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

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
36

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 22, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 31, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 15, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 27, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 27, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 10, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 10, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 27, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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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