https://orcid.org/0000-0002-8594-155X
Figures
Abstract
Introduction
Spinal cord injury (SCI) at or above the thoracic sixth spinal cord level disrupts descending sympathetic and parasympathetic control, leading to severe autonomic dysfunctions including cardiovascular and pelvic organ function. These complications adversely affect the quality of life and are associated with increased morbidity and mortality after SCI. Transcutaneous spinal cord stimulation (tSCS) may offer therapeutic benefits for these functions. The safety of tSCS in subacute SCI, however, remains unknown. Therefore, this study aims to evaluate the feasibility of tSCS for autonomic recovery in individuals with subacute SCI within six months since injury.
Methods and analysis
We designed a two-phase clinical protocol consisting of a pilot randomized controlled trial conducted during inpatient rehabilitation (Project A), followed by a post-discharge outpatient phase with a single-arm quasi-experimental design (Project B). In Project A, 26 adults with cervical or upper thoracic (≥T6) American Spinal Injury Association Impairment Scale (AIS) A-C SCI are planned to be enrolled and randomly assigned to receive tSCS or sham stimulation for five sessions (up to 90 minutes each) in parallel with standard care. Following discharge from inpatient rehabilitation, eligible participants will be offered continuation in Project B. New eligible participants who have not participated in Project A will also be recruited into Project B. They will receive 18 tSCS sessions over six weeks in the laboratory setting. Primary outcomes focus on feasibility, including recruitment, retention, and stimulation-related adverse events. Clinical outcomes will be collected at baseline, after each intervention, and at six months and one-year post-injury. Feasibility results will be summarized descriptively, and exploratory analyses of autonomic outcomes, including cardiovascular and pelvic organ function, will provide preliminary estimates of autonomic responses.
Ethics and dissemination
The study has been approved by the University of Washington Institutional Review Board. Written informed consent will be obtained from all participants. Results will be submitted to peer-reviewed journals and shared with the scientific/clinical communities and individuals with lived experience of SCI.
Citation: Nakahara R, Nasson S, Bieler E, Putsche-Young E, Aguila B, Shen J, et al. (2026) Effects of non-invasive spinal cord stimulation on autonomic function in individuals with subacute spinal cord injury: A pilot clinical trial protocol. PLoS One 21(4): e0347211. https://doi.org/10.1371/journal.pone.0347211
Editor: Johanna Pruller, PLOS: Public Library of Science, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND
Received: March 15, 2026; Accepted: March 26, 2026; Published: April 20, 2026
Copyright: © 2026 Nakahara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made publicly available upon study completion.
Funding: S.S. was supported by the Craig H. Neilsen Foundation (https://chnfoundation.org/), the Paralyzed Veterans of America Fellowship (https://pva.org/research-resources/research-foundation/), the Wings for Life Spinal Cord Research Foundation (https://www.wingsforlife.com/us/), the Foundation for Physical Therapy Research (https://foundation4pt.org/), the Mission Yogurt Fund (https://missionyogurt.com/), and the Morton Cure Paralysis Fund (https://mcpf.org/). R.N. was supported by the Nakatomi Foundation (https://www.nakatomi.or.jp/en/), the Foundation for Physical Therapy Research (https://foundation4pt.org/), and the Craig H. Neilsen Foundation (https://chnfoundation.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: C.M. is a paid consultant for Onward Medical, Inc. A.V.K. serves on the advisory board for Onward Medical, Inc. All other authors have no potential conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Background
Recent global estimates indicate that approximately one million new spinal cord injuries (SCI) occur each year, and more than 20 million individuals are living with SCI [1]. While paralysis is widely recognized as the most apparent and debilitating consequence of SCI, cardiovascular dysfunction is consistently reported as a leading health concern and the primary cause of mortality in this population [2–5]. Injuries at or above the level of sixth thoracic spinal cord segment (≥T6) disrupt descending supraspinal sympathetic control [6]. Loss of sympathetic outflow compromises vascular tone, which is essential for maintaining of arterial blood pressure [7].
Following SCI, the autonomic nervous system enters a state of neurogenic shock due to the loss of descending tonic sympathetic control and the dominance of parasympathetic activity [8]. Neurogenic shock typically lasts days to weeks following the injury onset [9]. During neurogenic shock, individuals with SCI experience profound hypotension and bradycardia, often requiring vasopressor support [10]. Although neurogenic shock itself eventually resolves, cardiovascular instability frequently persists beyond the acute phase because of loss of supraspinal regulation of autonomic spinal cord circuits below the lesion [11]. This impaired control manifests by variety of cardiovascular dysfunction including orthostatic hypotension, characterized by blood pressure (BP) reductions during postural changes [12], and autonomic dysreflexia, marked by excessive hypertension in response to visceral stimuli such as bladder and bowel distension [13]. Both orthostatic hypotension and autonomic dysreflexia can cause rapid and severe BP changes that are life-threatening [14].
SCI disrupts the crucial communication between spinal autonomic circuits and supraspinal control centers, resulting not only in impaired cardiovascular control but also in gastrointestinal and genitourinary system dysfunction [15]. These autonomic impairments are among the most important determinants of dignity, autonomy, and health [16,17]. Neurogenic bowel dysfunction results from impaired complex autonomic and somatic systems following SCI, and cardiovascular dysregulation during bowel management can induce clinically serious hypertensive episodes of autonomic dysreflexia, particularly in individuals with cervical and high thoracic SCI [18,19]. Therefore, there is a critical and urgent need for therapeutic approaches that extend beyond cardiovascular control and address multiple autonomic domains, including bowel and bladder function.
