Healthy VolunteersNCT07657260
Investigating the Transcutaneous vs. Transcranial Mechanisms of Trigeminal Nerve Stimulation (eTNS) Using fMRI
A study testing Topical Lidocaine and Direct Current eTNS (DC-eTNS) in people with Healthy Volunteers and Neurophysiology, run by Xidian University at 1 site in China.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers, Neurophysiology, fMRI Research
- What is being tested?
- Topical Lidocaine and Direct Current eTNS (DC-eTNS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteChina
- Study dates
- 21 Jun 2026to 5 Jul 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
China1 site, 1 recruiting
- Recruiting
Xidian University
Xi'an, Shaanxi, 71000
Xue-Juan Yang, 13227038185, xjyang@xidian.edu.cn
About this study
Official title: 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.
Read the 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.
- Conditions
- Healthy Volunteers, Neurophysiology, fMRI Research
- Being tested
- Topical Lidocaine, Direct Current eTNS (DC-eTNS), Sham DC-eTNS
- 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
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Topical LidocaineDrug
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.
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.
Sham DC-eTNSDevice
An inactive or sensory-matched sham stimulation administered during a 7-minute and 30-second BOLD fMRI sequence to serve as a baseline comparator.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Device: Direct Current eTNS (DC-eTNS); Device: Sham DC-eTNS |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Computed from the multi-modal data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jun 2026
- Study start21 Jun 2026 (estimated)
- Primary completion5 Jul 2026 (estimated)
- Study completion5 Jul 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Xidian University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07657260
- Sponsor's protocol ID
- 20260618
- Status last verified
- Jun 2026
- First submitted
- 15 Jun 2026
- Last updated
- 18 Jun 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07657260
- Acronym / sponsor ID
- 20260618
- Conditions
- Healthy Volunteers, Neurophysiology, fMRI Research
- Keywords
- Direct Current Trigeminal Nerve Stimulation, DC-eTNS, Lidocaine, Transcutaneous Mechanism, Transcranial Mechanism, Trigeminal Nerve, Functional Magnetic Resonance Imaging / fMRI, Central-Autonomic Coupling
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- Xidian UniversityUniversity, hospital or other
- Study start
- 21 Jun 2026 (estimated)
- Primary completion
- 5 Jul 2026 (estimated)
- Study completion
- 5 Jul 2026 (estimated)
- First posted
- 18 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lidocaine Anesthesia Session | Experimental | Drug: Topical Lidocaine, Device: Direct Current eTNS (DC-eTNS), Device: Sham DC-eTNSIn 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. |
| No-Anesthesia Session | Active comparator | Device: Direct Current eTNS (DC-eTNS), Device: Sham DC-eTNSIn 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. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Topical LidocaineApplication of a local anesthetic over the forehead targeting the supraorbital nerve branch prior to the MRI scan, intended to block peripheral transcutaneous nerve conduction. | Drug | Lidocaine Anesthesia Session |
| 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 | Lidocaine Anesthesia Session, No-Anesthesia Session |
| Sham DC-eTNSAn inactive or sensory-matched sham stimulation administered during a 7-minute and 30-second BOLD fMRI sequence to serve as a baseline comparator. | Device | Lidocaine Anesthesia Session, No-Anesthesia Session |
Primary outcome
Amplitude of Low-Frequency Fluctuations (ALFF) in the Brainstem
Time frame: Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
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.
4 secondary outcomes
Brainstem-to-Cortex Functional Connectivity
Time frame: Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
Whole-Brain Cortical Activation Levels
Time frame: During the 7-minute and 30-second fMRI scan for each stimulation condition.
Autonomic Nervous System (ANS) Activity Metrics
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 the multi-modal data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2026.
- Individual participant dataSharing planned: No
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Screening Protocol
Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Topical Lidocaine and Direct Current eTNS (DC-eTNS) in people with Healthy Volunteers and Neurophysiology, run by Xidian University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Xue-Juan Yang (13227038185, xjyang@xidian.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Amplitude of Low-Frequency Fluctuations (ALFF) in the Brainstem (time frame: Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2026.