Enhancing Sympathetic Outflow Control Following Spinal Cord Injury Using Targeted Plasticity Therapy

Abstract Almost all sympathetic outflow control pathways travel through the spinal cord for affecting the peripheral tissues. Cervical spinal cord injury impacts sympathetic outflow control, leading to several debilitating deficits (in addition to paralysis), including an inability to redistribute blood to active tissues and muscle fatigue. There are currently no consistently effective treatments for sympathetic outflow control dysfunction following cervical spinal cord injury. The long-term goal of this research is to address this significant gap using vagus nerve stimulation paired with rehabilitation to enhance sympathetic outflow control following cervical spinal cord injury. Pairing vagus nerve stimulation with movements during rehabilitation leads to the rapid release of plasticity enhancing neuromodulators, leading to the reorganization of motor control systems. The objective of this proposal is to determine the specific effects of vagus nerve stimulation paired with rehabilitation on sympathetic outflow control following cSCI, and determine the neural pathways contributing to these effects. We will also assess the optimal delivery regime for vagus nerve stimulation (with or without rehabilitation). Our central hypothesis is that vagus nerve stimulation precisely paired with movements during rehabilitation enhances the plasticity of spared sympathetic outflow control circuits, leading to improved motor endurance and muscle fatigue resistance following cSCI. We will assess this hypothesis via three specific aims: 1) determine the effects of vagus nerve stimulation paired with rehabilitation on forelimb muscle and cardiovascular function; and measure changes in 2) cortical and 3) subcortical plasticity related to sympathetic outflow control. We will pursue these aims using multidisciplinary assessments, leveraging electrophysiological and neuroanatomical techniques. The proposed research is significant, as it will determine if vagus nerve stimulation paired with rehabilitation is a viable therapy for treating sympathetic control dysfunction following cervical spinal cord injury. Furthermore, these results will elucidate the critical relationships between forelimb function, sympathetic outflow control, vagus nerve stimulation therapy, and neuroplasticity.