Engaging in targeted therapies during the acute and subacute phase, the critical window, may promote autonomic recovery [12,20]. Although sensorimotor function has been studied in the acute phase [21], only a few studies have focused on autonomic recovery. Evidence suggests that maintaining an optimal BP range during the acute phase promotes spinal cord recovery [22], and mean arterial BP management with vasopressor within one week of onset improves long-term neurological outcomes [23]. Pharmacological agents such as midodrine improve orthostatic tolerance in the acute phase [24,25]. Although midodrine may be effective for some individuals with SCI, its widespread use for treating orthostatic hypotension and orthostatic intolerance in this population remains questionable [26], and it may also exacerbate autonomic dysreflexia [27,28]. Prazosin can reduce autonomic dysreflexia severity but may induce a ‘first-dose phenomenon.’ Given the transient and fluctuating nature of BP in SCI, long-acting agents such as midodrine and Prazosin may not be ideal [12,29]. While topical nitropaste is also effective for acute management of autonomic dysreflexia, it has important limitations, including the risk of potential exacerbation of orthostatic hypotension and contraindications with phosphodiesterase-5 inhibitors [30]. In addition, non-pharmacological approaches such as verticalization in intensive care units have also shown long-term benefits [31]. However, the efficacy of interventions remains limited [32], and current clinical options are insufficient [12,29]. Therefore, there is an unmet need for novel therapeutic approaches that can prevent and target multiple dysfunctions while minimizing adverse effects.
Recent studies demonstrate that invasive epidural spinal cord stimulation (eSCS) can enhance autonomic function after cervical and upper thoracic SCI [33–36]. In acute and subacute SCI, animal studies in rodents and non-human primates demonstrate that eSCS can restore and maintain hemodynamic stability within hours after SCI [37]. Despite these benefits, the requirement for surgery and the associated costs restrict its broader application. In contrast, transcutaneous spinal cord stimulation (tSCS) offers a practical alternative that is non-invasive, less expensive, and allows electrode repositioning to target multiple spinal regions. Evidence suggests that tSCS engages spinal neural pathways in a manner similar to eSCS [38–40]. The real-time application of tSCS can potentially improve BP control and mitigate the episodes of autonomic dysreflexia in response to digital anorectal stimulation without delayed onset in individuals with chronic SCI [41,42]. Long-term application of tSCS has been shown to produce neurological and motor improvements that persist in the absence of stimulation in multicenter clinical trials [43].
In parallel, growing evidence suggests that recurrent tSCS may modulate autonomic cardiovascular regulation and neurogenic bowel dysfunction in chronic SCI with the absence of significant cardiovascular adverse events [44–46]. Clinical trials conducted in inpatient rehabilitation settings have demonstrated significant improvements in motor function, walking function, and functional independence at short-term follow-up [47]. Additionally, a recent study conducted in an inpatient rehabilitation setting examined the safety and feasibility of single-session, real-time tSCS for immediate blood pressure control in individuals with SCI [48]. However, there are no studies that have yet tested the effect of recurrent tSCS on comprehensive cardiovascular function including orthostatic hypotension and autonomic dysreflexia as well as pelvic organ function in subacute SCI, up to six-month post-injury. Thus, we aim to investigate the safety and feasibility of tSCS following acute SCI to treat a comprehensive range of autonomic dysfunctions.
Studying neuromodulation–based interventions in subacute SCI presents substantial ethical, logistical, and methodological challenges. Thus, transparent protocol-level reporting is therefore essential to ensure methodological rigor, mitigate selective reporting and publication bias, and enhance the interpretability and reproducibility of findings [49–51]. Publishing this protocol separately provides a pre-specified and transparent account of the study design, helping to mitigate selective outcome reporting and undisclosed analytical flexibility [52–54], while supporting scientific rigor and reproducibility through detailed documentation of stimulation parameters, titration procedures, and implementation strategies [55,56]. In accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines, this protocol aims to provide a standardized and reproducible framework that may inform future trials incorporating rigorous randomized designs, appropriate sham controls, and standardized outcome measures, as well as clinical implementation of tSCS for autonomic recovery after SCI [57,58].
Trial objectives
We hypothesize that tSCS can be safely administered during subacute SCI and will result in superior recovery of cardiovascular and pelvic organ functions. Our study is formed of the following aims: to assess the feasibility of single tSCS sessions in subacute SCI (Aim 1), to assess the feasibility of recurrent tSCS on autonomic function in subacute SCI (Aim 2), and to evaluate the preliminary effects of recurrent tSCS on autonomic recovery (Aim 3). These trial objectives and following study design are constructed based on the CONSORT statement and extension to pilot trials.
Methods and analysis
Study design and setting
The trial timeline, flow and experimental design is illustrated in Figs 1 and 2. We designed a two-phase clinical protocol consisting of a pilot randomized controlled trial (RCT) (Project A, Fig 2) followed by an outpatient continuation phase (Project B) designed as a within-subject, longitudinal feasibility study. Changes across a comprehensive range of autonomic dysfunctions are examined over repeated sessions, without a parallel control group, to reduce participant burden and allow inclusion of individuals transitioning from inpatient rehabilitation.
V = Visit. tSCS = transcuntaneous spinal cord stimulation. ECG = Electrocardiography. BP = Blood pressure. SCI = Spinal cord injury.
SCI = spinal cord injury. IRF = inpatient rehabilitation facilities. tSCS = transcuntaneous spinal cord stimulation.
