Background: Cervical vagus nerve stimulation (VNS) is an emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. Methods: In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (DHR) and breathing interval (DBI). Quantitative models were established to capture the relationship between A-, Band C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results: In bivariate analyses, we found that EMG correlates with A-fiber, DHR with B-fiber and DBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS.

Threshold-intensity (122 trains) Supra-threshold intensity (75 trains) C. caud. C. ceph. Pol. diff. C. caud. C. ceph. Pol. diff.

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in 4 research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.

The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.