Spinal Cord Stimulation to Improve Autonomic Regulation After Spinal Cord Injury: Can Reflex Control Be Restored?

Spinal cord electrical stimulation has recently become popular as a research tool to improve function in individuals with spinal cord injuries (SCI). Headline-worthy study after study demonstrate that this form of neuromodulation can allow individuals with paralysis to move, stand, and even walk— a previously unthinkable achievement.1–4 Subsequent work has sought to replicate these gains within the autonomic nervous system.5–7 This is a commendable undertaking; autonomic dysfunction has broad and significant clinical implications and is the source of many patients’ top health concerns.8 Studies using spinal cord stimulation to address autonomic dysfunction have largely been aimed at ameliorating orthostatic hypotension9 by supporting blood pressure.10 Blood pressure falls with upright tilt in those with SCI due to lack of sympathetic activity below the injury, despite appropriate compensatory tachycardia.11 Hence, spinal cord stimulation may be used to stimulate vascular sympathetic outflow below the lesion, preventing hypotension and obviating the need for tachycardia. This would suggest improved autonomic regulation, where the nervous system compensates to dynamic challenges to maintain homeostasis. The premise for this theory of improved autonomic regulation is modeled from responses to stimulation of the motor system wherein weak signaling pathways through the cord are amplified to achieve volitional movement. However, the motor and autonomic systems encompass vastly different regulatory mechanisms. For volitional muscle activation, central motor command elicits volleys of efferent signals down the cord proportional to perceived effort.12 After chronic paralysis, one can imagine the voluntary effort and corresponding efferent volleys are near maximal with attempted movement. However, the autonomic system is not subject to voluntary control. There is a myriad of redundancies in regulatory systems to maintain homeostasis. Indeed, autonomic responses can be either sympatho-excitatory or sympatho-inhibitory.13 Perhaps the best example of the former is the isometric exercise pressor response. At the end of sustained isometric exercise to fatigue, central command, the “feedforward mechanism involving parallel activation of motor and cardiovascular centers,”14 is maximal. In addition, group III and IV afferent feedback from the ischemic exercising muscle is maximal. As a result, directly measured neural sympathetic outflow can approach some of its highest levels.15 However, this response is not independent of autonomic sympatho-inhibitory regulation. The arterial baroreflex is sympatho-inhibitory, wherein increased stretch of barosensory vessels (the aortic arch and carotid sinus) increase afferent baroreceptor nerve firing, inhibiting sympathetic outflow to maintain pressure.16 In the context of orthostasis, reduced barosensory vessel stretch results in a “permissive” rise in sympathetic outflow. This is essentially taking the foot off the brake to promote compensatory vasoconstriction and vagal withdrawal for tachycardia. Following SCI, this spinal cord-mediated vasoconstriction is often impaired below the level of the injury.17Spinal cord stimulation in those with SCI during orthostasis may increase blood pressure through sympathetic activation, but it may not involve improved autonomic regulation by boosting weak regulatory pathways through the injured cord. In fact, spinal cord stimulation could induce unperceived pain or activation of local branched calcitonin gene-related peptide (CGRP)–related afferent fibers in the dorsal horns,18 leading to sympatho-excitation through autonomic dysreflexia.10,19 It could also cause venoconstriction, reducing venous pooling and allowing for a more effective compensatory tachycardia.20 Although preventing orthostatic intolerance is important for health in those with SCI, further work is necessary to define the exact mechanism. Inducing repeated dysreflexia would not represent an effective strategy for long-term health. Autonomic dysreflexia is associated with transient immunosuppression21 and chronic stimulation may lead to potentially dangerous hypertensive crises.To identify whether autonomic regulation can be improved, appropriate tests encompassing both sympatho-excitatory and sympatho-inhibitory pathways must be employed with and without spinal cord stimulation and comprehensive measures must be made (e.g., regional blood flows). Only in this way can we discern the ability of stimulation to truly enhance reflex autonomic regulation.