In Project A, we propose a pilot RCT with blinding subject and assessor, two-arm sham-control to evaluate the safety and efficacy of tSCS over the lower thoracic and upper lumbar spinal cord segments for cardiovascular function in adults (18–65 years old) with cervical and upper thoracic SCI (≥T6) American Spinal Injury Association Impairment Scale (AIS) A-C during subacute inpatient rehabilitation. We will recruit 26 individuals with SCI, admitted to inpatient rehabilitation facilities (IRF) (average 8–10 days post-injury). We will conduct this study in the University of Washington Harborview Medical Center (HMC).
Eligible participants will be randomly assigned into two groups as follows: One arm will receive sham stimulation for 30–60 minutes for a total of five sessions, during their IRF stay while maintaining intensive rehabilitation (Sham Group, n = 13). A second arm will receive tSCS for 30–60 minutes for a total of five sessions, in IRFs while maintaining intensive rehabilitation (tSCS Group, n = 13). The intervention frequency and duration are constrained due to the inpatient schedule. We will apply tSCS at rest while maintaining conventional physical therapy, occupational therapy and speech therapy to control for the combinatory effect. This study design also controls for the placebo effect by blinding participants, healthcare professionals, and assessors but not researchers who deliver the intervention. We will collect all outcomes over six months, with three assessments, one at each timepoint of IRF admission, post-interventions, and six-month follow-up.
Following discharge, participants who remain eligible and are able to commute will be offered enrolment in Project B. In addition, new eligible participants, who did not participate in Project A and are less than four months since the injury onset, will be screened and recruited into Project B. All participants who remain eligible from Project A, including those who received sham stimulation during Project A, will be eligible to participate. This project will utilize a single-arm quasi-experimental design in the laboratory setting. Participants will receive a total of 18 sessions of active tSCS for 60–90 minutes over six weeks to assess feasibility and longer-term autonomic adaptations. tSCS will be delivered at rest, separate from scheduled physical or occupational therapy sessions. All outcomes will be collected up to six months post-injury, with assessments conducted at three time points: baseline, after completion of the 18-session outpatient phase (Project B), and at six months follow-up. Participant recruitment for this study began on December 1, 2024, and is expected to be completed by September 30, 2026, with data collection for all study phases including six months follow-up anticipated to conclude by April 30, 2027. Final analyses and dissemination of the study results are expected by July 30, 2027. Written informed consent is obtained from all participants prior to enrolment. This study was approved by the University of Washington Institutional Review Board on May 6, 2024. This trial was registered at ClinicalTrials.gov (NCT06540859). The authors confirm that all ongoing and related trials for this intervention are registered.
Sample size
We aim to recruit 26 participants with SCI for Project A admitted to IRF (average 8–10 days post-injury). Project B will include participants continuing from Project A as well as additional eligible participants recruited post-discharge. A sample size calculation was performed using G*power software [59] with power set at 0.80 and α at 0.05. We conducted the power analysis based on one SCS study for BP control assessed by head-up tilt test with and without eSCS (n = 4, cervical motor-complete AIS A or B) [33]. A minimum sample of 11 participants is required to detect a significant change in systolic BP during head-up tilt test (mean systolic BP change between stim-off and stim-on = 16.2 ± 12.6 mmHg, effect size = 1.29). Considering a potential 20% dropout rate [60], we aim to recruit 13 individuals with SCI to each group, for a total of 26 individuals with SCI.
Recruitment
To control the effect of age, we will use 65-year-old cut-off considered as the conventional threshold for cardiovascular disease risk as indicated by the literature review of clinical trials. We aim to stratify participants based on relevant biological variables (e.g., age and sex) and secure a balanced representation of diverse demographic groups, thereby increasing the generalizability of our findings. Cardiovascular dysfunction becomes particularly prominent at neurological levels ≥T6. Such impaired control of the heart rate and blood vessels elevates ischemic risks and damages endothelial cells within the vessels, and fosters various vascular diseases, leading to increased mortality risk following SCI. Thus, our target population is 18–65-year-old adults with AIS A–C ≥ T6.
All subjects will be recruited from the inpatient rehabilitation program at the HMC. The screening will begin prior to admission to the inpatient rehabilitation program. The research assistant will follow the physicians’ referral for any potentially eligible patients. Those patients identified as potentially eligible will be approached in person by research study staff (coordinator or research assistant) in their hospital room during their first week of inpatient rehabilitation and request permission to both screen for and discuss the study based on approved screening form. People interested in volunteering will be evaluated for eligibility by one of the investigators and medical coordinators. Candidate participants will be asked for their oral consent to receive the screening questionnaires. This includes a yes-no questionnaire and multiple-choice questions in person. Inclusion and exclusion criteria are outlined in Table 1.
Transcutaneous Spinal Cord Stimulation (tSCS)
A portable tSCS device (SCONE and TESCoN, SpineX Inc., USA, ARC-EX, ONWARD Medical, Netherland) will be used to deliver biphasic 1ms pulses with 10kHz carrier frequency at 30 Hz. The device will be selected based on availability. This stimulation paradigm has demonstrated autonomic recovery in our previous studies [41,42,45]. The location of tSCS is predetermined at T11-T12 and L1-L2 vertebral levels. The stimulation intensity will range from 10 to 230 mA, and selecting the optimal therapeutic stimulation parameters will involve the following criteria: 1) a strong but comfortable sensory experience (initial slight tingling at the site of the electrode followed by some pressure or paraesthesia in skeletal muscles), described as a 5–7 on a 10 point Likert scale, 2) a stable systolic BP not more than 20 mmHg above baseline, and 3) without any symptoms of autonomic dysreflexia (i.e., sweating, goosebumps, tunnel vision, headache, etc.). The stimulation will be reduced if any of the above criteria is not satisfied as well if there are visually detectable skeletal muscle contractions. We will use two self-adhesive round electrodes (diameter of 2.0 cm) placed on the skin between spinous processes at the midline over the vertebral column as a cathode, and two rectangular 7.5 × 12.5 cm self-adhesive electrodes located symmetrically on the skin over the iliac crests as anodes. The tSCS stimulator will be set with an open-loop stimulation using the same intensity throughout the session.
