Frequency-Dependent Effects of Auricular Vagus Nerve Stimulation on Autonomic and Cardiovascular Parameters (AVNS-DRC)

November 27, 2025 updated by: SEFA HAKTAN HATIK

Acute Effects of Different Frequencies of Auricular Vagus Nerve Stimulation on HRV, Blood Pressure, and Respiratory Rate: A Sham-Controlled, Randomized, Crossover Dose-Response Study

This randomized, sham-controlled, crossover study investigates the acute autonomic effects of transcutaneous cervical vagus nerve stimulation (tcVNS) applied at five different frequencies (0 Hz/sham, 10 Hz, 25 Hz, 50 Hz, 100 Hz) in healthy adults. The primary objective is to determine how stimulation frequency modulates heart rate variability (HRV), blood pressure, and respiratory rate. The study aims to establish a frequency-specific dose-response model using validated physiological measurements.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Transcutaneous cervical vagus nerve stimulation (tcVNS) is a non-invasive neuromodulation technique capable of activating afferent vagal pathways projecting to autonomic brainstem nuclei. Although previous studies demonstrate tcVNS-related modulation of autonomic functions, the frequency-response relationship remains insufficiently explored.

This crossover trial randomizes participants to receive five stimulation conditions (sham, 10 Hz, 25 Hz, 50 Hz, 100 Hz) in counterbalanced order. HRV (Polar H10), blood pressure (Omron), and respiratory rate (Kinovea-based thoracoabdominal video tracking) are collected pre- and post-stimulation. Washout between sessions is ≥48 hours.

The study provides one of the first systematic evaluations of frequency-dependent tcVNS effects in healthy adults.

Study Type

Interventional

Enrollment (Estimated)

36

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Turkey (Türkiye)
    • Sinop
      • Türkeli, Sinop, Turkey (Türkiye), 57900
        • Sinop University, Türkeli Vocational School (Türkeli MYO)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • 18-30 years
  • Healthy (self-reported)
  • No cardiovascular, neurological, metabolic or psychiatric disorders
  • No regular medication affecting autonomic function
  • Non-smoker
  • BMI 18-29.9

Exclusion Criteria:

  • Pregnancy
  • Cardiac arrhythmia
  • Hypertension or hypotension
  • Chronic respiratory disorders
  • Active infection
  • Metal implants in cervical area
  • Epilepsy
  • Syncope history
  • Prior vagus stimulation experience

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Sham Comparator: 1 - Sham (0 Hz)

Intervention Type: Pulsetto FIT™ tcVNS Device Intervention Name: Sham tcVNS Description: Device placed on bilateral cervical region; no electrical current delivered.

Dose: 10 minutes
Device: Pulsetto FIT™ - Sham tcVNS

The Pulsetto FIT™ device is placed bilaterally on the cervical region (posterior margin of the sternocleidomastoid muscle).

In the sham condition, the device displays normal operational lights but delivers no electrical stimulation (0 Hz; inactive mode).

This condition is used for blinding and as the control comparator. Dose: 10 minutes
Experimental: 2 - 10 Hz tcVNS
Intervention Type:Pulsetto FIT™ tcVNS Device Intervention Name: tcVNS (10 Hz) Description: Bilateral cervical stimulation at 10 Hz, 250 μs pulse width. Duration: 10 minutes
Device: Pulsetto FIT™ - tcVNS 10 Hz

Bilateral transcutaneous cervical vagus nerve stimulation delivered via the Pulsetto FIT™ device at 10 Hz, 250 µs pulse width.

Current intensity adjusted to a mild, non-painful tingling sensation, individualized for each participant.

Dose: 10 minutes
Experimental: 3 - tcVNS 25 Hz
Intervention Type:Pulsetto FIT™ tcVNS Device Intervention Name: tcVNS (25 Hz) Description: Bilateral cervical stimulation at 25 Hz, 250 μs pulse width. Duration: 10 minutes
Device: Pulsetto FIT™ - tcVNS 25 Hz
Bilateral tcVNS using the Pulsetto FIT™ device at 25 Hz, 250 µs pulse width. Stimulation intensity set at a comfortable sensory level. Dose: 10 minutes
Experimental: 4 - tcVNS 50 Hz
Intervention Type:Pulsetto FIT™ tcVNS Device Intervention Name: tcVNS (50 Hz) Description: Bilateral cervical stimulation at 50 Hz, 250 μs pulse width. Duration: 10 minutes
Device: Pulsetto FIT™ - tcVNS 50 Hz

Bilateral cervical vagus nerve stimulation via Pulsetto FIT™ at 50 Hz, 250 µs pulse width.

