VNS Modulation of the Central Autonomic Network and its Effects on ANS

ANCILLARY PROJECT 3 Abstract: The effects of high frequency microburst VNS on peripheral organ systems LivaNova recently introduced an IDE-regulated novel VNS device called Microburst which enables a wider range of stimulation parameters than what is clinically available. It is thought to have more robust electrophysiological effects on the brain and possibly the cardiovascular system. We propose to expand REVEAL and the Common Study Protocol’s (CSP) scope and low frequency VNS modulation (1 to 30 Hz) of multiple peripheral organs and their unique responses to higher frequency (100 to 350 Hz), pulse set and interburst intervals. Newly implanted Microburst VNS patient (m-VNS; N=30) will complete the CSP with standard parameters. Once they exit the main protocol, they will undergo a 3-week washout period (VNS OFF) and repeat the CSP with Microburst settings. We will test participants on multi-organ measured physiological outcomes twice: immediately after a 3- week washout period (Early Microburst Effects - Visit 3; Visit 1 and 2 being the main CSP) and 12 weeks after (Late Microburst Effects - Visit 4). Three different stimulation settings (100, 200 and 350 Hz) per patient will be evaluated within and between each of these 2 visits. Outcome measures include: arterial pressure, cardiac sympatho-vagal tone, muscle sympathetic nerve activity (MSNA), autonomic reflex function, cardiac mechanics, glucose and lipid metabolism, and immune function. Results will also be compared to those from the CSP and standard stimulation parameters. m-VNS patients will be followed for up to one year on clinical outcomes for regulatory purposes and to ensure patient safety. We have assembled a multi-disciplinary team of highly qualified investigators. Through a rigorous study design with newly implanted high frequency m-VNS and a comprehensive battery of relevant and leading-edge outcome measures, we will complement REVEAL’s multi- system view of the vagus nerve’s functional connectivity in humans and lay the groundwork for new VNS-based research and therapies.