Control of spatiotemporal activation of organ-specific fibers in the swine vagus nerve by intermittent interferential current stimulation

Nicolò Rossetti, Weiguo Song, Philipp Schnepel, Naveen Jayaprakash, Dimitrios A. Koutsouras, Mark Fichman, Jason Wong, Todd Levy, Mohamed Elgohary, Khaled Qanud, Alice Giannotti, Mary F. Barbe, Frank Liu Chen, Geert Langereis, Timir Datta-Chaudhuri, Vojkan Mihajlović and Stavros Zanos ()
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Nicolò Rossetti: imec
Weiguo Song: Feinstein Institutes for Medical Research and Northwell Health
Philipp Schnepel: imec
Naveen Jayaprakash: Feinstein Institutes for Medical Research and Northwell Health
Dimitrios A. Koutsouras: imec
Mark Fichman: imec
Jason Wong: Feinstein Institutes for Medical Research and Northwell Health
Todd Levy: Feinstein Institutes for Medical Research and Northwell Health
Mohamed Elgohary: Feinstein Institutes for Medical Research and Northwell Health
Khaled Qanud: Feinstein Institutes for Medical Research and Northwell Health
Alice Giannotti: Sant’Anna School of Advanced Study
Mary F. Barbe: Temple University School of Medicine
Frank Liu Chen: Temple University School of Medicine
Geert Langereis: imec
Timir Datta-Chaudhuri: Feinstein Institutes for Medical Research and Northwell Health
Vojkan Mihajlović: imec
Stavros Zanos: Feinstein Institutes for Medical Research and Northwell Health

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59595-4

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