Exploring the Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation in Alleviating Nausea in Healthy Adults: a Double-blind Randomized Controlled Trial

Visit 1 Interested study participants will receive a verbal explanation of the study over the phone and will be sent a comprehensive electronic information letter. At least 7 days later, they will be invited to attend an inclusion visit at Maastricht University. During this visit, participants will undergo eligibility screening and receive detailed instructions regarding the study procedures. Eligible participants will be asked to provide written informed consent before proceeding. Subsequently, eligible participants will be asked to complete several (digital) questionnaires, including a baseline characteristics questionnaire, the Generalized Anxiety Disorder 7-Item Scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), and the Big Five Inventory (BFI). All information obtained during the screening visit, including participant data and study-related details, will be securely recorded using Castor, an electronic data capture system. After this screening visit participants will be randomized in a 1:1 parallel design by an investigator to receive either taVNS or sham stimulation on the second test day, with appropriate blinding procedures in place.

Visit 2 A second visit, which serves as the test day, will be scheduled. During this visit, participants will receive either taVNS or sham stimulation, administered immediately after nausea induction, based on their randomization.

Participants will arrive at the NUTRIM CRU at Maastricht University after an overnight fast. Compliance with test day regulations will be checked (e.g. fasting, no alcohol). Once compliance is confirmed, the coordinating investigator will properly set up the tVNS device to ensure it can be used immediately after nausea induction. This setup includes adjusting the stimulation current of the tVNS device according to each participant's sensitivity, ensuring it remains below the sensitivity threshold, with current intensities ranging from 0.25 to 10 mA. This is important because active stimulation will be programmed to deliver only subthresholdstimuli. Next, an intravenous cannula will be placed for blood collection. Thereafter, the investigator (a medical doctor) will manually place a nasogastric tube to facilitate the intragastric infusion of a 50% fat emulsion in water. This method of infusion is selected to replicate the conditions under which dietary fat is ingested as part of a meal. The infusion will be administered at a rate of 5 ml/min, consistent with previous research in which nausea was induced through similar methodologies (1). Participants will be closely monitored throughout the infusion for the onset of nausea, with assessments every 5 minutes using a 0-100 Visual Analogue Scale (VAS) to quantify the nausea severity. Participants will receive clear instructions on how to rate their nausea and indicate its intensity. If a predetermined VAS score of 50/100 is reached, or should the participant start retching, the lipid infusion will be promptly halted to prevent excessive discomfort. Participants will be informed in advance about the 50/100 VAS threshold and provided with guidance on how to interpret and apply this rating. Following the cessation of the infusion, the nasogastric tube will be removed for patient comfort, after which either taVNS or sham stimulation will be administered for 30 minutes.

A duration of 30 minutes was selected based on the mechanism of action of taVNS, which is assumed to act via the activation of the nucleus of the solitary tract (NTS) in the brainstem. Furthermore, this choice is also consistent with other studies on taVNS conducted within our department (NL87188.068.24/METC 24-029). The NTS serves as the primary relay station for vagal input and plays a critical role in modulating autonomic functions. In a previous study by Frangos et al. (24), NTS activity gradually decreased during stimulation but peaked shortly after the cessation of a 7-min stimulation of the cymba conchae. Furthermore, other brain regions exhibited a gradual increase in activity during stimulation, reaching their peak during the post-stimulation phase, with this heightened activity persisting for up to 11 minutes. Hence, a stimulation period of 30 minutes is expected to provide an optimal timeframe for taVNS to exert its maximum effect and to counterbalance the effects of nausea.

Both the taVNS treatment and sham stimulation will be administered using a tVNS device that provides stimulation to the cymba conchae of the left ear. The left side is chosen due to the innervation pattern of the left vagus nerve, which predominantly innervates the stomach and the pyloric area (25, 26). This choice aligns with our ultimate clinical interest in conditions such as gastroparesis and functional dyspepsia. Additionally, it ensures comparability with other studies conducted within our department, including the "tVNS and GI motility" study (NL86446.068.24).