Publications

Vagus nerve stimulation (VNS) is emerging as potential treatment for several chronic diseases. However, limited control of fiber activation, e.g., to promote desired effects over side effects, restricts clinical translation. Towards that goal, we describe a VNS method consisting of intermittent, interferential sinusoidal current stimulation (i2CS) through multi-contact epineural cuffs. In experiments in anesthetized swine, i2CS elicits nerve potentials and organ responses, from lungs and laryngeal muscles, that are distinct from equivalent non-interferential sinusoidal stimulation. Resection and micro-CT imaging of a previously stimulated nerve, to resolve anatomical trajectories of nerve fascicles, demonstrate that i2CS responses are explained by activation of organ-specific fascicles rather than the entire nerve. Physiological responses in swine and activity of single fibers in anatomically realistic, physiologically validated biophysical vagus nerve models indicate that i2CS reduces fiber activation at the interference focus. Experimental and modeling results demonstrate that current steering and beat and repetition frequencies predictably shape the spatiotemporal pattern of fiber activation, allowing tunable and precise control of nerve and organ responses. When compared to equivalent sinusoidal stimulation in the same animals, i2CS produces reduced levels of a side-effect by larger laryngeal fibers, while attaining similar levels of a desired effect by smaller bronchopulmonary fibers.

Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders, but clinical applications are limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, researchers engineered VaStim, a realistic and efficient in-silico model. They developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations by combining models with trials on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. The complete realistic model is available as a free, publicly accessible tool with a web-based platform for optimizing VNS paradigms and electrode designs.

Vagus nerve stimulation (VNS) is a bioelectronic therapy where selective activation of afferent or efferent vagal fibers can maximize efficacy and minimize off-target effects. Evidence for directional VNS with anodal block (ABL) has been scarce and inconsistent. Through a series of vagotomies, physiological markers for afferent and efferent fiber activation by VNS were established: stimulus-elicited change in breathing rate (ΔBR) and heart rate (ΔHR), respectively. Cathode cephalad polarity caused an afferent pattern of responses (relatively stronger ΔBR) whereas cathode caudad caused an efferent pattern of responses. The study provides concrete physiological and neurophysiological evidence that anodal block is a viable mechanism for functionally demonstrable directional biasing in VNS, for a range of clinically relevant stimulation parameters.