The Effect of taVNS and Upper GI Motility

Visit 1 (screening visit) Following written informed consent, the medical history of each subject will be checked during a structured interview. A pregnancy will be excluded by a urine test (due to the use or fluoroscopy during insertion of the manometry catheter) and a 12-lead ECG will be performed at the end of the screening visit. The rationale for this is to ensure no evidence of cardiac conduction disorders and an additional safety step to ensure no cardiac dysrhythmic affect with tVNS use. All information obtained during the screening visit will be recorded in using an electronic CRF provided by Castor EDC, provided by the Clinical Trial Centre Maastricht (CTCM).

Visit 2 (test day) Participants will arrive after an overnight fast at the GI physiology unit of the Maastricht University Medical Center, where a trained and experienced nurse will insert an antroduodenal manometry catheter through the nose into the duodenum under fluoroscopy control and supervision of a gastroenterologist (as per routine clinical procedure). Using this catheter, stomach and duodenum motility patterns will be recorded for 8 hours. After the manometry is inserted, the tVNS device will be connected with an electrode which delivers stimulation transcutaneous in the outer ear. Participants will receive two types of stimulation (i.e. tVNS vs sham) in 2 blocks of 4 hours during the 8-hour registration period. The order of stimulation applied is randomized. Gastric phase III contractions generally occur every 90 minutes, so the 4-hour period is considered sufficient to detect two phase III contractions considered sufficient to detect the two phase III contractions.(10)

An iv catheter will be inserted to draw blood during the 8-hour registration period. Blood samples, each witch a maximum volume of 10 mL, will be taken every 30 minutes to measure motilin and PP as surrogate markers of vagal efferent influence on GI motor function. In addition, autonomic parameters will be registered during the entire test period, using a Shimmer3 GSR sensor. After the 8-hour test period, the manometry catheter, the electrodes of the tVNS device and the iv cannula are removed.

Additionally, participants may opt to take part in a body surface gastric mapping assessment. This non-invasive, electrophysiological measurement is performed using the Gastric Alimetry system, which involves placing a large adhesive patch with multiple electrodes on the upper abdomen. The system records gastric myoelectrical activity over time, providing insight into gastric motility patterns. The measurement is conducted concurrently with the manometry registration period.

• A clinically relevant increase in other upper GI motility parameters [Time frame: Assessed during one single test day, from pre-intervention baseline to post-stimulation (approximately 8-9 hours)]
• Concentration of plasma motilin and pancreatic polypeptide [Time frame: Assessed during one single test day, from pre-intervention baseline to post-stimulation (approximately 8-9 hours)]
• Autonomic response: heart rate variability [Time frame: Assessed during one single test day, from pre-intervention baseline to post-stimulation (approximately 8-9 hours)]
• Electrodermal response: skin conductance [Time frame: Assessed during one single test day, from pre-intervention baseline to post-stimulation (approximately 8-9 hours)]
• Agreement between gastric motility measurements obtained by antroduodenal manometry and Gastric Alimetry [Time frame: Assessed during one single test day, from pre-intervention baseline to post-stimulation (approximately 8-9 hours)]