Sham stimulation
Sham stimulation is designed to control for placebo effects associated with the perception of the intervention. Sham-controlled randomized designs are essential in neuromodulation research because improvements in autonomic function, pain and overall well-being are highly susceptible to placebo effects, participant expectancy, and observer bias [61]. Sham stimulation will be administered at the same anatomical location. Such sham stimulation has been successfully incorporated as the control treatment in previous and ongoing studies [62–64]. We have adapted these procedures to reduce the possibility that participants will be able to determine their group randomization. The intensity of electrical stimulation will be briefly ramped up to a level at which the participants report perceiving the stimulation (i.e., sensory threshold), then ramped down and turned off for the remainder of the intervention.
Assessments
Cardiovascular Monitoring. Cardiovascular adverse events associated with tSCS at rest will be recorded. We will document the frequency and severity of abnormal BP responses, as well as cardiac responses including tachycardia, bradycardia, arrhythmia, and any associated symptoms. Twenty four-hour BP monitoring will also be used to track BP at day and night [65,66]. Participants will maintain a diary documenting daily activities such as sleep and wake, bowel and bladder management, taking medications, eating, and any instances of symptoms of autonomic dysreflexia and hypotension [67]. The monitoring involves wearing a compact digital BP device (Meditech Ltd., Budapest, Hungary), which is connected to a cuff around the upper arm. The device automatically measures BP at regular intervals, typically every 15 minutes during the day and 60 minutes at night. Heart rate variability will also be assessed. Time-domain and frequency-domain analyses will be performed to evaluate sympathetic and cardiac parasympathetic activity [68], in accordance with the European task force heart rate variability guidelines and based on our prior work [69]. Participants will fill out the Autonomic Dysfunction Following Spinal Cord Injury (ADFSCI) questionnaire at each assessment phase [70]. The ADFSCI questionnaire has participants self-report on the frequency and severity of autonomic dysreflexia episodes.
Continuous Hemodynamic Monitoring During Orthostatic Challenge. All participants will undergo continuous beat-by-beat BP monitoring and electrocardiography during a sit-up or head-up tilt test performed with and without tSCS to evaluate cardiovascular safety and real-time autonomic responses [71–73]. Orthostatic blood pressure responses are evaluated during transition from a supine to an upright position of at least 60 degrees [74].
Neurological Function. The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) [75] is used to determine the sensory and motor levels on both sides of the body, establish the overall neurological level of injury, and classify the completeness of the lesion (complete or incomplete). The ISNCSCI is a validated and standardized method for neurological assessment following SCI. The International Standards to document Autonomic Function after SCI (ISAFSCI) [76,77] provides a standardized framework for assessing key autonomic domains, including cardiovascular, thermoregulatory, sudomotor, bronchopulmonary, lower urinary tract, gastrointestinal tract, and sexual function, in conjunction with the ISNCSCI. The ISAFSCI will be administered at baseline and post-intervention to track changes in autonomic function along with the changes in neurological function.
Lower Urinary Tract Function. During each assessment phase, participants will complete a series of validated questionnaires to evaluate lower urinary tract function. These questionnaires include the Neurogenic Bladder Symptom Score [78], International SCI Lower Urinary Tract Function Dataset [79].
Bowel Function. Bowel function will be assessed using multiple validated measures. Time needed for bowel movement and the International SCI Bowel Function Dataset, which allows calculation of the Neurogenic Bowel Dysfunction score, [80] will be recorded at each assessment.
Primary outcomes
The primary outcome for Aim 1 is the feasibility of tSCS in subacute SCI. Safety will be evaluated by cardiovascular responses before, during, and after single and repeated tSCS sessions, including changes in systolic and diastolic BP and heart rate, as well as the occurrence and severity of cardiovascular adverse events related to tSCS or study procedures.
The primary outcome for Aim 2 is the feasibility of recurrent tSCS during the inpatient rehabilitation phase (Project A), defined by (1) adherence to the stimulation and assessment protocols, (2) recruitment and retention rates throughout the study period, and (3) the frequency and severity of adverse events related to tSCS or study procedures. These feasibility indicators align with established guidelines for pilot and feasibility trials [81]. In addition, between-group differences in preliminary autonomic and cardiovascular outcomes will be explored following completion of the five-session inpatient phase (Project A). These outcomes include physiological and clinical measures of autonomic and cardiovascular function, such as systolic BP responses during the sit-up test, the frequency and severity of autonomic dysreflexia and orthostatic hypotension during 24-hour BP monitoring, and patient-reported symptoms of autonomic dysfunction assessed using the ADFSCI.
The primary outcome for Aim 3 is the change in systolic BP during orthostatic stress, assessed using the sit-up test or head-up tilt test, measured at baseline, following completion of the intervention, and at six-month follow-up.
