Exoskeletal-assisted Walking Combined with Transcutaneous Spinal Cord Stimulation: Effect on Imaging and Serum Biomarkers of Skeletal Muscle Mass and Bone Strength

Significance to VA: In the protocol proposed in my CDA-2 application, I hypothesize that combining exoskeleton-assisted walking (EAW) training with lumbosacral transcutaneous spinal cord stimulation (tSCS) (EAW + active tSCS group) will lead to greater muscle-activation and a more normal gait pattern, leading to a greater effect on magnetic resonance imaging (MRI) derived muscle cross-sectional area (CSA), muscle recruitment using electromyography (EMG), blood biomarkers of muscle and bone cell activity, and bone imaging outcomes, than that of an EAW + sham tSCS group. These findings will increase the body of knowledge regarding how rehabilitation techniques such as EAW + tSCS can promote a series of positive adaptations in the muscle- bone unit in Veterans with SCI. Innovation and Impact: To the best of our knowledge, this is the first randomized control trial testing the effect of combining EAW + tSCS training, of a sufficient duration, on the change in the muscle-bone unit. A healthier musculoskeletal system in Veterans with chronic SCI will reduce fracture risk thereby allowing Veterans to engage more securely and confidently in the community and when participating in other rehabilitation activities. Specific Aims: Aim 1: To compare the effects of 108 sessions of EAW + sham tSCS versus EAW + active tSCS on the muscle- bone unit in [24 (12 participants/group)] wheelchair-dependent chronic SCI participants. Hypotheses: H1a. EAW + active tSCS will increase muscle size (mid-thigh CSA on MRI; primary outcome) compared to EAW + sham tSCS; H1b. EAW + active tSCS will increase muscle recruitment (electromyography) and bone outcomes at the femur and tibia [vBMD and aBMD] compared to EAW + sham tSCS; H1c. Increases in muscle size, recruitment, and mass will correlate with greater BMD. Aim 2 (exploratory): To determine the acute time-course responses for serum/plasma biomarkers of bone resorption and formation, muscle contractile activity, and the mRNA profiles of circulating exosomes collected prior to (time 0), and again 30, 60, 120, 180, minutes and 24, and 48 hours following an acute session of both the EAW + active tSCS and EAW + sham tSCS training interventions. Hypothesis: Compared to EAW + sham tSCS, EAW + active tSCS will lead to lower myostatin levels, greater increases in P1NP, and will induce a larger number of upregulated RNAs in circulating exosomes. Methodology: After meeting eligibility criteria, wheelchair users with chronic SCI will be block randomized into the EAW + active tSCS group or the EAW + sham tSCS group (n=12 in each group). Both groups will receive 60 minutes of EAW overground training per session for a total of 108 sessions (3 X week for 36 weeks). In addition to the EAW training, the EAW + active tSCS group will receive simultaneous lumbosacral tSCS targeted to activate the locomotor central pattern generator. At baseline, we will perform imaging to measure bone density and strength, surface EMG to assess muscle contractility, and a time-course response for serum muscle and bone biomarkers following an acute bout of EAW. We will capture these same data again after ~54 training sessions (mid-point), and after 108 training sessions (month 9 timepoint). In addition, MRI of both legs for muscle CSA will be performed at the baseline and month 9 time point. Path to Translation/Implementation: The first step in the path to translating the proposed intervention to the clinic is dissemination of these findings in top-tier medical journals and by delivering platform presentations at national and international conferences. Beyond the scope of this project, and with funding from VA Merit awards, my plan is to leverage the knowledge gained from this work to design EAW + tSCS strategies that Veterans with SCI could utilize in the community alone or, possibly, combined with pharmacological agents that preserve or rebuild the muscle-bone unit. Project Number: 1IK2RD000484-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Christopher Cirnigliaro | Institution: JAMES J PETERS VA MEDICAL CENTER, BRONX, NY | Activity Code: IK2 | Study Section: Career Development Program - Panel I[RRD8] View on NIH RePORTER: https://reporter.nih.gov/project-details/11349085