Computational modeling of human vagus nerve stimulation with three-dimensional fascicular morphology

Implanted vagus nerve stimulation is FDA-approved to treat epilepsy, depression, and stroke sequelae and is under development for other disorders such as heart failure and rheumatoid arthritis. Anatomically realistic computational models enable the design of electrodes and stimulation parameters that activate nerve fibers that mediate therapeutic responses, and avoid activating fibers that cause side effects. Conventional modeling techniques assume constant longitudinal morphology, extruding a single cross section to define the three-dimensional nerve geometry. However, recent imaging data showed that human vagus nerves have extensive fascicle splitting and merging along their length. Therefore, we developed a pipeline to simulate true three-dimensional (true-3D) models of peripheral nerve stimulation from segmentations of micro-computed tomography imaging. We implemented models of n = 4 human vagus nerves and systematically evaluated extrusion vs true-3D model responses to electrical stimulation across population dose-response relationships, fiber-specific thresholds, recruitment order, and spatial selectivity. Despite the complex morphology of the human vagus nerve, extrusion models replicated the true-3D neural responses if: (1) the nerve morphology was deformed to a circular cross section, as occurs with chronic cuff implants, and (2) the extruded cross section was centered under the depolarizing electrode contact. Our pipeline provides a foundation for advanced modeling of peripheral nerve stimulation and the design of more selective stimulation therapies.