Investigating the Transcutaneous vs. Transcranial Mechanisms of Trigeminal Nerve Stimulation (eTNS) Using fMRI

NCT07657260 | Recruiting

• 1 other identifier: 20260618
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Transcutaneous Trigeminal Nerve Stimulation (eTNS) is a non-invasive technique that modulates brain activity by applying electrical currents to the forehead. However, it remains unclear whether its effects are primarily driven by activating peripheral nerves in the skin (the transcutaneous pathway) or by the electrical current passing directly through the skull into the brain (the transcranial pathway). This study aims to differentiate these two mechanisms in healthy volunteers. Participants will complete two separate MRI scanning sessions. In one session, a local anesthetic (lidocaine) will be applied to numb the skin over the forehead (specifically the supraorbital nerve branch) to temporarily block the peripheral nerve signals. In the other session, no anesthesia will be used. During both sessions, participants will receive active direct current eTNS (DC-eTNS) and a sham (inactive) stimulation while inside a 3T MRI scanner. Researchers will simultaneously measure brain activity (fMRI) and physiological signals (breathing and heart rate). By comparing the brain and bodily responses between the anesthetized and non-anesthetized conditions, the study seeks to determine exactly how eTNS signals travel to and affect the brainstem, cortex, and autonomic nervous system.

Conditions

Healthy Volunteers; fMRI Research; Neurophysiology

Keywords

Direct Current Trigeminal Nerve Stimulation; DC-eTNS; Lidocaine; Transcutaneous Mechanism; Transcranial Mechanism; Trigeminal Nerve; Functional Magnetic Resonance Imaging / fMRI; Central-Autonomic Coupling; Amplitude of Low-Frequency Fluctuations / ALFF

Outcome Measures

Primary Outcomes (1)

• Amplitude of Low-Frequency Fluctuations (ALFF) in the Brainstem

  The primary neuroimaging metric is the ALFF of the BOLD signal, specifically targeting the brainstem regions that encompass the primary nodes of the trigeminal nerve. To differentiate the transcutaneous and transcranial mechanisms, the core statistical analysis will evaluate the interaction effect by comparing the ALFF contrast of (DC-eTNS minus Sham) in the No-Anesthesia condition against the contrast of (DC-eTNS minus Sham) in the Anesthesia (Lidocaine) condition.

  Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.

Secondary Outcomes (4)

• Brainstem-to-Cortex Functional Connectivity

  Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.

• Whole-Brain Cortical Activation Levels

  During the 7-minute and 30-second fMRI scan for each stimulation condition.

• Autonomic Nervous System (ANS) Activity Metrics

  Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.

• Central-Autonomic Coupling Index

  Computed from the multi-modal data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.

Study Arms (2)

Lidocaine Anesthesia Session

EXPERIMENTAL

In this crossover phase, participants will have a local anesthetic (Lidocaine) applied to the skin over the supraorbital branch of the trigeminal nerve to temporarily block somatosensory afferent pathways. Following the anesthesia, participants will undergo a 3T fMRI scan, during which they will receive both active Direct Current eTNS (DC-eTNS) and a Sham stimulation. Each stimulation sequence lasts for 7 minutes and 30 seconds.

Drug: Topical Lidocaine; Device: Direct Current eTNS (DC-eTNS); Device: Sham DC-eTNS

No-Anesthesia Session

ACTIVE COMPARATOR

In this crossover phase, participants will NOT receive any local anesthesia. They will undergo the 3T fMRI scan with intact somatosensory pathways. Similar to the other arm, they will receive both active Direct Current eTNS (DC-eTNS) and a Sham stimulation. Each stimulation sequence lasts for 7 minutes and 30 seconds.

Device: Direct Current eTNS (DC-eTNS); Device: Sham DC-eTNS

Interventions

Topical Lidocaine DRUG

Application of a local anesthetic over the forehead targeting the supraorbital nerve branch prior to the MRI scan, intended to block peripheral transcutaneous nerve conduction.

Lidocaine Anesthesia Session

Direct Current eTNS (DC-eTNS) DEVICE

Active direct current electrical stimulation applied via electrodes on the forehead. The stimulation is synchronized with a 7-minute and 30-second BOLD fMRI sequence, which includes a 15-second current ramp-up phase at the beginning and a 15-second current ramp-down phase at the end.

Lidocaine Anesthesia Session; No-Anesthesia Session

Sham DC-eTNS DEVICE

An inactive or sensory-matched sham stimulation administered during a 7-minute and 30-second BOLD fMRI sequence to serve as a baseline comparator.

Lidocaine Anesthesia Session; No-Anesthesia Session

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• Known allergy, hypersensitivity, or adverse reactions to Lidocaine or other amide-type local anesthetics. (Crucial for this specific study design)
• 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 transcranial or transcutaneous electrical stimulation (e.g., personal or family history of epilepsy/seizures, implanted brain stimulators).
• Any active skin disease, inflammation, lesions, cuts, or abrasions on the forehead (specifically over the supraorbital area), which could alter electrical impedance or anesthetic absorption.
• History of trigeminal neuralgia, facial nerve palsy, or chronic facial pain. Current or recent (within the past month) use of any medications known to affect the central nervous system, autonomic nervous system, or pain perception (e.g., analgesics, antidepressants, beta-blockers, or sedatives).
• 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 sessions.

Sponsors & Collaborators

• Xidian University: lead

Study Sites (1)

Xidian University

Xi'an, Shaanxi, 71000, China

RECRUITING

MeSH Terms

Interventions

Lidocaine

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Central Study Contacts

Xue-Juan Yang

CONTACT

13227038185; xjyang@xidian.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2026
• First Posted: June 18, 2026
• Study Start: June 21, 2026
• Primary Completion: July 5, 2026
• Study Completion: July 5, 2026
• Last Updated: June 18, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)