Organ- and function-specific anatomical organization and bioelectronic modulation of the vagus nerve

Afferent and efferent fibers in the vagus travel inside nerve fascicles and form branches to innervate organs and regulate organ functions. The organization of fibers and fascicles in the vagus trunk, with respect to the functions they mediate and the organs they innervate, remains largely unknown. Accordingly, it is unknown whether that anatomical organization can be leveraged by bioelectronic devices for function- and organ-specific neuromodulation. To characterize the microscopic functional anatomy of the vagus we developed a pipeline consisting of micro-computed tomography-based morphometry of fascicles and quantitative immunohistochemistry of single fibers. We found that, in the swine vagus, fascicles form clusters specific to afferent and efferent functions, increasingly separated in the rostral direction, and other clusters specific to the innervated organs, including larynx, lungs and heart, increasingly separated in the caudal direction. Large myelinated and small unmyelinated efferents have small counts, occupy large area of the nerve, and are limited to specific fascicles; small unmyelinated afferents have large counts, occupy small area, and are uniformly distributed across fascicles. To test whether fiber populations can be selectively modulated, we developed a multi-contact cuff electrode that observes the fascicular vagus anatomy. Targeting of different nerve sub-sections evokes compound action potentials from different fiber types and elicits differential organ responses, including laryngeal muscle contraction, cough reflex, and changes in breathing and heart rate. Our results indicate that vagus fibers are spatially clustered according to functions they mediate and organs they innervate and can be differentially modulated by spatially selective nerve stimulation. ### Competing Interest Statement The authors have declared no competing interest.