Background and Objectives Transcutaneous spinal cord stimulation (tSCS) is an emerging treatment for motor recovery following spinal cord injury (SCI). However, the extent of motor recovery with tSCS and the reasons why some individuals with motor-complete SCI respond less effectively, despite having the same injury classification, remain unclear. Here, we demonstrate that lumbosacral tSCS can enable anti-gravity voluntary movement following motor-complete SCI, and identify markers that distinguish responders from non-responders.

Methods Ten individuals with chronic motor-complete SCI received 30Hz lumbosacral tSCS for 60 min, 2-5 times per week, for a minimum of 6 weeks. Post-intervention, volitional movement was measured using surface electromyography (EMG) over the quadriceps and tibialis anterior (TA), and knee and ankle joint range of motion. To identify markers of responsiveness, we assessed the integrity of the corticospinal tract (motor evoked potentials; MEPs), ascending sensory pathways (somatosensory evoked potentials; SEPs), spinal cord reflexes (H-reflex), and motor neurons (compound muscle action potential, CMAP), along with muscle morphology using ultrasound echo-intensity.

Results Five of 10 individuals demonstrated voluntary anti-gravity knee extension and ankle dorsiflexion strength in the presence of tSCS. TA MEPs were observed in one responder only and tibial nerve SEPs were not observed in any participants. All participants showed poor TA muscle morphology. Four responders had a soleus H-reflex (compared to 2/5 non-responders) and a normal amplitude fibular CMAPs (compared to 2/5 non-responders).

Discussion These results show that tSCS can enable volitional motor activity against gravity in people with motor-complete SCI, but there is variability in responsiveness. Using conventional neurophysiological techniques, we were unable to consistently demonstrate the pathways facilitating voluntary control or the factors differentiating responders versus non-responders, but trends were observed. Spinal cord reflex and peripheral motor nerve integrity may be important for responding to tSCS but may not distinguish responders from non-responders. Additional assessments are needed to develop biomarkers for stratifying motor responders to tSCS.

Dr. Krassioukov serves on the advisory board for Onward Medical Inc. All other authors have no potential conflicts of interest to disclose.

NCT04726059, NCT04604951, NCT05369520

A.V.K. holds Endowed Chair in rehabilitation medicine, University of British Columbia, and his lab is supported by funds from the Canadian Institutes for Health Research (PJT-15603), Canada Foundation for Innovation and BC Knowledge Development Fund (CFI/ BCKDF) (35869), International Spinal Research Trust (#GR019728), Rick Hansen Foundation (35869 IOF), PRAXIS Spinal Cord Institute (#G2021-30), Wings for Life Research Foundation (WFL-CA-20/21), and US Department of Defense (W81XWH-22-1-0929). RNM is supported by the Paralyzed Veterans of America (#3196), Rick Hansen Foundation (#2007-21) Michael Smith Health Research BC (CANTAP-2023-03855 & CTTP-2024-04574), The Canadian Training Platform for Trials Leveraging Existing Networks (CAN-TAP-TALENT) (CANTAP-2023-03855), and the CANadian Consortium of Clinical Trial TRAINing platform (CANTRAIN) (CTTP-2024-04574). MJB is a Michael Smith Health Research British Columbia Health Professional-Investigator and his laboratory is supported with funding from WFL, US DOD, Rich Hansen Foundation. R.S. is supported by Wings for Life Spinal Cord Research Foundation and the US Department of Defense. C.S is supported by the Paralyzed Veterans of America Fellowship and Canadian Institute for Health Research Fellowship. S.S. is supported by Paralyzed Veterans of America Fellowship, Wings for Life Spinal Cord Research Foundation, Foundation for Physical Therapy Research, Craig H. Neilsen Foundation, Mission Yogurt Fund, Morton Cure Paralysis Fund. TM is supported by the Michael Smith Foundation for Health Research. SS, CS, and TM are also supported by the Rick Hansen Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trials and analyses used in this manuscript were approved by the University of British Columbias Clinical Research Ethics Board (H20-01307, H22-00365 H20-01163, H22-03727) and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation and completed a signed consent-to-disclose form for the use of their data and videos in this study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data generated and analyzed during this study are included in this published article and in the online-only materials, further inquiries can be directed to the corresponding authors.