Identification of low threshold off-target activation pathways during stimulation of carotid baroreceptor afferents...

Objective.Electrical stimulation of the baroreceptors pathways at the carotid sinus bulb-known as baroreflex activation therapy (BAT)-is intended to change autonomic tone and ultimately reduce blood pressure (BP) and heart rate. BAT is pre-market approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure and received an FDA humanitarian device exemption for drug resistant hypertension. However, responder rates are limited by side-effects including numbness in the head and neck, altered speech, respiratory constriction, dry cough, vomiting, and altered sensory and motor function of the tongue (TN). We hypothesized that these side-effects are driven by activation of other nearby nerve fibers of similar or lower threshold than the carotid sinus nerve. In this study, we sought to identify the neural sources responsible for off-target muscle activation contributing to these side-effects. These sources would inform strategies mitigating off-target activation in BAT therapy.Approach.Domestic swine were used in this work as the diameter and thickness of the swine carotid artery are closer to human than those of canine models. A monopolar disk electrode mimicking the clinical CVRx® Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in BP. Evoked responses were recorded during dose response testing from multiple neck muscles, and the corresponding off-target nerve pathways were identified by sequential transection of nearby nerves.Main results.The following activated off-target muscle groups and their corresponding nerve pathways were verified which included (1) the cricoarytenoid via recurrent laryngeal nerve, (2) cricothyroid via superior laryngeal nerve, (3) sternocleidomastoid via accessory nerve, and (4) the TN via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway.Significance.We identified multiple sources of therapy-limiting side-effects of BAT in the swine model. These results will help guide the design of improved stimulation electrodes, surgical placement, and parameter programming to reduce BAT-associated side-effects while increasing on-target activation in patients.