circumventing the exacerbation of spasticity frequently observed with conventional monophasic stimulation protocols. Notably, monthly EMG-guided re-evaluation of motor thresholds informed iterative adjustments of active electrode contacts, ensuring stimulation parameters remained synchronized with evolving neuroplastic changes. This dynamic optimization strategy substantially enhanced treatment durability, with 80% of patients achieving clinically meaningful improvement within six months of implantation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eComparative Functional Recovery Outcomes Between eSCS and Non-eSCS Groups\u003c/h2\u003e \u003cp\u003eTo visualize spatial and temporal recovery patterns, we integrated anatomical strength maps with functional heatmaps \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e \u003cb\u003eand Supplement Material eFig2,3\u003c/b\u003e). The anatomical visualization (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e) illustrates sequential strength changes across lower extremity muscle groups from preoperative baseline to Day 180, with color intensity representing strength improvement (scale 0 to +\u0026thinsp;2). In the eSCS group, this map reveals progressive reddening in key muscles such as the tibialis anterior (TA), rectus femoris (RF), and gastrocnemius medialis (GM), corroborating the quantitative score improvements from 3\u0026ndash;4 to 5 observed in the heatmaps (\u003cb\u003eSupplement Material eFig2,3\u003c/b\u003e). These improvements were most pronounced between Days 60\u0026ndash;180, suggesting that the therapeutic benefits of eSCS continue to accumulate over time. In contrast, the non-eSCS group demonstrated more limited functional recovery. While some initial improvements were observed in the first 60 days, many muscle groups plateaued or showed minimal further gains thereafter. The right quadriceps femoris (QF) initially improved from 4 to 5 but subsequently declined to 4 by Day 180. Notably, several critical muscle groups including the right tibialis anterior (TA) and extensor hallucis longus (EHL) showed no meaningful improvement beyond baseline scores, remaining at 3\u0026ndash;4 throughout the 6-month observation period. The left side muscle groups, particularly the extensor hallucis longus (EHL) and gastrocnemius medialis (GM), demonstrated minimal functional recovery, with scores remaining at 1\u0026ndash;2 throughout the entire follow-up period. The most striking difference between the two groups was observed in the functional recovery of the ankle dorsiflexors (TA and EHL), with the eSCS group achieving near-normal function (scores of 5) in these critical muscle groups by 180 days, while the non-eSCS group remained significantly impaired (scores of 1\u0026ndash;3). This differential recovery pattern underscores the therapeutic advantage of eSCS in promoting functional reorganization of spinal circuits, particularly for muscles essential to gait initiation and maintenance. These findings corroborate our earlier clinical observations that eSCS combined with physical therapy produces significantly greater improvements in sensory function (93.3% positive response rate), muscle spasticity control (73.3%), and pain reduction (60.0%) compared to physical therapy alone, with effects becoming more pronounced over time.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLong-term Functional Outcomes Following eSCS Combined with Physical Therapy\u003c/h2\u003e \u003cp\u003eThe ASIA sensory score demonstrated progressive improvement from baseline (168) to the 6-month evaluation (186), indicating enhanced sensory function following the intervention. The Modified Ashworth Scale scores showed substantial reduction from 20 preoperatively to 10 by day 15, with sustained improvement through the 180-day assessment, suggesting significant and persistent alleviation of spasticity. Similarly, pain levels as measured by the Visual Analog Scale exhibited a gradual decline from baseline (20) to complete resolution (0) at the 6-month follow-up. The ASIA motor score remained stable at 60 throughout the observation period, while urinary and bowel function scores showed no significant changes during the follow-up period. These findings collectively demonstrate that eSCS combined with physical therapy produces sustained improvements in sensory function, spasticity, and pain management, with effects becoming more pronounced over the 6-month follow-up period, while maintaining stable motor and autonomic functions. The temporal pattern of improvement\u0026mdash;particularly the rapid reduction in spasticity followed by progressive sensory recovery\u0026mdash;provides valuable insights into the therapeutic mechanisms of neuromodulation in spinal cord injury rehabilitation (\u003cb\u003eSupplement Material eFig4\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eCase Illustration of Cervical Spinal Cord Stimulation Implantation\u003c/h2\u003e \u003cp\u003eThe preoperative sagittal T2-weighted MRI revealing the extent of cervical cord injury at the C3-C4 level, which served as the anatomical reference for targeted electrode placement (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Intraoperative visualization in C confirms successful placement of the 16-contact paddle electrode array (PINS Medical) within the dorsal epidural space at the C3-C4 level, with careful positioning 1 mm lateral to the midline under direct visualization. The electrode was secured using the A6218C titanium anchor system to ensure stability during postoperative stimulation. Panels D and E provide postoperative fluoroscopic confirmation of accurate electrode positioning. Panel D shows the anteroposterior fluoroscopic view with the electrode array precisely aligned along the cervical spinal column, while Panel E presents the lateral fluoroscopic view with a grid overlay confirming optimal dorsoventral positioning relative to the spinal canal. The radiographic verification demonstrates stable electrode positioning without migration or displacement, confirming successful implementation of our lesion-proximal electrode placement strategy. This representative case exemplifies our approach of performing eSCS implantation during the initial decompression surgery, eliminating the need for a separate surgical procedure. The precise electrode placement adjacent to the injury epicenter enabled effective delivery of dual-mode stimulation parameters (1.2 kHz for spasticity management and 30\u0026ndash;60 Hz for motor facilitation), which contributed to the patient's significant functional improvements, including 72% reduction in spasticity and complete resolution of neuropathic pain within six months of implantation. This case illustrates the technical feasibility and clinical benefits of integrating eSCS implantation with initial spinal cord injury management.