Statistical analysis
This is a two-phase clinical trial consisting of a pilot RCT (Project A) followed by a single arm pre- and post-experimental trial (Project B). A total of 26 participants with subacute (<six months since injury) cervical or upper thoracic ≥T6 AIS A–C SCI will be enrolled (Sham group n = 13, tSCS group n = 13). Descriptive statistics will be generated for the primary outcomes, feasibility outcomes, as well as demographic a clinical characteristic. Between group comparisons at baseline will be conducted using independent sample t-tests, Chi-square analyses, and Mann Whitney U tests as appropriate. Statistical analysis will be performed using R version 4.1.2 and the R studio program. This study is designed as a pilot trial, and analyses will primarily focus on feasibility, safety, and exploratory trends. Results will be interpreted in accordance with the CONSORT extension for pilot and feasibility trials
For Aim 1, we will evaluate the feasibility of tSCS by comparing cardiovascular responses before, during and after single and repeated tSCS sessions. Changes in systolic and diastolic BP and heart rate will be analysed using linear mixed models for repeated measures, with time (session) as a within-subject factor. Additionally, feasibility outcomes, including adherence rate, recruitment rate, and the frequency of adverse events, will be summarized descriptively.
For Aim 2, we will use Between-participant analyses assessing group differences in feasibility and preliminary autonomic outcomes between the Sham and tSCS groups after completion of the five-session inpatient phase (Project A). Linear mixed models will be used to assess the effects of time and intervention group, with baseline values included as covariates.
For Aim 3, within-participant analyses will examine longitudinal changes following the 18-session outpatient continuation phase (Project B) and at six-month follow-up. Descriptive statistics and standardized effect sizes (Cohen’s d) will be reported to estimate the magnitude of changes.
Discussion and limitations
While spinal cord stimulation research is accelerating, few studies have assessed the applications of tSCS for use in inpatient settings and using a RCT design. Furthermore, there are no studies that have yet tested the effect of tSCS on comprehensive cardiovascular function including orthostatic hypotension and autonomic dysreflexia as well as pelvic organ function in IRF up to six-month post-injury. Thus, we propose to conduct the first study investigating the feasibility of tSCS following acute SCI.
Data management and safety
All data collected (electronic or hardcopy documents) will be coded with unique identification numbers and stored centrally on the database, a password-protected computer, or in a locked filing cabinet in a secure laboratory space only accessible to the study investigators. To ensure information quality and accuracy after publication, all data will be stored for 6 years, and then subsequently destroyed.
Any adverse events reported during the intervention will be documented with information pertaining to their severity and anatomical location. The study coordinator will immediately report adverse events to the ethics board and Data and Safety Monitoring Committee (DSMC), which is comprised of three external, independent physician scientists with no involvement in the study, as well as the appropriate ethics board. The DSMC is responsible for safeguarding the interests of trial participants, assessing the safety and effect of the interventions during the trial, and monitoring the overall conduct of the clinical trial. The DSMC also provides recommendations for continuing or discontinuing the trial and outcome data use for participants who discontinue the trial. The trial progress will be biannually reported to the DSMC.
Ethics and dissemination
This pilot study will be conducted in accordance with the Declaration of Helsinki and is consistent with the International Conference on Harmonisation Good Clinical Practice Guidelines, as well as applicable regulatory requirements. The study protocol was initially approved by the University of Washington Institutional Review Board (UW IRB) (STUDY00020243). The UW IRB and DSMC will be contacted when the trial makes any important protocol modifications. The feedback base on functional outcome measure results can be provided to participants for their adherence and benefits. The results of this pilot trial will be presented at national and international conferences and will be published in peer-reviewed journals. All subsequent manuscripts will be reported in conjunction with the Consolidated Standards of Reporting Trials. Extensive, individualized feedback will be provided to each participant upon completing the trial.
Supporting information
S1 Checklist. SPIRIT checklist is included as a supplemental document.
https://doi.org/10.1371/journal.pone.0347211.s001
(DOC)
Acknowledgments
The authors would like to acknowledge Dr. Parag Gad and SpineX Inc. for the provision of spinal cord stimulator used in this trial. We also thank all participants and family for their commitment and support in this pilot clinical trial.
Disclaimer: The funder has no role in the study design, recruitment, data collection and/or analyses, preparation, and review/approval of this manuscript.
References
- 1. Ding W, Hu S, Wang P, Kang H, Peng R, Dong Y. Spinal cord injury: the global incidence, prevalence, and disability from the global burden of disease study 2019. Spine. 2022;47(21):1532–40.
- 2. Garshick E, Kelley A, Cohen SA, Garrison A, Tun CG, Gagnon D, et al. A prospective assessment of mortality in chronic spinal cord injury. Spinal Cord. 2005;43(7):408–16. pmid:15711609
- 3. DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil. 1999;80(11):1411–9. pmid:10569435
- 4. Myers J, Lee M, Kiratli J. Cardiovascular disease in spinal cord injury. Am J Phys Med Rehabil. 2007;86(2):142–52.
- 5. Cragg JJ, Noonan VK, Krassioukov A, Borisoff J. Cardiovascular disease and spinal cord injury. Neurology. 2013;81(8):723–8.
- 6. West CR, Gee CM, Voss C, Hubli M, Currie KD, Schmid J, et al. Cardiovascular control, autonomic function, and elite endurance performance in spinal cord injury. Scand J Med Sci Sports. 2015;25(4):476–85. pmid:25175825
- 7. Brown DL, Guyenet PG. Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats. Circ Res. 1985;56(3):359–69. pmid:3971510
- 8. Curt A, Nitsche B, Rodic B, Schurch B, Dietz V. Assessment of autonomic dysreflexia in patients with spinal cord injury. J Neurol Neurosurg Psychiatry. 1997;62(5):473–7. pmid:9153603
- 9. Lehmann KG, Lane JG, Piepmeier JM, Batsford WP. Cardiovascular abnormalities accompanying acute spinal cord injury in humans: incidence, time course and severity. J Am Coll Cardiol. 1987;10(1):46–52. pmid:3597994
- 10.
