Selective Stimulation of the Vagus Nerve for the Mitigation of Laryngeal Side Effects
Vagus nerve stimulation (VNS) is an FDA-approved treatment for epilepsy and depression. VNS is further being investigated for a number of other maladies, including tinnitus, Crohn’s disease, and heart failure. While the mechanism of action is only partially understood, it involves the activation of visceral afferent fibers from organs like the heart, lungs, and gut to elicit changes in the brain via connections with the nucleus of the solitary tract. While effective, adverse effects limit the ability to provide stimulation to the nerve, as stimulation parameters are titrated to maximum tolerable levels. Some side effects, particularly dysphonia, the most common side effect, are mediated by stimulation of the fibers of the recurrent laryngeal nerve (RLN) branch. Therefore, VNS can be made more tolerable and possibly more efficacious if the stimulation of RLN fibers could be avoided. In this study, we utilize multi-contact electrode cuffs in the vagus nerve of the rat to restrict the volume of stimulation in order to avoid the fibers of the RLN. A morphometric analysis was performed on semi-thin sections of the main fascicle of the cervical vagus nerve. Clustering algorithms are used to determine that at the level of implantation in the rat, large myelinated fibers, which likely branch off with the RLN, cluster together in bundles that may be avoided. Additionally, small myelinated fibers, which are more likely to be the visceral afferent fibers that lend clinical efficacy to the treatment, are found to have their own regions of high density within the nerve. The data suggests that spatial targeting for the mitigation of laryngeal side effects might be possible by avoiding the stimulation of clusters of large myelinated fibers. Different spatial configurations of a multi-contact nerve cuff were used to stimulate the vagus nerve at different locations around the periphery of the nerve. Compound action potentials were recorded on a proximal site along the vagus nerve, and a distal site along the RLN. Examples of selective stimulation are analyzed and presented. Results show that selectivity of vagal activation, defined as the ability to stimulate small myelinated fibers in the VN while minimizing RLN activation, is possible with a multi-contact electrode cuff. This is further confirmed by looking at the distribution of large myelinated fibers relative to the placement of the electrode cuff in the harvested nerves of stimulated animals. However, the electrode configuration necessary for optimal selectivity is random, as knowledge of the location of fiber clusters in the nerve cannot be determined before implantation. In summary, the main fascicle of the rat cervical vagus nerve is organized such that large myelinated fibers and small myelinated fibers tend to cluster with each other and occupy separate regions of space in the nerve cross-section. A multi-contact electrode cuff can be used to selectively activate bundles of small myelinated fibers to avoid adverse laryngeal effects. Similar designs may be able to be translated into the clinic, where the selection of the ideal electrode configuration can be integrated into the already existing titration system for the determination of optimal stimulation parameters.