Effect of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Plasma Insulin Levels

Overview

The purpose of this study is to find out if investigators can stimulate the vagus nerve (a nerve in the body that runs from your brain to the large intestine), and influence insulin, C-peptide, and glucose levels. C-peptide is a substance that is created when insulin is produced and released into the body. The vagus nerve is a largely internal nerve that controls many bodily functions, including stomach function. Investigators hope that by stimulating the vagal nerve using the TeNS behind the ear, this stimulation can affect insulin levels, and this will help innovate treatment of patients with nausea, vomiting, and disordered stomach function, and patients with diabetes. Researchers hope to be able to measure the activity of the vagus nerve when it is stimulated in other ways. This could help investigators learn more about studying this nerve in the future.

Detailed description

STUDY OBJECTIVES

Primary: The research described in this protocol is best described as an extension of the researcher's current protocol which is designed to measure cervical compound vagal nerve action potentials in patients who have an implanted gastric electrical stimulation device (GESD). The difference is that only healthy volunteer subjects will be recruited and studied, and rather than undergoing gastric electrical stimulation (GES), volunteer subjects will undergo transcutaneous stimulation of the auricular branch of the vagus nerve (taVNS) to determine whether this modality will also influence plasma insulin, C-peptide and glucose levels. While not a part of the current proposal; if the results of this study are promising we anticipate applying electrical stimulation of the ABVN in future studies of gastroparetic patients with symptomatic nausea and vomiting.

Secondary/exploratory: If taVNS proves to have an effect on circulating plasma insulin levels, then a secondary component of this study is to determine which subject variables (age, gender, BMI) may influence this response. While not formally a part of this proposal, investigators anticipate future studies will be designed to determine the optimal stimulus parameters (stimulus current, frequency, pulse duration) needed to produce this effect. Researchers' previous investigation using percutaneous electrical nerve field stimulation (PENFS) have shown that this modality affects the sympathetic and parasympathetic controls or heart rate variability. The current proposal will also determine whether the same effect occurs with transcutaneous auricular vagus nerve stimulation (taVNS).

SPECIFIC AIM 1:

To determine if acute taVNS stimulation of the cymba concha area of the external ear in human subjects affects plasma insulin, C-peptide, and glucose levels.

Investigators' preliminary studies show that electrical stimuli applied to electrodes implanted in the serosa of the stomach augment plasma insulin levels in humans. Presumably this is due activation of sympathetic and parasympathetic nerves which also innervate the pancreas. Researchers propose to non-invasively access the vagus nerve by applying electrical stimuli to the cymba concha area of the human external ear. This area is innervated by the cutaneous branch of the vagus nerve which, in turn, sends branches to the sensory nucleus of the vagus nerve, the nucleus tractus solitarius, which then sends nerve fibers throughout the brainstem to control autonomic function throughout the autonomic nervous system.

SPECIFIC AIM 2:

To determine if acute taVNS of the cymba concha area of the external ear affects heart rate variability in human subjects.

Heart rate variability is governed by parasympathetic and sympathetic nerves. By using frequency-domain and time domain analysis it is possible to determine whether 1) taVNS activates the auricular branch of the vagus nerve, and 2) whether any observed effects are mediated through the parasympathetic and/or sympathetic autonomic nervous system.

SPECIFIC AIM 3:

To determine if the changes in plasma insulin, C-peptide, or glucose levels are associated with corresponding changes in parasympathetic or sympathetic activation.

By using frequency-domain and time-domain analysis of heart rate variability it is possible to determine whether any observed changes are due to activation of parasympathetic or sympathetic nervous system or a combination of both. Some subjects may show a greater change in plasma insulin, C-peptide or glucose levels than others during taVNS. Researchers propose to determine whether these changes are mirrored by corresponding alterations in parasympathetic and sympathetic nervous system activity.

Interventions

• Device Transcutaneous Auricular Vagus Nerve Stimulation
  Healthy adult participants will be assigned to either the stimulation group or the sham group. The stimulation group will receive mild stimulation from the TeNS device and the sham group will receive no stimulation but will believe that they are receiving stimulus.