Dave S, Dahlstrom JJ, Weisbrod LJ. Neurogenic shock. 2023.
- 11. Krassioukov AV, Weaver LC. Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats. Neuroscience. 1996;70(1):211–25. pmid:8848126
- 12. Krassioukov A, Eng JJ, Warburton DE, Teasell R, Spinal Cord Injury Rehabilitation Evidence Research Team. A systematic review of the management of orthostatic hypotension after spinal cord injury. Arch Phys Med Rehabil. 2009;90(5):876–85. pmid:19406310
- 13. Guttmann L, Whitteridge D. Effects of bladder distension on autonomic mechanisms after spinal cord injuries. Brain. 1947;70(Pt 4):361–404. pmid:18903252
- 14. Wan D, Krassioukov AV. Life-threatening outcomes associated with autonomic dysreflexia: a clinical review. J Spinal Cord Med. 2014;37(1):2–10. pmid:24090418
- 15.
Hou S, Rabchevsky AG. Autonomic consequences of spinal cord injury. In: Comprehensive physiology. Wiley; 2014. p. 1419–53.
- 16. Anderson KD. Targeting recovery: priorities of the spinal cord-injured population. J Neurotrauma. 2004;21(10):1371–83. pmid:15672628
- 17. Wheeler TL, Bowel and Bladder Workshop Participants, de Groat W, Eisner K, Emmanuel A, French J, et al. Translating promising strategies for bowel and bladder management in spinal cord injury. Exp Neurol. 2018;306:169–76. pmid:29753647
- 18. Johns J, Krogh K, Rodriguez GM, Eng J, Haller E, Heinen M, et al. Management of neurogenic bowel dysfunction in adults after spinal cord injury. Top Spinal Cord Inj Rehabil. 2021;27(2):75–151.
- 19. Inskip JA, Lucci V-EM, McGrath MS, Willms R, Claydon VE. A community perspective on bowel management and quality of life after spinal cord injury: the influence of autonomic dysreflexia. J Neurotrauma. 2018;35(9):1091–105. pmid:29239268
- 20. Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord trauma: description, intervention, and prediction of outcome. Neurosurgery. 1993;33(6):1007–16; discussion 1016-7. pmid:8133985
- 21. Dietz V, Fouad K. Restoration of sensorimotor functions after spinal cord injury. Brain. 2014;137(Pt 3):654–67. pmid:24103913
- 22. Lee Y-S, Kim K-T, Kwon BK. Hemodynamic management of acute spinal cord injury: a literature review. Neurospine. 2021;18(1):7–14. pmid:33211951
- 23. Walters BC, Hadley MN, Hurlbert RJ, Aarabi B, Dhall SS, Gelb DE. Guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery. 2013;60(Supplement 1):82–91.
- 24. Wood GC, Boucher AB, Johnson JL, Wisniewski JN, Magnotti LJ, Croce MA, et al. Effectiveness of pseudoephedrine as adjunctive therapy for neurogenic shock after acute spinal cord injury: a case series. Pharmacotherapy. 2014;34(1):89–93. pmid:23918202
- 25. Phillips AA, Krassioukov AV, Ainslie PN, Cote AT, Warburton DER. Increased central arterial stiffness explains baroreflex dysfunction in spinal cord injury. J Neurotrauma. 2014;31(12):1122–8. pmid:24634993
- 26. Wecht JM, Bauman WA. Implication of altered autonomic control for orthostatic tolerance in SCI. Auton Neurosci. 2018;209:51–8. pmid:28499865
- 27. Nieshoff EC, Birk TJ, Birk CA, Hinderer SR, Yavuzer G. Double-blinded, placebo-controlled trial of midodrine for exercise performance enhancement in tetraplegia: a pilot study. J Spinal Cord Med. 2004;27(3):219–25. pmid:15478524
- 28. Wecht JM, Rosado-Rivera D, Handrakis JP, Radulovic M, Bauman WA. Effects of midodrine hydrochloride on blood pressure and cerebral blood flow during orthostasis in persons with chronic tetraplegia. Arch Phys Med Rehabil. 2010;91(9):1429–35. pmid:20801263
- 29. Mills PB, Fung CK, Travlos A, Krassioukov A. Nonpharmacologic management of orthostatic hypotension: a systematic review. Arch Phys Med Rehabil. 2015;96(2):366-375.e6. pmid:25449193
- 30. Krassioukov A, Linsenmeyer TA, Beck LA, Elliott S, Gorman P, Kirshblum S, et al. Evaluation and management of autonomic dysreflexia and other autonomic dysfunctions: preventing the highs and lows. J Spinal Cord Med. 2021;44(4):631–83. pmid:34270391
- 31. Daunoraviciene K, Adomaviciene A, Svirskis D, Griškevičius J, Juocevicius A. Necessity of early-stage verticalization in patients with brain and spinal cord injuries: preliminary study. Technol Health Care. 2018;26(2_suppl):613–23.
- 32. Squair JW, West CR, Krassioukov AV. Neuroprotection, plasticity manipulation, and regenerative strategies to improve cardiovascular function following spinal cord injury. J Neurotrauma. 2015;32:609–21.
