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

Differentiating the Transcutaneous and Transcranial Mechanisms of Direct Current Trigeminal Nerve Stimulation on Brainstem and Autonomic Function: A Randomized, Sham-Controlled, Crossover fMRI Study With Local Anesthesia

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers; Neurophysiology; fMRI Research
• Intervention / Treatment: Drug: Topical Lidocaine; Device: Direct Current eTNS (DC-eTNS); Device: Sham DC-eTNS

Detailed Description

This is an exploratory, randomized, sham-controlled, crossover functional neuroimaging study designed to isolate and differentiate the transcutaneous (peripheral nerve mediated) versus transcranial (direct electrical penetration) mechanisms of direct current Trigeminal Nerve Stimulation (DC-eTNS).

Healthy participants will undergo two separate study sessions in a randomized order:

Anesthesia Condition: Local anesthesia (Lidocaine) will be applied to the skin area corresponding to the supraorbital branch of the trigeminal nerve to temporarily block somatosensory afferent pathways.

No-Anesthesia Condition: The participant will undergo the same procedures without the application of local anesthesia.

During each session, participants will be scanned in a 3T MRI scanner. The imaging protocol will consist of a high-resolution structural T1-weighted scan, followed by two functional Blood Oxygenation Level-Dependent (BOLD) sequences: one for active DC-eTNS and one for Sham stimulation. Each functional BOLD sequence will last for 7 minutes and 30 seconds. The active DC-eTNS stimulation paradigm includes a 15-second current ramp-up phase at the beginning and a 15-second current ramp-down phase at the end to ensure participant comfort and safety.

Concurrently with the fMRI acquisition, continuous physiological monitoring will be conducted using a respiratory belt and a photoplethysmography (PPG) finger sensor to capture peripheral autonomic nervous system metrics.

Data Analysis Plan:

Primary Analysis: The primary objective is to evaluate the Amplitude of Low-Frequency Fluctuations (ALFF) specifically within the brainstem, focusing on the principal nodes of the trigeminal nerve. The core statistical comparison will assess the contrast of (DC-eTNS - Sham) under the No-Anesthesia condition versus (DC-eTNS - Sham) under the Anesthesia condition.

Secondary Analyses: Secondary neuroimaging analyses will investigate changes in dynamic and static functional connectivity between the brainstem nuclei and cortical regions, as well as whole-brain cortical activation disparities between the two sensory states.

Physiological and Coupling Analyses: Concurrent respiratory and PPG data will be analyzed to detect variations in autonomic nervous system activity (e.g., Heart Rate Variability). Furthermore, central-autonomic coupling indices will be calculated to examine how the different transmission pathways of DC-eTNS modulate the synchronization between central neural networks and peripheral autonomic output.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xue-Juan Yang; Phone Number: 13227038185; Email: xjyang@xidian.edu.cn

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 71000
      • Recruiting
      • Xidian University
      • Contact: Xue-Juan Yang; Phone Number: 13227038185; Email: xjyang@xidian.edu.cn

Participation Criteria

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. Known allergy, hypersensitivity, or adverse reactions to Lidocaine or other amide-type local anesthetics. (Crucial for this specific study design)
2. Contraindications to MRI scanning (e.g., claustrophobia, cardiac pacemakers, artificial cochlea, metallic braces, or any other ferromagnetic implants).
3. Female participants who are pregnant, lactating, or suspect they might be pregnant.
4. Contraindications to transcranial or transcutaneous electrical stimulation (e.g., personal or family history of epilepsy/seizures, implanted brain stimulators).
5. 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.
6. 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).
7. History of substance abuse, heavy smoking, or excessive daily consumption of alcohol or caffeine.
8. Irregular sleep patterns, shift work, or severe sleep deprivation within 24 hours prior to the scanning sessions.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lidocaine Anesthesia Session; 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; 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.; Device: Direct Current eTNS (DC-eTNS); 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.; Device: Sham DC-eTNS; An inactive or sensory-matched sham stimulation administered during a 7-minute and 30-second BOLD fMRI sequence to serve as a baseline comparator.
Active Comparator: No-Anesthesia Session; 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); 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.; Device: Sham DC-eTNS; An inactive or sensory-matched sham stimulation administered during a 7-minute and 30-second BOLD fMRI sequence to serve as a baseline comparator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brainstem-to-Cortex Functional Connectivity	The strength of functional connectivity between the targeted brainstem nuclei and widespread cortical regions. Connectivity maps will be calculated and compared between the Anesthesia and No-Anesthesia conditions across the active DC-eTNS and Sham phases to evaluate how blocking peripheral pathways alters neural network communication.	Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
Whole-Brain Cortical Activation Levels	Differences in whole-brain BOLD signal activation and deactivation patterns. This will assess the overall cortical response to DC-eTNS and determine how these activation levels are modulated when the peripheral somatosensory afferent pathways are temporarily blocked by local anesthesia.	During the 7-minute and 30-second fMRI scan for each stimulation condition.
Autonomic Nervous System (ANS) Activity Metrics	Peripheral autonomic physiological changes assessed via continuous respiratory belt and photoplethysmography (PPG) signals. Key parameters include Heart Rate Variability (HRV) indices (e.g., LF/HF ratio, RMSSD) and respiratory amplitude/rate. The variations in these metrics will be compared between the Anesthesia and No-Anesthesia states during DC-eTNS and Sham.	Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.
Central-Autonomic Coupling Index	The degree of synchronization (coupling) between central neural activity (BOLD signal fluctuations in brainstem/cortical regions) and peripheral autonomic outputs (HRV and respiratory signals). This metric aims to reveal whether the transcutaneous or transcranial pathway is the primary driver of central-autonomic integration during DC-eTNS.	Computed from the multi-modal data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.

Collaborators and Investigators

• Sponsor: Xidian University

Study record dates

Study Major Dates

• Study Start (Estimated): June 21, 2026
• Primary Completion (Estimated): July 5, 2026
• Study Completion (Estimated): July 5, 2026

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: June 15, 2026
• First Posted (Actual): June 18, 2026

Study Record Updates

• Last Update Posted (Actual): June 18, 2026
• Last Update Submitted That Met QC Criteria: June 15, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Lidocaine; Trigeminal Nerve; Direct Current Trigeminal Nerve Stimulation; DC-eTNS; Transcutaneous Mechanism; Transcranial Mechanism; Functional Magnetic Resonance Imaging / fMRI; Central-Autonomic Coupling; Amplitude of Low-Frequency Fluctuations / ALFF
• Additional Relevant MeSH Terms: Organic Chemicals; Anilides; Amides; Aniline Compounds; Amines; Acetanilides; Lidocaine
• Other Study ID Numbers: 20260618

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