Non-Invasive Transcutaneous Auricular Vagus Nerve Stimulation Applied at Different Durations in Healthy Adults

Official title

Comparison of the Acute Effects of Non-Invasive Transcutaneous Auricular Vagus Nerve Stimulation Applied at Different Durations on the Autonomic Nervous System in Healthy Adults: A Sham-Controlled Study

Overview

This randomized, participant-blinded, sham-controlled interventional study aims to compare the acute effects of non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) applied at different durations on autonomic nervous system responses in healthy adults. Participants will be assigned to either an active taVNS group or a sham stimulation group. Within each group, participants will complete three separate study visits in which stimulation will be applied for 5, 10, and 15 minutes in randomized order, with 48- to 72-hour washout intervals between visits. Heart rate variability, heart rate, blood pressure, respiratory rate, and subjective discomfort will be assessed immediately before and after each intervention session. The study is designed to determine whether the acute autonomic effects of taVNS vary according to stimulation duration and whether a duration-related response pattern can be identified.

Detailed description

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation method in which electrical stimulation is applied to auricular regions innervated by the auricular branch of the vagus nerve. Because of its low-risk profile, non-surgical application, and potential autonomic regulatory effects, taVNS has attracted increasing interest in autonomic physiology and cardiovascular research.

Previous studies in healthy individuals suggest that taVNS may influence autonomic balance, particularly through changes in heart rate variability (HRV), heart rate, and related physiological parameters. However, substantial heterogeneity remains across published taVNS studies with regard to stimulation parameters such as frequency, pulse width, current intensity, and intervention duration. Among these parameters, stimulation duration is one of the least standardized, and sham-controlled comparisons of different application durations remain limited.

This study is designed to investigate whether the acute autonomic effects of taVNS differ according to stimulation duration. The study uses a randomized, participant-blinded, sham-controlled mixed design. Healthy adults aged 18 to 40 years will be randomized to either an active taVNS group or a sham stimulation group. Participants will remain in their assigned group throughout the study. Within each group, each participant will attend three separate visits and receive stimulation for 5, 10, and 15 minutes in randomized order. Visits will be separated by 48- to 72-hour washout intervals.

Active taVNS will be applied bilaterally to the cymba conchae region using non-invasive stimulation parameters consistent with the study protocol. Sham stimulation will be delivered under visually and procedurally similar conditions to minimize expectancy effects. Before and immediately after each intervention session, autonomic and physiological outcomes will be assessed, including heart rate variability derived from RR interval recordings, heart rate, systolic and diastolic blood pressure, respiratory rate, and subjective discomfort measured by a visual analog scale.

The primary objective is to compare the acute autonomic responses to active taVNS and sham stimulation across different stimulation durations. The study also aims to explore whether a duration-response relationship exists for autonomic outcomes in healthy adults. Findings from this trial may help inform duration selection in future experimental and clinical taVNS research.

Interventions

• Device Active taVNS
  Active transcutaneous auricular vagus nerve stimulation will be applied bilaterally to the cymba conchae region. Stimulation frequency will be 25 Hz, pulse width 200 to 300 microseconds, and intensity will be individually adjusted to a clearly perceptible but comfortable level. Depending on the study visit, stimulation will be delivered for 5, 10, or 15 minutes.
• Device Sham stimulation
  Sham stimulation will be delivered using the same device under visually similar conditions. The sham procedure will be applied at a non-vagal auricular site or with minimal non-therapeutic stimulation, depending on the study protocol, for 5, 10, or 15 minutes according to the study visit.

Primary outcome measures

• Change in RMSSD [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in high-frequency heart rate variability (HF-HRV) [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]

Secondary outcome measures (7)

• Change in heart rate [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in systolic blood pressure [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in diastolic blood pressure [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in respiratory rate [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in subjective discomfort assessed by visual analog scale (VAS) [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in SDNN [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]
• Change in LF/HF ratio [Time frame: [Time Frame: Baseline (pre-intervention) and immediately after intervention, at each study visit (5, 10, and 15 minutes)]]

Eligibility criteria

Inclusion criteria

Healthy adults aged 18 to 40 years No known chronic systemic disease Non-smoker No regular medication use, including medications that may affect autonomic or cardiovascular function Able to understand the study procedures and provide written informed consent Willing to comply with study instructions and restrictions related to caffeine, alcohol, and strenuous exercise

Exclusion criteria

Any known chronic systemic disease Current smoker Regular medication use, including medications that may affect autonomic or cardiovascular function Inability to understand the study procedures or provide written informed consent Unwillingness or inability to comply with study instructions and restrictions related to caffeine, alcohol, and strenuous exercise

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

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Basic science

Study locations

Turkey (Türkiye) · 1 center

• Artvin Coruh University, Artvin Vocational School, Disabled Care and Rehabilitation Labora — Artvin

Publications

• Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul. 2015 May-Jun;8(3):624-36. doi: 10.1016/j.brs.2014.11.018. Epub 2014 Dec 6. PMID 25573069
• Farmer AD, Strzelczyk A, Finisguerra A, Gourine AV, Gharabaghi A, Hasan A, Burger AM, Jaramillo AM, Mertens A, Majid A, Verkuil B, Badran BW, Ventura-Bort C, Gaul C, Beste C, Warren CM, Quintana DS, Hammerer D, Freri E, Frangos E, Tobaldini E, Kaniusas E, Rosenow F, Capone F, Panetsos F, Ackland GL, Kaithwas G, O'Leary GH, Genheimer H, Jacobs HIL, Van Diest I, Schoenen J, Redgrave J, Fang J, Deuch PMID 33854421
• Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014 Nov-Dec;7(6):871-7. doi: 10.1016/j.brs.2014.07.031. Epub 2014 Jul 16. PMID 25164906

Identifiers

NCT: NCT07532005 · TAVNS5

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