Novel approaches to study vagus nerve functional anatomy and signaling in different species

A new interdisciplinary field called Bioelectronic Medicine (BM) has produced an unprecedented revolution in the medical field, challenging the classical pharmacological approach to treat chronic diseases. The goal of BM is to treat diseases with an electrical modulation of the autonomic nervous system activity. The autonomic nervous system is a master regulator of whole-body homeostasis, and it comprises a twisted tangle of visceral nerves that mediate bidirectional communications between the central nervous system and visceral organs. In this intricate forest, the vagus nerve (VN) stands out as the most complex and widespread nerve, endowed with a wide variety of fibers that extensively innervate organs of different systems and regulate several physiological processes. Given its multifaceted role, the VN is one of the most promising targets in BM, with several clinical trials investigating VN stimulation (VNS) as a new therapeutic approach for different conditions. However, the current VNS strategy has several limitations, including the optimal anatomical target site, the most biocompatible neural interface to use, and the most efficient stimulation strategies to adopt. A potential solution would be to develop a temporally- and spatially-selective closed-loop strategy that incorporates both anatomical and electrophysiological VN properties. However, this approach would rely on the precise knowledge of VN functional anatomy and signaling, which is still incomplete and deserves further investigations in animal models and ultimately in humans. The goal of the studies presented in this thesis is to fill this gap of knowledge by studying VN anatomy and electrophysiology in different species through novel approaches and techniques. Herein, I first review most of the relevant literature about the VN to depict the vagal system complexity. Secondly, I describe the most relevant clinical achievements in the field of BM and the VNS outstanding challenges. Finally, I present three experimental studies performed by our laboratory to address these challenges. The first study consisted of developing multimodal structural analysis to characterize vagal fascicular comparative anatomy in pigs, sheep, and humans. The second study implemented and validated an ultrasound-guided microneurography approach that allows unitary recordings from the human cervical vagus nerve. The last study combined multichannel intraneural VN recordings with a novel decoding algorithm to detect functional changes in the cardiovascular and respiratory systems and revealed functional compartmentalization of vagal fascicles within the cervical trunk. These studies represent an important step towards a more complete comprehension of VN signaling and functional anatomy, paving the way for the development of effective closed-loop VNS systems.