Frequency Effects of Transcutaneous Trigeminal Nerve Stimulation (eTNS) on Brain and Autonomic Function

June 21, 2026 updated by: Xidian University

A Randomized, Sham-Controlled, Crossover fMRI Study on the Frequency Effects of Transcutaneous Trigeminal Nerve Stimulation on Central-Autonomic Coupling in Healthy Subjects

This study aims to investigate how different frequencies of transcutaneous Trigeminal Nerve Stimulation (eTNS) affect brain activity and the autonomic nervous system in healthy individuals. Participants will undergo a 3T functional magnetic resonance imaging (fMRI) scan while receiving three different types of nerve stimulation: 2Hz eTNS, 120Hz eTNS, and a sham (inactive) stimulation. The order of these stimulations will be randomly assigned. During the brain scan, researchers will simultaneously monitor the participants' breathing and heart rhythms (using a finger sensor). The main goal is to understand how changing the frequency of eTNS influences the connection between the brain's networks and the body's unconscious physiological responses.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is an exploratory, randomized, sham-controlled, within-subject crossover fMRI study designed to evaluate the frequency-dependent effects of transcutaneous Trigeminal Nerve Stimulation (eTNS) on central-autonomic coupling in healthy volunteers.

Participants will undergo functional neuroimaging in a 3T MRI scanner. The imaging protocol consists of a structural T1-weighted scan and three functional Blood Oxygenation Level-Dependent (BOLD) sequences corresponding to three intervention arms: 2Hz-eTNS, 120Hz-eTNS, and Sham stimulation. The order of the three stimulation conditions will be randomized for each participant. To minimize potential carryover effects, the structural T1 scan will be acquired between the two active (real) stimulation sequences.

Each functional BOLD sequence will last for 7 minutes and 30 seconds and will utilize a block design. This design consists of alternating 30-second "ON" blocks (where the stimulation is active) and 30-second "OFF" blocks (where the stimulation is inactive).

Concurrently with the fMRI acquisition, continuous physiological monitoring will be conducted. This includes recording respiratory effort and photoplethysmography (PPG) via a finger pulse oximeter to capture peripheral autonomic metrics.

The primary and secondary analyses will focus on quantifying BOLD signal responses, evaluating dynamic changes in brain functional connectivity, assessing variations in autonomic nervous system metrics (such as heart rate variability derived from the PPG), and exploring the mechanisms of central-autonomic coupling across the different stimulation frequencies.

Study Type

Interventional

Enrollment (Estimated)

25

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 Contact

Study Locations

  • China
    • Shaanxi
      • Xi'an, Shaanxi, China, 71000
        • Recruiting
        • Xidian University
        • Contact:

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:

  1. Healthy volunteers, aged 18 to 40 years old.
  2. Right-handed.
  3. Generally healthy with no history of neurological, psychiatric, or severe cardiovascular diseases.
  4. Normal physical and neurological examinations.
  5. Capable of understanding the study procedures and voluntarily signing the written informed consent form.

Exclusion Criteria:

  1. Contraindications to MRI scanning (e.g., claustrophobia, cardiac pacemakers, artificial cochlea, metallic braces, or any other ferromagnetic implants).
  2. Female participants who are pregnant, lactating, or suspect they might be pregnant.
  3. Contraindications to transcutaneous electrical stimulation (e.g., personal or family history of epilepsy/seizures, trigeminal neuralgia, facial skin lesions, or active skin diseases on the forehead).
  4. Current or recent (within the past month) use of any medications known to affect the central nervous system or the autonomic nervous system (e.g., antidepressants, beta-blockers, sedatives, or sympathomimetics).
  5. History of substance abuse, heavy smoking, or excessive daily consumption of alcohol or caffeine.
  6. Irregular sleep patterns, shift work, or severe sleep deprivation within 24 hours prior to the scanning session.

