Transcutaneous Spinal Cord Stimulation for Autonomic Recovery after Spinal Cord Injury: Therapeutic Potential and Underlying Mechanisms

Abstract The public often perceives paralysis as the most devastating consequence of SCI. Yet among individuals with SCI, autonomic dysfunctions [e.g. blood pressure (BP) dysregulation, bladder and bowel dysfunction] are primary health concerns and leading causes of morbidity and mortality. Not surprisingly, regaining autonomic control is rated among the highest priorities for recovery in individuals with SCI, and is also recognized among clinicians, researchers and funding organizations. SCI triggers a pernicious cascade of autonomic dysfunctions, among which the cardiovascular, bladder and bowel dysfunctions are key determinants of quality of life. Cardiovascular dysfunction manifests as extremely labile BP, where systolic BP can spike up to 300mmHg [autonomic dysre?exia (AD)] causing cerebral hemorrhage, seizures and even death. Surprisingly within the same individual, BP can drop to as low as 50mmHg (orthostatic hypotension), resulting in fatigue, inability to participate in rehabilitation, cognitive decline and ischemic stroke. Furthermore, these individuals also su?er from debilitating urinary tract and bowel dysfunctions. Not only do these issues exert individual negative impacts on quality of life, they also have life-threatening interactions. For example, stimuli from bowel and bladder (during care, catheterization or evaluation) are most frequent triggers of severe episodes of AD. Although considerable strides have been made in the management of symptoms, promoting meaningful functional recovery has largely remained a challenge. Despite wide clinical use, the pharmacological agents have signi?cant limitations as they require approximately an hour to become active and result in prolonged cardiovascular side-e?ects. Conversely, the BP instability in people with SCI commonly occurs over just a few minutes and tends to cease rapidly. Thus, using long-acting agents to manage short-acting conditions is not the most appropriate approach. Recently, there has been a paradigm shift in the treatment of dysautonomia in SCI. Many reports have now shown that invasive methods of spinal cord stimulation (i.e. epidural electrodes) can promote motor as well as autonomic recovery. Encouragingly, it is now established that non-invasive TCS activates similar neural networks as epidural stimulation. Along with our clinical ?ndings, the pre-clinical pilot data demonstrates that non-invasive TCS improves autonomic function after SCI, without the need for surgery and permanently implanted devices. This warrants a systematic exploration of this therapeutically promising avenue. Clear delineation of the mechanisms is a crucial knowledge gap before wider clinical deployment of this therapy. Therefore, we propose to investigate TCS that is arguably more e?cient and modi?able to modulate most vital autonomic functions (i.e. cardiovascular, bladder and bowel control) in rats with clinically relevant SCI. Timely completion of the proposed pre-clinical experiments will not only examine underlying mechanisms but also augment and expedite the clinical translation of this non-invasive therapy to potentially improve the quality of life in individuals with SCI.