- 33. Harkema SJ, Legg Ditterline B, Wang S, Aslan S, Angeli CA, Ovechkin A, et al. Epidural spinal cord stimulation training and sustained recovery of cardiovascular function in individuals with chronic cervical spinal cord injury. JAMA Neurol. 2018;75(12):1569–71. pmid:30242310
- 34. Samejima S, Shackleton C, Malik RN, Cao K, Bohorquez A, Nightingale TE. Spinal cord stimulation prevents autonomic dysreflexia in individuals with spinal cord injury: a case series. J Clin Med. 2023;12(8).
- 35. Sachdeva R, Dwivedi A, Law M, Lam C, Wilcox JT, Alilain WJ, et al. Regeneration and remyelination promoting effects of spinal cord stimulation following spinal cord injury: a scoping review. Exp Neurol. 2026;396:115519. pmid:41130382
- 36. Herrity AN, Williams CS, Angeli CA, Harkema SJ, Hubscher CH. Lumbosacral spinal cord epidural stimulation improves voiding function after human spinal cord injury. Sci Rep. 2018;8(1):8688.
- 37. Squair JW, Gautier M, Mahe L, Soriano JE, Rowald A, Bichat A, et al. Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury. Nature. 2021;590(7845):308–14. pmid:33505019
- 38. Engel-Haber E, Bheemreddy A, Bayram MB, Ravi M, Zhang F, Su H, et al. Neuromodulation in spinal cord injury using transcutaneous spinal stimulation-mapping for a blood pressure response: a case series. Neurotrauma Rep. 2024;5(1):845–56. pmid:39391052
- 39. Capogrosso M, Wenger N, Raspopovic S, Musienko P, Beauparlant J, Bassi Luciani L, et al. A computational model for epidural electrical stimulation of spinal sensorimotor circuits. J Neurosci. 2013;33(49):19326–40.
- 40. Hofstoetter US, Freundl B, Binder H, Minassian K. Common neural structures activated by epidural and transcutaneous lumbar spinal cord stimulation: elicitation of posterior root-muscle reflexes. PLoS One. 2018;13(1):e0192013. pmid:29381748
- 41. Phillips AA, Squair JW, Sayenko DG, Edgerton VR, Gerasimenko Y, Krassioukov AV. An autonomic neuroprosthesis: noninvasive electrical spinal cord stimulation restores autonomic cardiovascular function in individuals with spinal cord injury. J Neurotrauma. 2018;35(3):446–51. pmid:28967294
- 42. Sachdeva R, Nightingale TE, Pawar K, Kalimullina T, Mesa A, Marwaha A. Noninvasive neuroprosthesis promotes cardiovascular recovery after spinal cord injury. Neurotherapeutics. 2021;18(2):1244–56.
- 43. Moritz C, Field-Fote EC, Tefertiller C, van Nes I, Trumbower R, Kalsi-Ryan S, 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):1276–83. pmid:38769431
- 44. Kreydin E, Zhong H, Lavrov I, Edgerton VR, Gad P. The effect of non-invasive spinal cord stimulation on anorectal function in individuals with spinal cord injury: a case series. Front Neurosci. 2022;16:816106. pmid:35250456
- 45. Samejima S, Shackleton C, Malik RN, Hosseinzadeh A, Rempel L, Phan A-D, et al. Multi-system benefits of non-invasive spinal cord stimulation following cervical spinal cord injury: a case study. Bioelectron Med. 2025;11(1):20. pmid:40908490
- 46. Samejima S, Malik RN, Ge J, Rempel L, Cao K, Desai S, et al. Cardiovascular safety of transcutaneous spinal cord stimulation in cervical spinal cord injury. Neurotherapeutics. 2025;22(2):e00528. pmid:39893085
- 47. Comino-Suárez N, Moreno JC, Megía-García Á, del-Ama AJ, Serrano-Muñoz D, Avendaño-Coy J. Transcutaneous spinal cord stimulation combined with robotic-assisted body weight-supported treadmill training enhances motor score and gait recovery in incomplete spinal cord injury: a double-blind randomized controlled clinical trial. J Neuroeng Rehabil. 2025;22(1):15.
- 48. Chavez J, Curtis GL, Weir JP, Tsai CY, Fox FE, Harel NY. Protocol for safety, feasibility, and efficacy of using targeted transcutaneous spinal cord stimulation to treat hypotension during acute inpatient rehabilitation in individuals with SCI. Top Spinal Cord Inj Rehabil. 2025.
- 49. Ioannidis JPA, Munafò MR, Fusar-Poli P, Nosek BA, David SP. Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention. Trends Cogn Sci. 2014;18(5):235–41. pmid:24656991
- 50. Agha RA. Advancing research by publishing research protocols and negative studies. Int J Surg Protoc. 2016;1:1–2. pmid:31852013
- 51. Murad MH, Chu H, Lin L, Wang Z. The effect of publication bias magnitude and direction on the certainty in evidence. BMJ Evid Based Med. 2018;23(3):84–6. pmid:29650725
- 52. Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan A-W, Cronin E, et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One. 2008;3(8):e3081. pmid:18769481
- 53. Al Shakarchi J. How to write a research study protocol. J Surg Protoc Res Methodol. 2022;2022(1).
- 54. Vorland CJ, Brown AW, Kilicoglu H, Ying X, Mayo-Wilson E. Publication of results of registered trials with published study protocols, 2011-2022. JAMA Netw Open. 2024;7(1).
- 55. Taylor BP, Rebok GW, Marsiske M. Good clinical practice improves rigor and transparency: lessons from the ACTIVE trial. Psychol Aging. 2022;37(1):43–50. pmid:35113613
- 56. Bradley SH, DeVito NJ, Lloyd KE, Richards GC, Rombey T, Wayant C. Reducing bias and improving transparency in medical research: a critical overview of the problems, progress and suggested next steps. J R Soc Med. 2020;113(11).
