A simple, non-invasive approach to detect vagal nerve response patterns that predict a positive treatment response to gastric electrical stimulation therapy for gastroparesis v1
Authors: Ward Matthew , Rajwa Bartek , M Wo John , Gupta Anita , Furness John , Powley Terry , V Nowak Thomas 
Published: November 2020

Protocol Title: A simple, non-invasive approach to detect vagal nerve response patterns that predict a positive treatment response to gastric electrical stimulation therapy for gastroparesis [1] Background: Gastric electrical stimulation (GES) can be a life-changing, device-based treatment option for drug-resistant nausea and vomiting associated with diabetic or idiopathic gastroparesis (GP).Despite over two decades of clinical use, the mechanism of action remains unclear.We hypothesize a vagal mechanism, whereby GES activates vagal sensory afferents that project to the nucleus of the solitary tract and onward to influence brain structures that mediate the biological processes leading to nausea and vomiting (e.g., area postrema). Here, we describe a noninvasive method to investigate vagal nerve involvement in GES therapy in human subjects.We have developed transcutaneous recording of cervical vagal activity that is synchronized with GES in conscious subjects, along with methods of discriminating the activity of different nerve fiber groups that are activated.We are refining the system of recording and analysis so that it can be applied in the clinic. New Method: Sixty-six adults receiving GES therapy (Medtronic Enterra I/II) to treat refractory nausea and vomiting secondary to diabetic, idiopathic, or postoperative GP were enrolled in the study (IRB #:1206008988). Subjects completed a GCSI symptom survey upon enrollment. The left and right cutaneous vagal electroneurograms (vENG) were collected from the skin surface over the left and right cervical vagal nerves, respectively, without changing the prescribed GES parameters. The mean response to GES was computed for each subject and classified according to the Letter System for nerve fiber classification. Symptom scores were compared between groups of subjects with or without significant Ab, Ag, Ad, or B fiber responses, defined as volleys in the mean response to GES whose peak amplitude is significantly different from 0 V ata=0.05. Nerve responses were correlated with GP symptoms. Results: Of the 66 subjects, 28 had diabetic GP (type 1:9; type 2:19), 35 had idiopathic GP, and 3 had postsurgical GP. Stimulus pulse current and charge did not predict treatment efficacy, but did predict a significant increase in total symptom score in type 1 diabetics as GES stimulus charge per pulse increased (p < 0.01), representing a notable side effect and providing a method to identify it. In contrast, the number of significant left and right vagal fiber responses that were recorded was directly related to patient symptom improvement.Increased vagal responses correlated with significant decreases in total symptom score (p < 0.05). Taken together, our analysis suggests that it is possible to extract meaningful information pertaining to vagal activity with noninvasive electrodes and that specific fiber response profiles predict improvements in specific symptoms of gastroparesis. Conclusions: Cutaneous vagal CNAP analysis is a useful technique to unmask relationships among GES parameters, vagal recruitment, efficacy and side-effect management. Our results suggest that CNAP-guided GES optimization will provide the most benefit to patients with idiopathic and type 1 diabetic GP, especially when tuned for left vagal Ag and right vagal Ad/B fiber responses. The possible side effects associated with left vagal Abactivation in type 1 diabetics underscore the need to consider disease etiology and fiber recruitment profiles in the patient and parameter selection process. Funding Acknowledgment This work is supported, in part, by NIH SPARC OT2OD028183 and NIH SPARC OT2OD023847. Publication/Abstract Reference: [1] Ward M.P., Rajwa B., Wo J.M.,Gupta A.,Furness J.B., Powley T.L., and T.V. Nowak. An emerging method to noninvasively measure and identify vagal response markers to enable bioelectronic control of gastroparesis symptoms with gastric electrical stimulation.Journal of Neuroscience Methods 336, pp. 1-13, Feb 2020. PMID:32087238 DOI:10.1016/j.jneumeth.2020.108631