The Impact of Transcutaneous Spinal Cord Stimulation on Autonomic Regulation after Spinal Cord Injury: A randomized crossover trial

Abstract Importance Individuals with spinal cord injury (SCI) have significant autonomic nervous system dysfunction. However, despite recent findings postulated to support that spinal cord stimulation improves dynamic autonomic regulation, limited scope of previous testing means the true effects remain unknown. Objective To determine whether transcutaneous spinal cord stimulation improves dynamic autonomic regulation after SCI. Design Single-blinded, randomized crossover trial with matched cohorts. Setting Academic autonomic physiology laboratory. Participants Two pairs of well-matched individuals with and without high-thoracic, complete SCI. Interventions Sub-motor threshold transcutaneous spinal cord stimulation delivered at T10-T11 using 120Hz, 30Hz, and 30Hz with 5kHz carrier frequency at separate autonomic testing sessions. Main Outcomes and Measures Baseline autonomic regulation was characterized with tests of above injury level sympathoexcitation (Valsalva’s maneuver), sympathoinhibition (progressive doses of bolus intravenous phenylephrine), and below level sympathoexcitation (foot cold pressor test). At three subsequent visits, this testing battery was repeated with the addition of spinal cord stimulation at each frequency. Changes in autonomic regulation for each frequency were then analyzed relative to baseline testing for each individual and within matched cohorts. Results Uninjured controls demonstrated no autonomic deficits at baseline and had no changes with any frequency of stimulation. Contrasting this, and as expected, individuals with SCI had baseline autonomic dysfunction. In a frequency-dependent manner, spinal cord stimulation enhanced sympathoexcitatory responses, normalizing previously impaired Valsalva’s maneuvers. However, stimulation exacerbated already impaired sympathoinhibitory responses, resulting in significantly greater mean arterial pressure increases with the same phenylephrine doses compared to baseline. Impaired sympathoexcitatory response below the level of injury were also further exacerbated with spinal cord stimulation. At baseline, neither individual with SCI demonstrated autonomic dysreflexia with the noxious foot cold pressor test; the addition of stimulation led to a dysreflexic response in every trial, with greater relative hypertension and bradycardia indicating no improvement in autonomic regulation. Conclusions and Relevance Transcutaneous spinal cord stimulation does not improve autonomic regulation after SCI, and instead likely generates tonic, frequency-dependent sympathoexcitation which may lower the threshold for autonomic dysreflexia. Trial Registration Transcutaneous Spinal Cord Neuromodulation to Normalize Autonomic Phenotypes; NCT04858178 . https://clinicaltrials.gov/ct2/show/NCT04858178 Key Points Does electrical spinal cord stimulation, at any previously advocated stimulation frequency, improve regulation of the autonomic nervous system for individuals with spinal cord injuries? In this randomized crossover trial, transcutaneous spinal cord stimulation generated tonic, frequency-dependent sympathetic activation below the level of injury, without improved dynamic autonomic regulation. Tonic sympathetic activation below the level of injury could lower the threshold for potentially dangerous autonomic dysreflexia in individuals with spinal cord injury and future work should employ appropriate monitoring.