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eClinical manifestations of functional recovery following spinal cord stimulation implantation\u003c/h2\u003e \u003cp\u003eRepresentative clinical improvements in somatosensory and motor functions observed in five patients following successful eSCS implantation and subsequent neuromodulation therapy \u003cb\u003e(Supplement Material eFig5)\u003c/b\u003e. Panel a demonstrates remarkable restoration of proprioceptive function in a female with chronic cervical SCI (C2-6, AIS C), as evidenced by his ability to accurately identify joint position changes in lower extremities without visual feedback, a capability absent prior to eSCS intervention. Panels b-e display progressive recovery of voluntary motor control in four distinct patients with varying injury levels and durations. Patient in panel b and c achieved independent knee extension against gravity within two weeks of initiating combined high-frequency and low-frequency stimulation protocols. The patient in panel d and e exhibited marked enhancement in hip flexor strength, facilitating controlled stair climbing with minimal upper extremity support, who regained sufficient plantarflexor strength to achieve push-off during terminal stance phase of gait. These representative cases collectively demonstrate that targeted epidural stimulation, particularly when employing the dual-mode protocol combining high-frequency stimulation for spasticity management and low-frequency stimulation for motor facilitation, can elicit significant improvements in both sensory perception and voluntary motor control across diverse SCI presentations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe conventional paradigm of restricting eSCS electrode placement to cervical and lumbar enlargements has dominated the field for nearly three decades\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. The pioneering studies by Harkema's group established that epidural stimulation of the lumbosacral enlargement could facilitate weight-bearing standing and stepping in individuals with motor-complete SCI when combined with intensive rehabilitation\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e. Subsequent work by Angeli et al. and Gill et al. further validated this approach, demonstrating restoration of voluntary movement below the injury level through careful parameter optimization at the lumbar enlargement\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e. The efficacy of distal stimulation diminishes significantly with increasing distance from the injury site, particularly in individuals with mid-thoracic injuries where signal propagation across multiple spinal segments becomes increasingly inefficient\u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e. The one-size-fits-all approach to electrode placement fails to account for the significant heterogeneity in injury patterns, sparing, and functional priorities among individuals with SCI.\u003c/p\u003e \u003cp\u003eThis study demonstrates that eeSCS, particularly when implemented through a dual-mode protocol combining HF-eSCS for spasticity management and LF-eSCS for motor facilitation, produces substantial improvements in multiple functional domains for patients with spinal cord injury. Our results align with and extend the groundbreaking work by Romeni et al.\u003csup\u003e58\u003c/sup\u003e, confirming that targeted neuromodulation can effectively address pyramidal signs while simultaneously enhancing voluntary motor control. The most pronounced improvements were observed in sensory function (93.3% positive response rate), muscle spasticity control (73.3%), and pain reduction (60.0%) during the short-term evaluation. Longitudinal assessment over six months revealed persistent therapeutic effects, with significant improvements in ASIA sensory scores (159 to 183 points, p\u0026thinsp;=\u0026thinsp;0.001), motor function (p\u0026thinsp;=\u0026thinsp;0.016), spasticity reduction (Modified Ashworth Scale 20 to 10 points, p\u0026thinsp;=\u0026thinsp;0.003), and complete resolution of neuropathic pain (Visual Analog Scale 20 to 0 points, p\u0026thinsp;=\u0026thinsp;0.039). These findings collectively demonstrate that eSCS represents a transformative therapeutic approach for SCI rehabilitation, particularly when integrated with intensive physical therapy protocols.\u003c/p\u003e \u003cp\u003eThe therapeutic mechanisms underlying eSCS efficacy in our cohort appear multifaceted. The rapid reduction in spasticity observed within days of implantation supports the hypothesis that HF-eSCS functions primarily through kilohertz-frequency neural blockade of pathological proprioceptive afferents\u0026mdash;a mechanism first systematically characterized by Romeni et al\u003csup\u003e58\u003c/sup\u003e. Our implementation of dynamic electrode reconfiguration based on intraoperative H-reflex recovery cycle mapping represents a significant technical innovation over the fixed-contact approach used in previous studies, potentially explaining the enhanced efficiency of spasticity suppression observed in our cohort. The progressive improvement in sensory function over the six-month period suggests additional mechanisms involving activity-dependent neuroplasticity and circuit reorganization, consistent with Edgerton's seminal work on spinal learning\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur lesion-proximal electrode placement strategy directly addresses these limitations by positioning stimulation electrodes adjacent to the primary pathology rather than defaulting to anatomically predetermined regions. This approach leverages emerging evidence that the injured spinal segment retains significant neural processing capability and that targeted modulation of this region can simultaneously address multiple pathological processes. The successful implementation of this strategy across diverse spinal levels in our cohort demonstrates its technical feasibility and clinical potential.