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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Устройство 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.
• Устройство 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.

Первичные конечные точки

• Amplitude of Low-Frequency Fluctuations (ALFF) in the Brainstem [Срок оценки: Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.]

Вторичные конечные точки (4)

• Brainstem-to-Cortex Functional Connectivity [Срок оценки: Computed from the data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.]
• Whole-Brain Cortical Activation Levels [Срок оценки: During the 7-minute and 30-second fMRI scan for each stimulation condition.]
• Autonomic Nervous System (ANS) Activity Metrics [Срок оценки: Continuously recorded during the 7-minute and 30-second fMRI scan for each stimulation condition.]
• Central-Autonomic Coupling Index [Срок оценки: Computed from the multi-modal data acquired during the 7-minute and 30-second fMRI scan for each stimulation condition.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Простое слепое

Основная цель

Фундаментальное исследование

Центры проведения

Китай · 1 центр

• Xidian University — Сиань

Идентификаторы

NCT: NCT07657260 · 20260618

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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