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
Experimental: 2Hz-eTNS Condition
In this crossover phase, participants will receive 2Hz transcutaneous Trigeminal Nerve Stimulation (eTNS) during the 3T fMRI scan. The stimulation will be delivered during a 7-minute and 30-second BOLD sequence using a block design, which alternates between 30-second "ON" periods (active 2Hz stimulation) and 30-second "OFF" periods (no stimulation).
Device: 2Hz Transcutaneous Trigeminal Nerve Stimulation
Active electrical stimulation applied over the skin of the forehead targeting the branches of the trigeminal nerve. The stimulation frequency is set at 2Hz. It is synchronized with the fMRI sequence and continuous physiological monitoring (respiration and photoplethysmography).
Experimental: 120Hz-eTNS Condition
In this crossover phase, participants will receive 120Hz transcutaneous Trigeminal Nerve Stimulation (eTNS) during the 3T fMRI scan. Similar to other active conditions, the stimulation will be delivered during a 7-minute and 30-second BOLD sequence using a block design, alternating between 30-second "ON" periods (active 120Hz stimulation) and 30-second "OFF" periods (no stimulation).
Device: 120Hz Transcutaneous Trigeminal Nerve Stimulation
Active electrical stimulation applied over the skin of the forehead targeting the branches of the trigeminal nerve. The stimulation frequency is set at 120Hz. It is synchronized with the fMRI sequence and continuous physiological monitoring (respiration and photoplethysmography).
Sham Comparator: Sham-eTNS Condition
In this crossover phase, participants will undergo the same fMRI scanning procedure and wear the exact same electrode pads as the active conditions, but will receive a sham stimulation. This phase also lasts for 7 minutes and 30 seconds and utilizes a simulated 30-second "ON" / 30-second "OFF" block design to maintain double-blinding.
Device: Sham Transcutaneous Trigeminal Nerve Stimulation
An inactive or sensory-matched sham electrical stimulation designed to mimic the physical sensation of the device being active without delivering the therapeutic frequencies (2Hz or 120Hz). It is administered synchronously with the fMRI BOLD sequence and physiological monitoring to serve as a baseline comparator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in Blood Oxygenation Level-Dependent (BOLD) Signal Amplitude in the Brainstem
Time Frame: During the 7-minute and 30-second fMRI scan for each stimulation condition.
The metric is the percent signal change in BOLD amplitude within predefined Regions of Interest (ROIs) of the brainstem (e.g., trigeminal nuclei, locus coeruleus, nucleus tractus solitarii). It is calculated as the BOLD signal difference between the 30-second stimulation "ON" blocks and the 30-second "OFF" blocks. Data will be aggregated as the mean percentage of BOLD signal change for each stimulation condition.
During the 7-minute and 30-second fMRI scan for each stimulation condition.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional Connectivity (FC) within and outside the Central Autonomic Network
Time Frame: During the 7-minute and 30-second fMRI scan for each stimulation condition.
The strength of dynamic and static functional connectivity between key nodes of the CAN and other whole-brain regions. Connectivity matrices will be computed and compared across the 2Hz-eTNS, 120Hz-eTNS, and Sham conditions to evaluate how different stimulation frequencies modulate brain network communications.
During the 7-minute and 30-second fMRI scan for each stimulation condition.
Change in Heart Rate Variability Assessed by Low Frequency to High Frequency (LF/HF) Ratio
Time Frame: Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.
The LF/HF ratio is a frequency-domain measure of heart rate variability derived from PPG data, reflecting the sympathovagal balance. Data will be aggregated as the mean LF/HF ratio during each stimulation condition.
Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.
Change in Respiratory Rate
Time Frame: Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.
Respiratory rate is extracted from concurrent respiratory belt signals to assess respiratory patterns. Data will be aggregated as the mean respiratory rate (measured in breaths per minute) during each stimulation condition.
Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.
Central-Autonomic Coupling Index
Time Frame: Computed from data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
The degree of synchronization between central neural activity and peripheral autonomic output. This will be quantified by calculating the correlation coefficients or mutual information between the low-frequency fluctuations of the BOLD signals in CAN regions and the concurrent peripheral autonomic time-series data (HRV and respiration). The coupling strength will be compared between the 2Hz and 120Hz conditions.
Computed from data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.

Collaborators and Investigators

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

Sponsor

Xidian University

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)

August 6, 2026

Primary Completion (Estimated)

August 20, 2026

Study Completion (Estimated)

August 20, 2026

Study Registration Dates

First Submitted

June 15, 2026

First Submitted That Met QC Criteria

June 21, 2026

First Posted (Actual)

June 23, 2026

Study Record Updates

Last Update Posted (Actual)

June 23, 2026

Last Update Submitted That Met QC Criteria

June 21, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 20260617

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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