\u003c/p\u003e \u003cp\u003eCompared to conventional rehabilitation approaches, our dual-mode eSCS protocol yielded substantially superior outcomes in sensory recovery, pain management, and spasticity control. Notably, the 24-point improvement in ASIA sensory scores exceeds gains typically reported in intensive rehabilitation studies without neuromodulation (typically 8\u0026ndash;12 points over similar timeframes)\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e. The complete resolution of neuropathic pain in our cohort is particularly significant given the limited efficacy of pharmacological interventions in this population, with conventional analgesics achieving only 30\u0026ndash;50% pain reduction in most clinical trials while introducing substantial side effect burdens\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe differential response across functional domains provides critical insights for clinical implementation. The minimal improvement in bowel function despite significant gains in sensory and motor domains suggests autonomic pathways may require distinct stimulation parameters or longer treatment durations. This finding aligns with emerging evidence from Henderson et al. that specific spinal segments must be selectively targeted based on desired functional outcomes: T9-T11 for pulmonary functions, T11-L1 for volitional motor control, and L1-S1 for genitourinary functions\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePatient selection emerged as a critical determinant of therapeutic success. Our cohort demonstrated particularly robust responses in patients with incomplete injuries (AIS C-D) who maintained some residual sensory pathways, supporting the hypothesis that eSCS functions by amplifying residual supraspinal inputs rather than generating wholly new motor outputs. This aligns precisely with the mechanistic framework established by Courtine and Bloch, who demonstrated that spared but functionally dormant descending pathways serve as the substrate for eSCS-mediated functional recovery\u003csup\u003e\u003cspan additionalcitationids=\"CR79 CR80 CR81\" citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e. For patients with complete injuries (AIS A), improvements were more limited and predominantly restricted to spasticity management and pain reduction.\u003c/p\u003e \u003cp\u003eOur implementation of closed-loop parameter adjustment guided by real-time EMG patterns represents a significant advancement over conventional open-loop stimulation systems\u003csup\u003e\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e. By dynamically modulating stimulation parameters based on detected muscle coordination patterns during gait cycles, we achieved more physiologic movement patterns and reduced antagonist co-contraction. This approach addresses a fundamental limitation of conventional eSCS protocols: the exacerbation of spasticity during movement facilitation\u003csup\u003e\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u003c/sup\u003e. The monthly adjustment of electrode contacts based on EMG-guided thresholds further enhanced therapeutic efficiency, particularly for managing spasticity \"hotspots\" that shifted over time\u0026mdash;a phenomenon not previously documented in the literature.\u003c/p\u003e \u003cp\u003eThe positional dependence of stimulation parameters we observed\u0026mdash;requiring different settings for supine, sitting, standing, and ambulatory positions\u0026mdash;corroborates findings from Wagner et al. and Rowald et al. that spinal cord position within the dural sac fundamentally alters the distance between electrodes and targeted neural structures\u003csup\u003e\u003cspan additionalcitationids=\"CR86 CR87\" citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e\u003c/sup\u003e. This biomechanical reality necessitates individualized parameter optimization for each functional position, explaining why standardized stimulation protocols often fail to produce consistent results across patients.\u003c/p\u003e \u003cp\u003eThe favorable safety profile of our eSCS implementation is particularly noteworthy. With only minor adverse events reported (primarily transient skin irritation), our approach demonstrates significantly fewer complications than previously documented in large case series\u003csup\u003e\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e\u003c/sup\u003e. The absence of serious adverse events such as lead migration, infection, or neurological deterioration over the six-month follow-up period suggests that contemporary surgical techniques and improved hardware design have substantially mitigated historical safety concerns\u003csup\u003e\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e\u003c/sup\u003e. This safety advantage, coupled with the demonstrated efficacy, positions eSCS as a compelling therapeutic option compared to pharmacological alternatives that often introduce systemic side effects, or invasive surgical interventions like selective dorsal rhizotomy that carry permanent morbidity risks.\u003c/p\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eLimitations and Future Directions\u003c/h2\u003e \u003cp\u003eSeveral limitations warrant acknowledgment. The relatively small sample size limits generalizability, particularly across different injury levels and severities. The lack of a dedicated control group for the long-term follow-up analysis makes it difficult to definitively attribute observed improvements to the neuromodulation intervention versus intensive rehabilitation alone. Additionally, the open-label design introduces potential bias in subjective outcome measures, though objective measures like ASIA scores and gait kinematics corroborate the clinical findings.\u003c/p\u003e \u003cp\u003eFuture research should prioritize several critical questions. First, systematic dose-response studies are needed to identify optimal stimulation parameters for specific functional outcomes and patient subpopulations. Second, comparative effectiveness trials directly evaluating different electrode configurations (percutaneous versus paddle leads) would clarify hardware selection criteria. Third, the integration of advanced imaging techniques (such as diffusion tensor imaging) could provide biomarkers for predicting treatment response and personalizing electrode placement. Finally, the development of truly closed-loop systems that respond to real-time physiological signals\u0026mdash;not just pre-programmed movement patterns\u0026mdash;represents the next frontier in neuromodulation technology.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides robust evidence that personalized epidural spinal cord stimulation, particularly when implemented through a dual-mode protocol combining high-frequency and low-frequency stimulation parameters, produces significant and clinically meaningful improvements in multiple functional domains for patients with spinal cord injury. The integration of advanced surgical techniques, individualized parameter optimization, and intensive rehabilitation protocols creates a synergistic therapeutic effect that substantially exceeds outcomes achievable through conventional rehabilitation approaches alone. While significant questions remain regarding optimal patient selection, parameter configuration, and long-term maintenance of therapeutic gains, our findings confirm that neuromodulation represents a paradigm shift in SCI rehabilitation\u0026mdash;transitioning from compensatory strategies toward genuine functional restoration. The field now stands at an inflection point where technological advances in electrode design, closed-loop control algorithms, and computational modeling converge to create unprecedented opportunities for recovery after previously untreatable neurological injuries.