Intensity adjusted to a tolerable sensory level without discomfort. Dose: 10 minutes
Experimental: 5 - tcVNS 100 Hz
Intervention Type:Pulsetto FIT™ tcVNS Device Intervention Name: tcVNS (100 Hz) Description: Bilateral cervical stimulation at 100 Hz, 250 μs pulse width. Duration: 10 minutes
Device: Pulsetto FIT™ - tcVNS 100 Hz

Bilateral tcVNS delivered with the Pulsetto FIT™ device at 100 Hz, 250 µs pulse width.

Highest stimulation frequency used in this protocol; current intensity individualized per participant comfort.

Dose: 10 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Heart Rate Variability (HRV) Changes (ΔRMSSD, ΔHF, ΔLF/HF)
Time Frame: Pre- vs Post-stimulation (5-min segments)(5-minute baseline, 5-minute stimulation, 5-minute post period)

HRV is recorded using a validated high-resolution heart rate monitor (Polar H10) during a 5-minute resting baseline (T0) and a 5-minute post-stimulation period (T2).

The following time- and frequency-domain parameters are analyzed: RMSSD, HF (ms²), and LF/HF ratio.

Artefact correction is performed using standard HRV processing methods. Acute autonomic response is quantified by calculating change scores (Δ = post-pre) for each stimulation frequency.
Pre- vs Post-stimulation (5-min segments)(5-minute baseline, 5-minute stimulation, 5-minute post period)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Pressure (SBP, DBP, MAP)
Time Frame: Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)

Two readings are taken at each time point from the right arm with a validated automatic sphygmomanometer, and the average systolic, diastolic, and mean arterial pressure values are used for analysis.

Changes are calculated as post-pre (Δ values) to assess the acute physiological effect of each stimulation frequency..
Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)
Respiratory Rate (breaths per minute)
Time Frame: Pre- vs Post-stimulation (5-minute video segments) (5-minute baseline, 5-minute stimulation, 5-minute post period)

Respiratory rate is assessed by video-based thoracoabdominal motion tracking at baseline (T0) and after stimulation (T2).

Videos are analyzed using Kinovea motion-tracking software, and a 1-minute stable segment is used to determine breaths per minute by counting inspiratory peaks.

Respiratory changes are expressed as Δ values (post-pre) to account for individual differences and improve HRV interpretability.Respiratory rate is assessed by video-based thoracoabdominal motion tracking at baseline (T0) and after stimulation (T2).

Videos are analyzed using Kinovea motion-tracking software, and a 1-minute stable segment is used to determine breaths per minute by counting inspiratory peaks.

Respiratory changes are expressed as Δ values (post-pre) to account for individual differences and improve HRV interpretability.
Pre- vs Post-stimulation (5-minute video segments) (5-minute baseline, 5-minute stimulation, 5-minute post period)
Discomfort Level (Visual Analog Scale, 0-10)
Time Frame: Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)

Participants report their perceived discomfort level at baseline (T0) and immediately after stimulation (T2) using a 0-10 Visual Analog Scale (VAS).

The scale captures any sensory discomfort associated with tcVNS. Changes are calculated by subtracting the pre-stimulation score from the post-stimulation score (ΔVAS).
Pre- vs Post-stimulation (5-minute baseline, 5-minute stimulation, 5-minute post period)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

SEFA HAKTAN HATIK

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 22, 2025

Primary Completion (Estimated)

January 31, 2026

Study Completion (Estimated)

March 15, 2026

Study Registration Dates

First Submitted

November 27, 2025

First Submitted That Met QC Criteria

November 27, 2025

First Posted (Actual)

December 10, 2025

Study Record Updates

Last Update Posted (Actual)

December 10, 2025

Last Update Submitted That Met QC Criteria

November 27, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • tcVNS1
  • IRB Number (Pending) (Registry Identifier: Gümüşhane University Clinical Research Ethics Committee)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will not be shared because the study includes physiological recordings (HRV, blood pressure, respiratory videos) that cannot be fully anonymized. Data sharing may pose a risk of indirect identification.

Only aggregated results will be reported in publications and presentations.

IPD Sharing Time Frame:

Not applicable.

IPD Sharing Access Criteria:

Not applicable.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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