PROJECT SUMMARY Spinal cord injury (SCI) greatly impairs standing and walking ability, which severely compromises daily living activities. While these deficits are partially improved by locomotor training, even after multiple training sessions, abnormal muscle activity and coordination still persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits. As such, treatment interventions that effectively promote neuromodulation of spinal locomotor networks and strengthen neural connectivity of the injured human spinal cord are greatly needed. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a pre-requisite for functioning descending and local inputs. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after SCI is unknown. The goal of this clinical trial is to use high frequency (30 Hz) transspinal stimulation to prime locomotor training and ultimately improve standing and walking ability in individuals with chronic incomplete SCI (iSCI). Forty-five individuals with iSCI will undergo 40 sessions of body weight- supported step training primed with high-frequency transspinal stimulation. Participants will be randomized to receive transspinal stimulation during standing (real or sham) or while supine (real). Aim 1 evaluates how priming locomotor training with high-frequency transspinal stimulation in iSCI alters corticomotoneuronal connectivity strength, as indicated by motor evoked potentials recorded from the legs. Aim 2 evaluates how priming locomotor training with high-frequency transspinal stimulation in iSCI affects reorganization and appropriate engagement of spinal neuronal circuits. Finally, Aim 3 evaluates improvement in intralimb coordination and the ability to stand and walk. These results will support the notion that tonic high-frequency transspinal stimulation strengthens corticomotoneuronal connectivity through posture-dependent corticospinal neuroplasticity. Additionally, these results will indicate appropriate neuromodulation and facilitation of spinal locomotor neuronal networks. We anticipate that the information gained from this mechanistic clinical trial will greatly impact clinical practice. This is because in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that represents a true clinical approach. Indeed, this multi-faceted approach meets the priorities of the National Institutes of Health for rehabilitation.

We lack specific knowledge on the benefits of concomitant utilization of multiple therapeutic interventions after SCI in humans. We will use comprehensive neurophysiological and clinical approaches to investigate recovery of standing and walking when transspinal stimulation primes locomotor training in persons with SCI. This work will have a great impact on clinical practice and may change the standard of care.