Tsiptsis, C. | Search bioRxiv

bioRxiv2026

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

ObjectiveElectrical 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 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. 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. MethodsDomestic 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(R) Neo electrode was surgically placed proximal to the carotid bifurcation with the position optimized for stimulation dose responsive changes in blood pressure. 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. ResultsThe 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 tongue via hypoglossal nerve. The constrictor muscle group was also activated through a more complex neural pathway. ConclusionWe 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.

bioengineering↗

bioRxiv2025

Micro-CT Analysis of a Needle to Nerve Approach for Interfascicular Peripheral Nerve Stimulation in Porcine Nerves

MotivationPeripheral nerve interfaces typically have a tradeoff between selectivity and invasiveness. Interfascicular interfaces placed within the peripheral nerve, but outside of the fascicles preserving the perineurium are a promising avenue in balancing this tradeoff. This study quantifies electrode placement using novel tools designed to deliver flexible microwires interfascicularly in a porcine model. MethodsSeven Yorkshire pigs were implanted with Minimally invasive interfascicular Nerve Stimulation (MiiNS) arrays in the nerves of the brachial plexus resulting in a total of ten implanted nerve samples. High-resolution micro-computed tomography (micro-CT) of implanted nerves stained with phosphotungistic acid (PTA) showed contact placement relative to fascicular anatomy and all other contacts. The analysis also examined the relationship between microwire trajectory angle and fascicle traversal. Further, in a subset of samples (n=4), hematoxylin and eosin (H&E) histological analysis was performed after micro-CT imaging. These histological images were coregistered with the micro-CT to validate the positional information of the micro-CT. ResultsAcross the 56 total MiiNS microwire placements, 84% were interfascicular, while 16% were intrafascicular, characterized by traversal through a fascicle. Contacts were broadly distributed throughout the nerves cross section and the majority (79%) were in the central half of the nerves cross section (R>0.707), with no evidence of angular clustering in any single direction. On average, nearest neighbor distances between contacts measured 2256.26{+/-}1760.28 {micro}m in 3D and 730.71 {+/-}564.83 {micro}m transversely, with implants spanning 10.3 {+/-} 4.3 mm along length of nerve. The angle of wire trajectory into the nerve was correlated with fascicle traversal, with steeper angles of insertion associated with more instances of fascicle traversal. Histological analysis corroborated the fascicular borders and wire placements found on micro-CT and demonstrated perineurium integrity. SignificanceInterfascicular implantation can reliably access both central and distributed regions of the nerve, while not being confined to a single plane, enabling access to regions which have been historically challenging to stimulate effectively. The observed nearest-neighbor transverse spacing between contacts is within the range of reported ideal values for selective activation. The MiiNS placement characteristics show its potential as an effective peripheral nerve interface alternative which achieves distributed contact placement, including in the center of the nerve volume, while remaining predominantly outside of the perineurium.

bioengineering↗