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

Official title

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

Overview

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.

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.

Interventions

• 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).
• 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).
• 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.

Primary outcome measures

• 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.]

Secondary outcome measures (4)

• 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.]
• 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.]
• Change in Respiratory Rate [Time frame: 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.]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• Contraindications to MRI scanning (e.g., claustrophobia, cardiac pacemakers, artificial cochlea, metallic braces, or any other ferromagnetic implants).
• Female participants who are pregnant, lactating, or suspect they might be pregnant.
• 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).
• 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).
• History of substance abuse, heavy smoking, or excessive daily consumption of alcohol or caffeine.
• Irregular sleep patterns, shift work, or severe sleep deprivation within 24 hours prior to the scanning session.

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

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

China · 1 center

• Xidian University — Xi'an

Identifiers

NCT: NCT07662291 · 20260617

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