Abstracts

Rationale: Vagus nerve stimulation (VNS) is a device-based therapy for treatment-resistant temporal lobe epilepsy. Patterned electrical stimulation of the left vagus nerve mediates the therapeutic effects, but the mechanisms remain unclear. The same stimulus yields differential vagal nerve activation across patients, making efficacy comparisons between studies impossible and those within limited. If the effects of VNS are conveyed by nerve fibers activated in response to stimulation, then a more objective method of investigation and therapy is with respect to the type, proportion and rate (or pattern) of nerve fiber activation. This methodology enables comparisons of therapeutic efficacy and biomarker level changes with respect to the biological conduit of the therapy. Furthermore, it opens avenues for closed-loop control of VNS efficacy. Methods: An Automated Nerve Control (ANC) System is presented. The closed-loop system autonomously predicts the level of nerve activation in response to any rectangular stimulus pulse. In doing so, it analogously derives a customized guide for activating 0-100% of A, B, or C fiber types within a nerve. A feedback signal between the predicted and measured nerve response is used to maintain any level of A, B, or C fiber activation. A single adjustment to the stimulus pulse amplitude or duration, as predicted by the ANC System, yields any desired A, B, or C fiber activation level. Results: In rats, the ANC System rapidly predicts the level of vagal A, B, or C fiber activation in response to any rectangular stimulus pulse. Depending on the pulse repetition frequency (PRF) and ambient noise, the nerve activation prediction routine takes 0.5-5 min to complete. Then, the nerve activation level is maintained or adjusted in real time by entering a new activation level for one of the identifiable fiber types. Initial prediction accuracy is typically greater than 90% and improves over time as the therapy is delivered. Data demonstrate a unique ability to overcome natural and stimulus-induced changes in nerve excitability. Relative to the gold standard, constant stimulation mode of VNS therapy, the ANC System provides more consistent and reproducible control over the activity of structures innervated by the various fiber types in the vagus nerve. Conclusions: The ANC System provides a simplified dosing mechanism for electrical stimulation therapy by using the activation level of identifiable fiber types within a nerve and the PRF (or pattern) as the basis of efficacy tuning. It therefore provides a path to more consistent, efficacious and robust treatment responses as well as a less intensive stimulus adjustment period for device recipients. This enhanced treatment response stems from patient-tailored, algorithm-guided control over vagal afferent and/or efferent structures via controlled vagal nerve activation therapy.