Spinal neuromodulation targeting synergistically acting locomotor networks facilitates walking recovery after spinal cord injury

Background: Non-invasive spinal cord transcutaneous stimulation (scTS) to the lumbosacral cord, combined with activity-based locomotor training (ABLT) and pharmacological intervention, enhances residual motor activity of the lower extremity muscles in individuals with chronic spinal cord injury (SCI). However, improvements in locomotor function remain limited. Recent findings suggest that locomotor and stepping ability post-SCI can be better regulated by the simultaneous delivery of scTS to synergistically acting locomotor-related neural networks along the spinal cord. We developed a novel multimodal neuromodulation that combines continuous scTS delivery to the spinal cord with alternating stimulation of the posterior nerve roots during ABLT to increasefunctional coupling between multilevelintegrated locomotor neural circuitries. Additionally, pharmacological neuromodulation was incorporated to increase spinal cord excitability and motor output further, thereby promoting locomotor recovery after SCI. Methods: We tested the developed neuromodulatory approach in two individuals, one with complete SCI and the other with motor-incomplete SCI. ScTS was delivered to the cervical, lumbosacral, and coccygeal spinal segments. Simultaneously, gait phase-dependent scTS was used to activate flexor-extensor motor pools in a spatiotemporally appropriate manner. ScTS delivery was coupled with ABLT to progressively increase body weight loading in incrementally challenging environments, transitioning from a non-weight-bearing position to body-weight-supported treadmill training and finally to overground walking. Both participants received periodic buspirone administration to further enhance spinal plasticity. Results: Within the first session, both participants generated electromyography activity in inactive or hypoactive muscles. Post-intervention, robust improvements in stepping and locomotor capabilities were observed across multiple testing environments. Notably, independent step initiation was observed for the first time in the participant with complete SCI, and the participant with motor-incomplete SCI progressed from AIS C to D. Kinematic, electromyography, and neurophysiological assessments revealed more symmetrical, task-appropriate muscle activation and increased spinal–supraspinal connectivity. Conclusion: This is the first report of improved locomotor function in humans with complete and incomplete SCI via the combination of coordinated activation of distinct locomotor networks, ABLT, and pharmacological intervention. This novel multimodal neuromodulation strategy offers a compelling rehabilitation approach to restore walking capabilities post-SCI. Trial Registration: The study was prospectively registered atClinicalTrials.gov (NCT04105114) on 26 September 2019.