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Key R\u0026amp;D Program of the Xinjiang Uygur Autonomous Region (\u003cstrong\u003eNo.2025B03015/2025B03015-1)\u003c/strong\u003e; Key Project of the Xinjiang Uygur Autonomous Region (\u003cstrong\u003eNo. 2025D01D36\u003c/strong\u003e); Xinjiang Uygur Autonomous Region Leading Talent Project (\u003cstrong\u003eNo.2023TSYCLJ0030\u003c/strong\u003e); State Key Laboratory Co-constructed by Ministry and Province-Open Project of the State Key Laboratory of High (\u003cstrong\u003eNo.SKL-HIDCA-2022-NKX2\u003c/strong\u003e); International Joint Laboratory for Prevention and Control of Major Diseases in Central Asia (\u003cstrong\u003eNo.JIRL-MDCA-2024-GH2\u003c/strong\u003e); Health Commission of Xinjiang Uygur Autonomous Region-Science and Technology Plan Project of the Autonomous Region Health Commission (\u003cstrong\u003eNo.2025001ZYWGHZSYTSTGXM650023294\u003c/strong\u003e); Science Fund for Distinguished Young Scholars of Xinjiang Autonomous Region (\u003cstrong\u003eNo. 2025D01E37\u003c/strong\u003e); Science and Technology Support Xinjiang Program of the Autonomous Region (\u003cstrong\u003eNo. 2024E02064\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eY.D.F\u003c/strong\u003e. and \u003cstrong\u003eM.N\u003c/strong\u003e. contributed equally as \u003cstrong\u003eco-first authors\u003c/strong\u003e: conceptualization, study design, methodology, patient recruitment, surgical procedures, data curation, formal analysis, investigation, visualization, and writing the original draft. \u003cstrong\u003eM.L.Z\u003c/strong\u003e. and \u003cstrong\u003eH.F.G\u003c/strong\u003e. contributed equally as \u003cstrong\u003eco-first authors\u003c/strong\u003e: methodology, data acquisition, electrophysiological monitoring, statistical analysis, data interpretation, visualization, and writing the original draft. \u003cstrong\u003eK.L.\u003c/strong\u003e: conceptualization, supervision, validation, funding acquisition, project administration, resources, and writing-review \u0026amp; editing (\u003cstrong\u003ecorresponding author\u003c/strong\u003e). \u003cstrong\u003eL.R.\u003c/strong\u003e: experimental design, electrophysiological measurements, data analysis, and technical support. \u003cstrong\u003eY.A\u003c/strong\u003e.: clinical assessment, patient follow-up, surgical procedures, and radiographic verification. \u003cstrong\u003eM.M.\u003c/strong\u003e: patient recruitment, clinical assessment, rehabilitation protocol implementation, and data collection. \u003cstrong\u003eA.A.\u003c/strong\u003e: electrophysiological monitoring, statistical analysis, clinical follow-up. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests related to this research.\u0026nbsp;None of the authors have financial interests, consultancy agreements, or other relationships with PINS Medical or other companies manufacturing spinal cord stimulation devices that could potentially influence the research findings or interpretation of data presented in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and materials availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to privacy and confidentiality restrictions from the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Medical Ethics Committee of The First Affiliated Hospital of Xinjiang Medical University (ethics approval number: \u003cstrong\u003eK202509-03\u003c/strong\u003e). All study procedures adhered to the principles of the Declaration of Helsinki.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhuo M, Deng Z, Yuan L, Mai Z, Zhong M, Ye J. Association of systemic inflammatory response index and clinical outcome in acute traumatic spinal cord injury patients. \u003cem\u003eSci Rep-Uk\u003c/em\u003e 2024;14(1):19085.doi: 10.1038/s41598-024-69699-4.PubMed: 39154138\u003c/li\u003e\n\u003cli\u003eBlex C, Kreutztr\u0026auml;ger M, Ludwig J, et al. Baseline predictors of in-hospital mortality after acute traumatic spinal cord injury: data from a level I trauma center. \u003cem\u003eSci Rep-Uk\u003c/em\u003e 2022;12(1):11420.doi: 10.1038/s41598-022-15469-z.PubMed: 35794189\u003c/li\u003e\n\u003cli\u003eSchwendner M, Kanaris M, DiGiorgio AM, Huang MC, Manley GT, Tarapore PE. Diagnostic and prognostic value of navigated transcranial magnetic stimulation to assess motor function in patients with acute traumatic spinal cord injury. \u003cem\u003eBrain \u0026amp; Spine\u003c/em\u003e 2025;5:104229.doi: 10.1016/j.bas.2025.104229.PubMed: 40165994\u003c/li\u003e\n\u003cli\u003eAzad TD, Ran KR, Materi JD, et al. A multi-analyte blood test for acute spinal cord injury. \u003cem\u003eThe Journal of Clinical Investigation\u003c/em\u003e 2025;135(5):e185463.doi: 10.1172/JCI185463.PubMed: 40026254\u003c/li\u003e\n\u003cli\u003eWitiw CD, Fehlings MG. Acute Spinal Cord Injury. \u003cem\u003eJournal of Spinal Disorders \u0026amp; Techniques\u003c/em\u003e 2015;28(6):202-210.doi: 10.1097/BSD.0000000000000287.PubMed: 26098670\u003c/li\u003e\n\u003cli\u003eLu Y, Shang Z, Zhang W, et al. Global, regional, and national burden of spinal cord injury from 1990 to 2021 and projections for 2050: A systematic analysis for the Global Burden of Disease 2021 study. \u003cem\u003eAgeing Res Rev\u003c/em\u003e 2025;103:102598.doi: 10.1016/j.arr.2024.102598.PubMed: 39603465\u003c/li\u003e\n\u003cli\u003eKim M, Jeong W, Jang S, Park JH, Bae Y, Lee SW. Spinal Cord Injury Epidemiology and Causes: A Worldwide Analysis with 2050 Projections. \u003cem\u003eHealthcare (Basel, Switzerland)\u003c/em\u003e 2025;13(20):2552.doi: 10.3390/healthcare13202552.PubMed: 41154231\u003c/li\u003e\n\u003cli\u003eWong S, Kenssous N, Hillier C, et al. Detecting malnutrition risk and obesity after spinal cord injury: a quality improvement project and systematic review. \u003cem\u003eEur J Clin Nutr\u003c/em\u003e 2018;72(11):1555-1560.doi: 10.1038/s41430-018-0194-y.PubMed: 29849183\u003c/li\u003e\n\u003cli\u003eFarkas GJ, Sneij A, Gater DRJ. Dietetics After Spinal Cord Injury: Current Evidence and Future Perspectives. \u003cem\u003eTop Spinal Cord Inj\u003c/em\u003e 2021;27(1):100-108.doi: 10.46292/sci20-00031.PubMed: 33814888\u003c/li\u003e\n\u003cli\u003eChandrasekaran S, Davis J, Bersch I, Goldberg G, Gorgey AS. Electrical stimulation and denervated muscles after spinal cord injury. \u003cem\u003eNeural Regen Res\u003c/em\u003e 2020;15(8):1397-1407.doi: 10.4103/1673-5374.274326.PubMed: 31997798\u003c/li\u003e\n\u003cli\u003eIslam MA, Pulverenti TS, Knikou M. Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury. \u003cem\u003eFront Hum Neurosci\u003c/em\u003e 2021;15:620414.doi: 10.3389/fnhum.2021.620414.PubMed: 33679347\u003c/li\u003e\n\u003cli\u003eEdgerton VR, Courtine G, Gerasimenko YP, et al. Training locomotor networks. \u003cem\u003eBrain Research Reviews\u003c/em\u003e 2008;57(1):241-254.doi: 10.1016/j.brainresrev.2007.09.002.PubMed: 18022244\u003c/li\u003e\n\u003cli\u003eJo HJ, Perez MA. Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury. \u003cem\u003eBrain : A Journal of Neurology\u003c/em\u003e 2020;143(5):1368-1382.doi: 10.1093/brain/awaa052.PubMed: 32355959\u003c/li\u003e\n\u003cli\u003eGouveia D, Cardoso A, Carvalho C, et al. Approach to Small Animal Neurorehabilitation by Locomotor Training: An Update. \u003cem\u003eAnimals : An Open Access Journal From MDPI\u003c/em\u003e 2022;12(24):3582.doi: 10.3390/ani12243582.PubMed: 36552502\u003c/li\u003e\n\u003cli\u003eBarbeau H, Norman K, Fung J, Visintin M, Ladouceur M. Does neurorehabilitation play a role in the recovery of walking in neurological populations? \u003cem\u003eAnn Ny Acad Sci\u003c/em\u003e 1998;860:377-392.doi: 10.1111/j.1749-6632.1998.tb09063.x.PubMed: 9928326\u003c/li\u003e\n\u003cli\u003eGouveia D, Cardoso A, Carvalho C, et al. Early Intensive Neurorehabilitation in Traumatic Peripheral Nerve Injury-State of the Art. \u003cem\u003eAnimals : An Open Access Journal From MDPI\u003c/em\u003e 2024;14(6):884.doi: 10.3390/ani14060884.PubMed: 38539981\u003c/li\u003e\n\u003cli\u003eMartins \u0026Acirc;, Gouveia D, Cardoso A, et al. Functional Neurorehabilitation in Dogs with an Incomplete Recovery 3 Months following Intervertebral Disc Surgery: A Case Series. \u003cem\u003eAnimals : An Open Access Journal From MDPI\u003c/em\u003e 2021;11(8):2442.doi: 10.3390/ani11082442.PubMed: 34438900\u003c/li\u003e\n\u003cli\u003eGouveia D, Correia J, Cardoso A, et al. Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy. \u003cem\u003eFront Vet Sci\u003c/em\u003e 2023;10:1192744.doi: 10.3389/fvets.2023.1192744.PubMed: 37520009\u003c/li\u003e\n\u003cli\u003eBarbeau H. Locomotor training in neurorehabilitation: emerging rehabilitation concepts. \u003cem\u003eNeurorehab Neural Re\u003c/em\u003e 2003;17(1):3-11.doi: 10.1177/0888439002250442.PubMed: 12645440\u003c/li\u003e\n\u003cli\u003eCuomo G, Maglianella V, Ghanbari Ghooshchy S, et al. Motor imagery and gait control in Parkinson\u0026apos;s disease: techniques and new perspectives in neurorehabilitation. \u003cem\u003eExpert Rev Neurother\u003c/em\u003e 2022;22(1):43-51.doi: 10.1080/14737175.2022.2018301.PubMed: 34906019\u003c/li\u003e\n\u003cli\u003evan den Brand R, Mignardot J, von Zitzewitz J, et al. Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury. \u003cem\u003eAnn Phys Rehabil Med\u003c/em\u003e 2015;58(4):232-237.doi: 10.1016/j.rehab.2015.04.003.PubMed: 26100230\u003c/li\u003e\n\u003cli\u003eHubli M, Dietz V. The physiological basis of neurorehabilitation--locomotor training after spinal cord injury. \u003cem\u003eJ Neuroeng Rehabil\u003c/em\u003e 2013;10:5.doi: 10.1186/1743-0003-10-5.PubMed: 23336934\u003c/li\u003e\n\u003cli\u003eMartins \u0026Acirc;, Gouveia D, Cardoso A, et al. A Controlled Clinical Study of Intensive Neurorehabilitation in Post-Surgical Dogs with Severe Acute Intervertebral Disc Extrusion. \u003cem\u003eAnimals : An Open Access Journal From MDPI\u003c/em\u003e 2021;11(11):3034.doi: 10.3390/ani11113034.PubMed: 34827767\u003c/li\u003e\n\u003cli\u003eKoenig A, Luft A, Cajigas I. Guest editorial: From neuroscience to neuro-rehabilitation: transferring basic neuroscientific principles from laboratory to bedside. \u003cem\u003eJ Neuroeng Rehabil\u003c/em\u003e 2013;10:6.doi: 10.1186/1743-0003-10-6.PubMed: 23336967\u003c/li\u003e\n\u003cli\u003eColovic H, Nikolic D, Zlatanovic D, et al. Influence of Robotic Neurorehabilitation in Cerebral Palsy on Motor Function and Gait. \u003cem\u003eChildren (Basel, Switzerland)\u003c/em\u003e 2025;12(2):190.doi: 10.3390/children12020190.PubMed: 40003292\u003c/li\u003e\n\u003cli\u003eChoong ZJ, Huo D, Ponon N, Savidis R, Degenaar P, O\u0026apos;Neill A. A novel hybrid technique to fabricate silicon-based micro-implants with near defect-free quality for neuroprosthetics application. \u003cem\u003eMaterials Science \u0026amp; Engineering. C, Materials for Biological Applications\u003c/em\u003e 2020;110:110737.doi: 10.1016/j.msec.2020.110737.PubMed: 32204046\u003c/li\u003e\n\u003cli\u003eKoelewijn AD, Audu M, Del-Ama AJ, et al. Adaptation Strategies for Personalized Gait Neuroprosthetics. \u003cem\u003eFront Neurorobotics\u003c/em\u003e 2021;15:750519.doi: 10.3389/fnbot.2021.750519.PubMed: 34975445\u003c/li\u003e\n\u003cli\u003eSun SY, Giszter SF, Harkema SJ, Angeli CA. Modular organization of locomotor networks in people with severe spinal cord injury. \u003cem\u003eFront Neurosci-Switz\u003c/em\u003e 2022;16:1041015.doi: 10.3389/fnins.2022.1041015.PubMed: 36570830\u003c/li\u003e\n\u003cli\u003eIslam MA, Pulverenti TS, Knikou M. Neuronal Actions of Transspinal Stimulation on Locomotor Networks and Reflex Excitability During Walking in Humans With and Without Spinal Cord Injury. \u003cem\u003eFront Hum Neurosci\u003c/em\u003e 2021;15:620414.doi: 10.3389/fnhum.2021.620414.PubMed: 33679347\u003c/li\u003e\n\u003cli\u003eEdgerton VR, Courtine G, Gerasimenko YP, et al. Training locomotor networks. \u003cem\u003eBrain Research Reviews\u003c/em\u003e 2008;57(1):241-254.doi: 10.1016/j.brainresrev.2007.09.002.PubMed: 18022244\u003c/li\u003e\n\u003cli\u003eField-Fote EC, Roach KE. Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: a randomized clinical trial. \u003cem\u003ePhysical Therapy\u003c/em\u003e 2011;91(1):48-60.doi: 10.2522/ptj.20090359.PubMed: 21051593\u003c/li\u003e\n\u003cli\u003eMinassian K, McKay WB, Binder H, Hofstoetter US. Targeting Lumbar Spinal Neural Circuitry by Epidural Stimulation to Restore Motor Function After Spinal Cord Injury. \u003cem\u003eNeurotherapeutics : The Journal of the American Society for Experimental NeuroTherapeutics\u003c/em\u003e 2016;13(2):284-294.doi: 10.1007/s13311-016-0421-y.PubMed: 26843089\u003c/li\u003e\n\u003cli\u003eAngeli CA, Boakye M, Morton RA, et al. Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. \u003cem\u003eThe New England Journal of Medicine\u003c/em\u003e 2018;379(13):1244-1250.doi: 10.1056/NEJMoa1803588.PubMed: 30247091\u003c/li\u003e\n\u003cli\u003eGill ML, Grahn PJ, Calvert JS, et al. Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia. \u003cem\u003eNat Med\u003c/em\u003e 2018;24(11):1677-1682.doi: 10.1038/s41591-018-0175-7.PubMed: 30250140\u003c/li\u003e\n\u003cli\u003eWagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. \u003cem\u003eNature\u003c/em\u003e 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197\u003c/li\u003e\n\u003cli\u003eAngeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. \u003cem\u003eBrain : A Journal of Neurology\u003c/em\u003e 2014;137(Pt 5):1394-1409.doi: 10.1093/brain/awu038.PubMed: 24713270\u003c/li\u003e\n\u003cli\u003eDanner SM, Hofstoetter US, Freundl B, et al. Human spinal locomotor control is based on flexibly organized burst generators. \u003cem\u003eBrain : A Journal of Neurology\u003c/em\u003e 2015;138(Pt 3):577-588.doi: 10.1093/brain/awu372.PubMed: 25582580\u003c/li\u003e\n\u003cli\u003eCapogrosso M, Wenger N, Raspopovic S, et al. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. \u003cem\u003eThe Journal of Neuroscience : The Official Journal of the Society for Neuroscience\u003c/em\u003e 2013;33(49):19326-19340.doi: 10.1523/JNEUROSCI.1688-13.2013.PubMed: 24305828\u003c/li\u003e\n\u003cli\u003eCapogrosso M, Balaguer J, Prat-Ortega G, et al. Supraspinal control of motoneurons after paralysis enabled by spinal cord stimulation. \u003cem\u003eResearch Square\u003c/em\u003e 2024:rs.3.rs-3650257.doi: 10.21203/rs.3.rs-3650257/v1.PubMed: 38260333\u003c/li\u003e\n\u003cli\u003eDionne A, Mac-Thiong J, Alsofyani MA, Richard-Denis A. Are early-onset spasms predictive of poor neurological recovery after traumatic spinal cord injury? \u003cem\u003eThe Journal of Spinal Cord Medicine\u003c/em\u003e 2024;47(4):566-572.doi: 10.1080/10790268.2022.2150068.PubMed: 36622323\u003c/li\u003e\n\u003cli\u003eVeerakumar A, Cheng JJ, Sunshine A, Ye X, Zorowitz RD, Anderson WS. Baclofen dosage after traumatic spinal cord injury: a multi-decade retrospective analysis. \u003cem\u003eClin Neurol Neurosur\u003c/em\u003e 2015;129:50-56.doi: 10.1016/j.clineuro.2014.11.023.PubMed: 25532135\u003c/li\u003e\n\u003cli\u003eErden E. Evaluation of Clinical Characteristics and Comorbid Conditions in Pediatric Traumatic Spinal Cord Injury Patients. \u003cem\u003eCureus J Med Science\u003c/em\u003e 2023;15(9):e44512.doi: 10.7759/cureus.44512.PubMed: 37790003\u003c/li\u003e\n\u003cli\u003eGuest J, Datta N, Jimsheleishvili G, Gater DRJ. Pathophysiology, Classification and Comorbidities after Traumatic Spinal Cord Injury. \u003cem\u003eJ Pers Med\u003c/em\u003e 2022;12(7):1126.doi: 10.3390/jpm12071126.PubMed: 35887623\u003c/li\u003e\n\u003cli\u003eSk\u0026ouml;ld C, Levi R, Seiger A. Spasticity after traumatic spinal cord injury: nature, severity, and location. \u003cem\u003eArch Phys Med Rehab\u003c/em\u003e 1999;80(12):1548-1557.doi: 10.1016/s0003-9993(99)90329-5.PubMed: 10597805\u003c/li\u003e\n\u003cli\u003eHarkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. \u003cem\u003eLancet (London, England)\u003c/em\u003e 2011;377(9781):1938-1947.doi: 10.1016/S0140-6736(11)60547-3.PubMed: 21601270\u003c/li\u003e\n\u003cli\u003eAngeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. \u003cem\u003eBrain : A Journal of Neurology\u003c/em\u003e 2014;137(Pt 5):1394-1409.doi: 10.1093/brain/awu038.PubMed: 24713270\u003c/li\u003e\n\u003cli\u003eWagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. \u003cem\u003eNature\u003c/em\u003e 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197\u003c/li\u003e\n\u003cli\u003eRowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. \u003cem\u003eNat Med\u003c/em\u003e 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264\u003c/li\u003e\n\u003cli\u003eBorowski A, Littleton AG, Borkhuu B, et al. Complications of intrathecal baclofen pump therapy in pediatric patients. \u003cem\u003eJournal of Pediatric Orthopedics\u003c/em\u003e 2010;30(1):76-81.doi: 10.1097/BPO.0b013e3181c6b257.PubMed: 20032747\u003c/li\u003e\n\u003cli\u003eQureshi AZ, Shacfe H, Ilyas A, et al. Complications of Intrathecal Baclofen Pump Therapy: An Institutional Experience from Saudi Arabia. \u003cem\u003eHealthcare (Basel, Switzerland)\u003c/em\u003e 2023;11(21):2820.doi: 10.3390/healthcare11212820.PubMed: 37957965\u003c/li\u003e\n\u003cli\u003eTabard-Foug\u0026egrave;re A, Canavese F, Steiger CN, De Coulon G. Complications of intrathecal baclofen pump treatment in children with spastic cerebral palsy. A comparative analysis of patients weighing over or under 20\u0026thinsp;kg at the time of implantation. \u003cem\u003eJournal of Pediatric Orthopedics. Part B\u003c/em\u003e 2022;31(2):202-207.doi: 10.1097/BPB.0000000000000848.PubMed: 33448748\u003c/li\u003e\n\u003cli\u003eKaye AD, Cheon SY, Roque MH, et al. Efficacy, Indications, and Safety of Intrathecal Baclofen Pump: A Narrative Review. \u003cem\u003eCurr Pain Headache R\u003c/em\u003e 2025;29(1):9.doi: 10.1007/s11916-024-01310-x.PubMed: 39754631\u003c/li\u003e\n\u003cli\u003eHoltz KA, Lipson R, Noonan VK, Kwon BK, Mills PB. Prevalence and Effect of Problematic Spasticity After Traumatic Spinal Cord Injury. \u003cem\u003eArch Phys Med Rehab\u003c/em\u003e 2017;98(6):1132-1138.doi: 10.1016/j.apmr.2016.09.124.PubMed: 27780743\u003c/li\u003e\n\u003cli\u003eTedroff K, H\u0026auml;gglund G, Miller F. Long-term effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review. \u003cem\u003eDev Med Child Neurol\u003c/em\u003e 2020;62(5):554-562.doi: 10.1111/dmcn.14320.PubMed: 31342516\u003c/li\u003e\n\u003cli\u003eGrunt S, Becher JG, Vermeulen RJ. Long-term outcome and adverse effects of selective dorsal rhizotomy in children with cerebral palsy: a systematic review. \u003cem\u003eDev Med Child Neurol\u003c/em\u003e 2011;53(6):490-498.doi: 10.1111/j.1469-8749.2011.03912.x.PubMed: 21518341\u003c/li\u003e\n\u003cli\u003eRowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. \u003cem\u003eNat Med\u003c/em\u003e 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264\u003c/li\u003e\n\u003cli\u003eWagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. \u003cem\u003eNature\u003c/em\u003e 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197\u003c/li\u003e\n\u003cli\u003eRomeni S, Losanno E, Emedoli D, et al. High-frequency epidural electrical stimulation reduces spasticity and facilitates walking recovery in patients with spinal cord injury. \u003cem\u003eSci Transl Med\u003c/em\u003e 2025;17(780):eadp9607.doi: 10.1126/scitranslmed.adp9607.PubMed: 39772775\u003c/li\u003e\n\u003cli\u003ePatel YA, Butera RJ. Challenges associated with nerve conduction block using kilohertz electrical stimulation. \u003cem\u003eJ Neural Eng\u003c/em\u003e 2018;15(3):031002.doi: 10.1088/1741-2552/aaadc0.PubMed: 29415877\u003c/li\u003e\n\u003cli\u003ePe\u0026ntilde;a E, Pelot NA, Grill WM. Quantitative comparisons of block thresholds and onset responses for charge-balanced kilohertz frequency waveforms. \u003cem\u003eJ Neural Eng\u003c/em\u003e 2020;17(4):046048.doi: 10.1088/1741-2552/abadb5.PubMed: 32777778\u003c/li\u003e\n\u003cli\u003ePe\u0026ntilde;a E, Pelot NA, Grill WM. Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance. \u003cem\u003eSci Rep-Uk\u003c/em\u003e 2021;11(1):5077.doi: 10.1038/s41598-021-84503-3.PubMed: 33658552\u003c/li\u003e\n\u003cli\u003eChodankar D, Bhatt A, Davis S. Declaration of Helsinki 2024: Too much too late? \u003cem\u003ePerspectives in Clinical Research\u003c/em\u003e 2025;16(1):1-2.doi: 10.4103/picr.picr_218_24.PubMed: 39867527\u003c/li\u003e\n\u003cli\u003eDeclaration of Helsinki embraces health equity. \u003cem\u003eNat Med\u003c/em\u003e 2024;30(12):3383.doi: 10.1038/s41591-024-03433-5.PubMed: 39623088\u003c/li\u003e\n\u003cli\u003eJillala RR, Aude CA, Vattipally VN, et al. Assessing and validating machine learning-enhanced imputation of admission American Spinal Injury Association Impairment Scale grades for spinal cord injury. \u003cem\u003eJournal of Neurosurgery. Spine\u003c/em\u003e 2025;43(1):90-97.doi: 10.3171/2025.1.SPINE241135.PubMed: 40344756\u003c/li\u003e\n\u003cli\u003eMitchell MD, Yarossi MB, Pierce DN, Garbarini EL, Forrest GF. Reliability of surface EMG as an assessment tool for trunk activity and potential to determine neurorecovery in SCI. \u003cem\u003eSpinal Cord\u003c/em\u003e 2015;53(5):368-374.doi: 10.1038/sc.2014.171.PubMed: 25448189\u003c/li\u003e\n\u003cli\u003eAngeli CA, Rejc E, Ugiliweneza B, et al. Activity-based recovery training with spinal cord epidural stimulation improves standing performance in cervical spinal cord injury. \u003cem\u003eJ Neuroeng Rehabil\u003c/em\u003e 2025;22(1):101.doi: 10.1186/s12984-025-01636-6.PubMed: 40301929\u003c/li\u003e\n\u003cli\u003eHarkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. \u003cem\u003eLancet (London, England)\u003c/em\u003e 2011;377(9781):1938-1947.doi: 10.1016/S0140-6736(11)60547-3.PubMed: 21601270\u003c/li\u003e\n\u003cli\u003eAndrews B, Karem A, Harkema SJ, Rouffet DM. Artifact Adaptive Ideal Filtering of EMG Signals Contaminated by Spinal Cord Transcutaneous Stimulation. \u003cem\u003eIEEE Transactions On Neural Systems and Rehabilitation Engineering : A Publication of the IEEE Engineering in Medicine and Biology Society\u003c/em\u003e 2023;31:3047-3054.doi: 10.1109/TNSRE.2023.3294011.PubMed: 37428663\u003c/li\u003e\n\u003cli\u003eBoakye M, Ugiliweneza B, Madrigal F, et al. Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation. \u003cem\u003eNeuromodulation : Journal of the International Neuromodulation Society\u003c/em\u003e 2021;24(3):405-415.doi: 10.1111/ner.13381.PubMed: 33794042\u003c/li\u003e\n\u003cli\u003eAngeli CA, Rejc E, Ugiliweneza B, et al. Activity-based recovery training with spinal cord epidural stimulation improves standing performance in cervical spinal cord injury. \u003cem\u003eJ Neuroeng Rehabil\u003c/em\u003e 2025;22(1):101.doi: 10.1186/s12984-025-01636-6.PubMed: 40301929\u003c/li\u003e\n\u003cli\u003eAngeli CA, Gerasimenko Y. Combined cervical transcutaneous with lumbosacral epidural stimulation improves voluntary control of stepping movements in spinal cord injured individuals. \u003cem\u003eFront Bioeng Biotech\u003c/em\u003e 2023;11:1073716.doi: 10.3389/fbioe.2023.1073716.PubMed: 36815892\u003c/li\u003e\n\u003cli\u003eBoakye M, Ball T, Dietz N, et al. Spinal cord epidural stimulation for motor and autonomic function recovery after chronic spinal cord injury: A case series and technical note. \u003cem\u003eSurgical Neurology International\u003c/em\u003e 2023;14:87.doi: 10.25259/SNI_1074_2022.PubMed: 37025529\u003c/li\u003e\n\u003cli\u003eJohn AA, Rossettie S, Rafael J, Cox CT, Ducic I, Mackay BJ. Clinical Assessment of Pain and Sensory Function in Peripheral Nerve Injury and Recovery: A Systematic Review of Literature. \u003cem\u003eArchives of Plastic Surgery\u003c/em\u003e 2022;49(3):427-439.doi: 10.1055/s-0042-1748658.PubMed: 35832158\u003c/li\u003e\n\u003cli\u003eKnotkova H, Hamani C, Sivanesan E, et al. Neuromodulation for chronic pain. \u003cem\u003eLancet (London, England)\u003c/em\u003e 2021;397(10289):2111-2124.doi: 10.1016/S0140-6736(21)00794-7.PubMed: 34062145\u003c/li\u003e\n\u003cli\u003eDa Cunha PHM, Lapa JDDS, Hosomi K, de Andrade DC. Neuromodulation for neuropathic pain. \u003cem\u003eInt Rev Neurobiol\u003c/em\u003e 2024;179:471-502.doi: 10.1016/bs.irn.2024.10.013.PubMed: 39580221\u003c/li\u003e\n\u003cli\u003eLei S, Jia F, He Q, Gao L, Luo S. Effect of stimulation parameters on entrainment. \u003cem\u003eHeart Rhythm O2\u003c/em\u003e 2022;3(6Part A):715-717.doi: 10.1016/j.hroo.2022.09.012.PubMed: 36589909\u003c/li\u003e\n\u003cli\u003eVillalobos J, Payne SC, Ward GM, et al. Stimulation parameters for directional vagus nerve stimulation. \u003cem\u003eBioelectronic Medicine\u003c/em\u003e 2023;9(1):16.doi: 10.1186/s42234-023-00117-2.PubMed: 37464423\u003c/li\u003e\n\u003cli\u003eMoritz C, Field-Fote EC, Tefertiller C, et al. Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. \u003cem\u003eNat Med\u003c/em\u003e 2024;30(5):1276-1283.doi: 10.1038/s41591-024-02940-9.PubMed: 38769431\u003c/li\u003e\n\u003cli\u003eSquair JW, Milano M, de Coucy A, et al. Recovery of walking after paralysis by regenerating characterized neurons to their natural target region. \u003cem\u003eScience (New York, N.Y.)\u003c/em\u003e 2023;381(6664):1338-1345.doi: 10.1126/science.adi6412.PubMed: 37733871\u003c/li\u003e\n\u003cli\u003eHankov N, Caban M, Demesmaeker R, et al. Augmenting rehabilitation robotics with spinal cord neuromodulation: A proof of concept. \u003cem\u003eSci Robot\u003c/em\u003e 2025;10(100):eadn5564.doi: 10.1126/scirobotics.adn5564.PubMed: 40073082\u003c/li\u003e\n\u003cli\u003eDragutinovic B, Moser F, Notbohm HL, Ihalainen JK, Bloch W, Schumann M. Influence of menstrual cycle and oral contraceptive phases on strength performance, neuromuscular fatigue, and perceived exertion. \u003cem\u003eJournal of Applied Physiology (Bethesda, Md. : 1985)\u003c/em\u003e 2024;137(4):919-933.doi: 10.1152/japplphysiol.00198.2024.PubMed: 39052822\u003c/li\u003e\n\u003cli\u003eStreckmann F, Elter T, Lehmann HC, et al. Preventive Effect of Neuromuscular Training on Chemotherapy-Induced Neuropathy: A Randomized Clinical Trial. \u003cem\u003eJama Intern Med\u003c/em\u003e 2024;184(9):1046-1053.doi: 10.1001/jamainternmed.2024.2354.PubMed: 38949824\u003c/li\u003e\n\u003cli\u003eZbinden J, Edwards S. From sequential to simultaneous prosthetic control: Decoding simultaneous finger movements from individual ground truth EMG patterns. \u003cem\u003eAnnual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference\u003c/em\u003e 2024;2024:1-4.doi: 10.1109/EMBC53108.2024.10782980.PubMed: 40039569\u003c/li\u003e\n\u003cli\u003eP\u0026ouml;chhacker M, Conrad A, Marko D, Varga E. A novel extraction method of prymnesins from Prymnesium parvum whole culture samples and re-evaluation of existing protocols. \u003cem\u003eEcotox Environ Safe\u003c/em\u003e 2025;302:118745.doi: 10.1016/j.ecoenv.2025.118745.PubMed: 40743721\u003c/li\u003e\n\u003cli\u003eWagner R, Jagoda A. Spinal cord syndromes. \u003cem\u003eEmerg Med Clin N Am\u003c/em\u003e 1997;15(3):699-711.doi: 10.1016/s0733-8627(05)70326-6.PubMed: 9255141\u003c/li\u003e\n\u003cli\u003eWagner FB, Mignardot J, Le Goff-Mignardot CG, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. \u003cem\u003eNature\u003c/em\u003e 2018;563(7729):65-71.doi: 10.1038/s41586-018-0649-2.PubMed: 30382197\u003c/li\u003e\n\u003cli\u003eRowald A, Komi S, Demesmaeker R, et al. Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis. \u003cem\u003eNat Med\u003c/em\u003e 2022;28(2):260-271.doi: 10.1038/s41591-021-01663-5.PubMed: 35132264\u003c/li\u003e\n\u003cli\u003eHernandez-Charpak SD, Kinany N, Ricchi I, et al. Towards personalized mapping through lumbosacral spinal cord task fMRI. \u003cem\u003eImaging Neuroscience (Cambridge, Mass.)\u003c/em\u003e 2025;3:imag_a_00455.doi: 10.1162/imag_a_00455.PubMed: 40800855\u003c/li\u003e\n\u003cli\u003eSimopoulos T, Sharma S, Aner M, Gill JS. A Temporary vs. Permanent Anchored Percutaneous Lead Trial of Spinal Cord Stimulation: A Comparison of Patient Outcomes and Adverse Events. \u003cem\u003eNeuromodulation : Journal of the International Neuromodulation Society\u003c/em\u003e 2018;21(5):508-512.doi: 10.1111/ner.12687.PubMed: 28901641\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Souza RS, Olatoye OO, Butler CS, Barman RA, Ashmore ZM, Hagedorn JM. Adverse Events Associated With 10-kHz Dorsal Column Spinal Cord Stimulation: A 5-Year Analysis of the Manufacturer and User Facility Device Experience (MAUDE) Database. \u003cem\u003eThe Clinical Journal of Pain\u003c/em\u003e 2022;38(5):320-327.doi: 10.1097/AJP.0000000000001026.PubMed: 35132023\u003c/li\u003e\n\u003cli\u003eStreet JT, Thorogood NP, Cheung A, et al. Use of the Spine Adverse Events Severity System (SAVES) in patients with traumatic spinal cord injury. A comparison with institutional ICD-10 coding for the identification of acute care adverse events. \u003cem\u003eSpinal Cord\u003c/em\u003e 2013;51(6):472-476.doi: 10.1038/sc.2012.173.PubMed: 23318555\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuroengineering-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jner","sideBox":"Learn more about [Journal of NeuroEngineering and Rehabilitation](http://jneuroengrehab.biomedcentral.com/)","snPcode":"12984","submissionUrl":"https://submission.nature.com/new-submission/12984/3","title":"Journal of NeuroEngineering and Rehabilitation","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Spinal cord injury, eSCS, High-frequency stimulation, Neuromodulation, Rehabilitation","lastPublishedDoi":"10.21203/rs.3.rs-9430045/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9430045/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eEvaluate epidural spinal cord stimulation (eSCS) with lesion-proximal electrode placement and dual-mode stimulation for spasticity management and functional recovery in chronic spinal cord injury (SCI).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThirty traumatic SCI participants (ASIA A\u0026ndash;D, 0\u0026ndash;8 years post-injury) were randomized to eSCS+physical therapy (PT; n\u0026thinsp;=\u0026thinsp;15) or PT alone (n\u0026thinsp;=\u0026thinsp;15). eSCS\u0026thinsp;+\u0026thinsp;PT received 16-contact electrodes implanted 1\u0026ndash;2 segments rostral to the injury, with dual-mode stimulation: high-frequency (1.2 kHz) for spasticity suppression and low-frequency (30\u0026ndash;60 Hz) for motor facilitation, optimized intraoperatively and adjusted monthly. Outcomes: ASIA scores, Modified Ashworth Scale (MAS), Visual Analog Scale (VAS) for pain, and functional recovery at 30 days and 6 months.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt 30 days, eSCS\u0026thinsp;+\u0026thinsp;PT showed superior improvement versus PT in sensory function (93.3% vs. 60.0%), spasticity control (73.3% vs. 26.7%), and pain reduction (60.0% vs. 20.0%). At 6 months, eSCS\u0026thinsp;+\u0026thinsp;PT demonstrated sustained gains: ASIA sensory scores increased (159.0\u0026thinsp;\u0026plusmn;\u0026thinsp;37.0 to 183.0\u0026thinsp;\u0026plusmn;\u0026thinsp;25.1, p\u0026thinsp;=\u0026thinsp;0.001); motor scores improved (p\u0026thinsp;=\u0026thinsp;0.016); MAS decreased (20[10\u0026ndash;32] to 10[0\u0026ndash;20], p\u0026thinsp;=\u0026thinsp;0.003); VAS pain resolved (20[0\u0026ndash;30] to 0[0\u0026ndash;10], p\u0026thinsp;=\u0026thinsp;0.039). Eighty percent achieved clinically meaningful functional improvement, including ankle dorsiflexor and gait muscle recovery.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eLesion-proximal eSCS with adaptive dual-mode stimulation overcomes conventional eSCS limitations by simultaneously suppressing spasticity and facilitating voluntary movement, yielding superior, sustained sensorimotor recovery versus rehabilitation alone.\u003c/p\u003e","manuscriptTitle":"Evaluation of the therapeutic effect of spinal cord stimulation on improving spasticity and promoting functional recovery in patients with spinal cord injury","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-09 00:10:11","doi":"10.21203/rs.3.rs-9430045/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-13T06:52:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T22:44:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26297498545233882896674986592044193796","date":"2026-05-04T11:28:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275297076514696088274276475090115978338","date":"2026-04-27T16:24:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291980766474155187322372612774858577165","date":"2026-04-24T13:18:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-24T13:14:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-20T14:03:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-20T14:02:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of NeuroEngineering and Rehabilitation","date":"2026-04-15T17:25:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuroengineering-and-rehabilitation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jner","sideBox":"Learn more about [Journal of NeuroEngineering and Rehabilitation](http://jneuroengrehab.biomedcentral.com/)","snPcode":"12984","submissionUrl":"https://submission.nature.com/new-submission/12984/3","title":"Journal of NeuroEngineering and Rehabilitation","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"39b92b38-a640-412d-bd42-21f46c18a8de","owner":[],"postedDate":"May 9th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-13T06:52:16+00:00","index":18,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T22:44:01+00:00","index":17,"fulltext":""},{"type":"reviewerAgreed","content":"26297498545233882896674986592044193796","date":"2026-05-04T11:28:36+00:00","index":16,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-09T00:10:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-09 00:10:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9430045","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9430045","identity":"rs-9430045","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}