Primary outcome measures

• Association between acute transcutaneous auricular vagus nerve stimulation and change in plasma insulin levels [Time frame: one month]
• Association between acute transcutaneous auricular vagus nerve stimulation and change in C-peptide levels [Time frame: one month]
• Association between acute transcutaneous auricular vagus nerve stimulation and change in glucose levels [Time frame: one month]
• Association between acute transcutaneous auricular vagus nerve stimulation and heart rate variability [Time frame: one month]
• Association between changes in heart rate variability and plasma insulin levels [Time frame: one month]
• Association between changes in heart rate variability and C-peptide levels [Time frame: one month]
• Association between changes in heart rate variability and glucose levels [Time frame: one month]

Secondary outcome measures (3)

• Correlation between gender and changes in circulating plasma insulin levels [Time frame: one month]
• Correlation between age and changes in circulating plasma insulin levels [Time frame: one month]
• Correlation between body mass index and changes in circulating plasma insulin levels [Time frame: one month]

Eligibility criteria

Inclusion criteria

• Healthy Volunteers
• Aged 18-70
• Willing to have ECG electrodes placed on their neck and chest areas.
• Willing to have electrodes placed in the external ear.
• Willing to have an indwelling catheter placed to avoid multiple sticks for blood draw.

Exclusion criteria

• Unable to provide consent.
• Diabetes diagnosis per patient report
• Having known allergies to adhesive on electrode pads or bandages
• Having gastric motility issues as determined by the PI or clinical coordinator.
• Taking any medications that may affect gastric motility or cardiac variability, i.e. alpha or beta blockers for hypertension.
• Pregnant females
• Those unwilling to have the taVNS device placed in their ear.
• Those unwilling to consent to a blood draw.
• Prisoners

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

United States · 1 center

• Indiana University Hospital — Indianapolis

Publications

• van der Voort IR, Becker JC, Dietl KH, Konturek JW, Domschke W, Pohle T. Gastric electrical stimulation results in improved metabolic control in diabetic patients suffering from gastroparesis. Exp Clin Endocrinol Diabetes. 2005 Jan;113(1):38-42. doi: 10.1055/s-2004-830525. PMID 15662594
• Huang F, Dong J, Kong J, Wang H, Meng H, Spaeth RB, Camhi S, Liao X, Li X, Zhai X, Li S, Zhu B, Rong P. Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complement Altern Med. 2014 Jun 26;14:203. doi: 10.1186/1472-6882-14-203. PMID 24968966
• Vosseler A, Zhao D, Fritsche L, Lehmann R, Kantartzis K, Small DM, Peter A, Haring HU, Birkenfeld AL, Fritsche A, Wagner R, Preissl H, Kullmann S, Heni M. No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men. Sci Rep. 2020 Nov 24;10(1):20466. doi: 10.1038/s41598-020-77430-2. PMID 33235256
• Kozorosky EM, Lee CH, Lee JG, Nunez Martinez V, Padayachee LE, Stauss HM. Transcutaneous auricular vagus nerve stimulation augments postprandial inhibition of ghrelin. Physiol Rep. 2022 Apr;10(8):e15253. doi: 10.14814/phy2.15253. PMID 35441808
• Yin J, Ji F, Gharibani P, Chen JD. Vagal Nerve Stimulation for Glycemic Control in a Rodent Model of Type 2 Diabetes. Obes Surg. 2019 Sep;29(9):2869-2877. doi: 10.1007/s11695-019-03901-9. PMID 31222497
• Payne SC, Ward G, Fallon JB, Hyakumura T, Prins JB, Andrikopoulos S, MacIsaac RJ, Villalobos J. Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model. Physiol Rep. 2022 Apr;10(8):e15257. doi: 10.14814/phy2.15257. PMID 35439355
• Hampton RF, Jimenez-Gonzalez M, Stanley SA. Unravelling innervation of pancreatic islets. Diabetologia. 2022 Jul;65(7):1069-1084. doi: 10.1007/s00125-022-05691-9. Epub 2022 Mar 29. PMID 35348820
• Zhu Y, Xu F, Lu D, Rong P, Cheng J, Li M, Gong Y, Sun C, Wei W, Lin L, Chen JDZ. Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity. Am J Physiol Gastrointest Liver Physiol. 2021 May 1;320(5):G700-G711. doi: 10.1152/ajpgi.00426.2020. Epub 2021 Feb 24. PMID 33624527

Identifiers

NCT: NCT06597149 · 24300

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