Transcutaneous spinal cord stimulation at alternating intensities preferentially prevents the development of spasticity after contusion SCI in rat

Transcutaneous spinal cord stimulation (tSCS) has become an increasingly popular and effective research intervention for functional recovery after spinal cord injury (SCI). Despite its surge in application for clinical investigations, there is a current lack of systematic approaches to investigate the optimal design of electrical stimulation protocols for a desired outcome. Important parameters that can affect the outcome are stimulation frequency and intensity. Previous work in humans and rodents have identified tSCS as a promising strategy to reduce spasticity and hyperreflexia after SCI. However, the stimulation intensities used in these studies vary widely and it remains unknown whether sub- or supra-motor threshold stimulation intensity is preferable for restoring spinal inhibition and mitigating spasticity after SCI. The objective of this study was to deliver 6 weeks of tSCS to rats with a severe contusion injury using a stimulation protocol with the intensity set (1) above motor threshold, (2) below motor threshold or (3) alternating between supra- and subthreshold, and evaluate whether it differentially influenced diverse outcome measures associated with spasticity. Here, we show that these various protocols distinctly affect different aspects of spasticity. Collectively, multiple sessions of tSCS at alternating intensities more profoundly (1) decreased hyperreflexia, (2) increased the frequency-dependent modulation of the H-reflex, (3) reduced antagonist ankle muscle co-contractions and aberrant crossed-extensor reflexes, and (4) prevented the development of SCI-induced KCC2 membrane downregulation in lumbar motoneurons, when compared to the supra- and sub-motor threshold intensity protocols. Together, these results suggest that an alternating stimulation intensity protocol is preferential to supra- or subthreshold stimulation alone for treating spastic symptoms after SCI and begins to elucidate the impact of varying stimulation parameters in promoting neuroplasticity and functional recovery after SCI. KEY POINTS: Transcutaneous spinal cord stimulation (tSCS) has shown potential for targeting and improving spasticity after spinal cord injury (SCI) in both human and rodent research settings. However, the stimulation protocols used are variable and without consensus on the optimal stimulation parameters for targeting spasticity and hyperreflexia following SCI. We do not yet understand how various stimulation parameters, like frequency and intensity, influence neuroplasticity and functional recovery. Recent human and rodent work has identified a low frequency tSCS protocol to be effective for targeting spasticity after SCI. We used this established frequency to investigate the ideal tSCS intensity protocol for mitigating spasticity. We show that tSCS at alternating supra- and sub-motor threshold intensities preferentially improves hyperreflexia, the frequency-dependent modulation of the H-reflex, behavioural reflex activity, and neuroanatomical plasticity, collectively, compared to supra- or subthreshold stimulation alone. This study elucidates the impact of the stimulation intensity parameter on decreasing spasticity after SCI.