- 57. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–7. pmid:23295957
- 58. Hróbjartsson A, Boutron I, Hopewell S, Moher D, Schulz KF, Collins GS. SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials. BMJ. 2025;389.
- 59. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–91. pmid:17695343
- 60. Alrashidi AA, Nightingale TE, Currie KD, Hubli M, MacDonald MJ, Hicks AL, et al. Exercise improves cardiorespiratory fitness, but not arterial health, after spinal cord injury: the CHOICES trial. J Neurotrauma. 2021;38(21):3020–9. pmid:34314235
- 61. Kramer JLK, Lam T, Rossi FMV, Illes J. On the use of sham transcutaneous spinal cord stimulation in spinal cord injury clinical trials. Brain. 2025;148(5):1456–8.
- 62. Shackleton C, Samejima S, Williams AM, Malik RN, Balthazaar SJ, Alrashidi A, et al. Motor and autonomic concomitant health improvements with neuromodulation and exercise (MACHINE) training: a randomised controlled trial in individuals with spinal cord injury. BMJ Open. 2023;13(7):e070544. pmid:37451734
- 63. Estes S, Zarkou A, Hope JM, Suri C, Field-Fote EC. Combined transcutaneous spinal stimulation and locomotor training to improve walking function and reduce spasticity in subacute spinal cord injury: a randomized study of clinical feasibility and efficacy. J Clin Med. 2021;10(6):1167. pmid:33799508
- 64. Sayenko DG, Rath M, Ferguson AR, Burdick JW, Havton LA, Edgerton VR, et al. Self-assisted standing enabled by non-invasive spinal stimulation after spinal cord injury. J Neurotrauma. 2019;36(9):1435–50. pmid:30362876
- 65. Sachdeva R, Nightingale TE, Krassioukov AV. The blood pressure pendulum following spinal cord injury: implications for vascular cognitive impairment. Int J Mol Sci. 2019;20(10):2464.
- 66. Rosado-Rivera D, Radulovic M, Handrakis JP, Cirnigliaro CM, Jensen AM, Kirshblum S, et al. Comparison of 24-hour cardiovascular and autonomic function in paraplegia, tetraplegia, and control groups: implications for cardiovascular risk. J Spinal Cord Med. 2011;34(4):395–403. pmid:21903013
- 67. Hubli M, Krassioukov AV. Ambulatory blood pressure monitoring in spinal cord injury: clinical practicability. J Neurotrauma. 2014;31(9):789–97. pmid:24175653
- 68. Berntson GG, Bigger JT Jr, Eckberg DL, Grossman P, Kaufmann PG, Malik M, et al. Heart rate variability: origins, methods, and interpretive caveats. Psychophysiology. 1997;34(6):623–48. pmid:9401419
- 69. Dorey TW, Walter M, Krassioukov AV. Reduced reflex autonomic responses following intradetrusor onabotulinumtoxinA injections: a pre-/post-study in individuals with cervical and upper thoracic spinal cord injury. Front Physiol. 2021;12.
- 70. Hubli M, Gee CM, Krassioukov AV. Refined assessment of blood pressure instability after spinal cord injury. Am J Hypertens. 2015;28(2):173–81. pmid:24990527
- 71. Krassioukov A, Alexander MS, Karlsson A-K, Donovan W, Mathias CJ, Biering-Sørensen F. International spinal cord injury cardiovascular function basic data set. Spinal Cord. 2010;48(8):586–90. pmid:20101250
- 72. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69–72. pmid:21431947
- 73. Currie KD, Wong SC, Warburton DE, Krassioukov AV. Reliability of the sit-up test in individuals with spinal cord injury. J Spinal Cord Med. 2015;38(4):563–6. pmid:25738545
- 74. Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology. 1996;46(5).
- 75. Rupp R, Biering-Sørensen F, Burns SP, Graves DE, Guest J, Jones L, et al. International standards for neurological classification of spinal cord injury. Top Spinal Cord Inj Rehabil. 2021;27(2).
- 76. Wecht JM, Krassioukov AV, Alexander M, Handrakis JP, McKenna SL, Kennelly M, et al. International Standards to document Autonomic Function following SCI (ISAFSCI): Second Edition. Top Spinal Cord Inj Rehabil. 2021;27(2):23–49. pmid:34108833
- 77. Krassioukov A, Biering-Sorensen CF, Donovan W, Kennelly M, Kirshblum S, Krogh K, et al. International standards to document remaining autonomic function after spinal cord injury (ISAFSCI), First Edition 2012. Top Spinal Cord Inj Rehabil. 2012;18(3):282–96. pmid:23460763
- 78. Welk B, Lenherr S, Elliott S, Stoffel J, Presson AP, Zhang C, et al. The Neurogenic Bladder Symptom Score (NBSS): a secondary assessment of its validity, reliability among people with a spinal cord injury. Spinal Cord. 2018;56(3):259–64. pmid:29184133
- 79. Biering-Sørensen F, Kennelly M, Kessler TM, Linsenmeyer T, Pannek J, Vogel L. International spinal cord injury lower urinary tract function basic data set (version 2.0). Spinal Cord Ser Cases. 2018;4(1):60.
- 80. Krogh K, Emmanuel A, Perrouin-Verbe B, Korsten MA, Mulcahey MJ, Biering-Sørensen F. International spinal cord injury bowel function basic data set (Version 2.0). Spinal Cord. 2017;55(7):692–8. pmid:28195229
- 81. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;2016:i5239.