Understanding the Effects of Transauricular Vagus Nerve Stimulation on Neural Networks and Autonomic Nervous System

Understanding the Effects of Non-invasive Transauricular Vagus Nerve Stimulation (taVNS) on Neural Networks and Autonomic Nervous System: a Randomized Double-blind Sham-control Mechanistic Trial in Healthy Participants

This trial aims to perform an exploratory, mechanistic, randomized double-blind sham-control trial in healthy participants to assess the physiologic effects of a single 60 minutes session of bilateral taVNS, on neural networks and autonomic function.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Device: Transauricular vagus nerve stimulation (taVNS)

Detailed Description

Several studies have shown promising results of taVNS to treat various disorders such as depression, anxiety, Alzheimer's disease, headache, obesity, and diabetes. However, no mechanistic studies have investigated the taVNS neural network and autonomic nervous system effects of this technique. Therefore, we aim to assess how taVNS can affect EEG metrics and HRV and assess its safety. Also, we aim to evaluate predictors that can influence the response to taVNS, so understanding the variables associated with response to taVNS can help the design of future clinical trials to maximize the effects of this intervention.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02138
      • Spaulding Hospital Cambridge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Able to provide informed consent to participate in the study.
2. Subject is older than 18 years.
3. Subjects should be naive to the stimulation (taVNS)

Exclusion Criteria:

1. Pregnancy.
2. Subjects who have had a neuropsychiatric or a cardiac disorder diagnosis and have received treatment and chronic medication in the past six months, or who have functional deficits as a result.
3. History of alcohol or drug abuse within the past 6 months as self-reported.

4. Presence of the following contraindication to transauricular vagus nerve stimulation

   1. Ferromagnetic metal in the head and in the cranium (e.g., plates or pins, bullets, shrapnel)
   2. Implanted cranial electronic medical devices (e.g., cochlear implants)
   3. Implanted cardiac devices (e.g., pacemaker)
5. Unstable medical conditions (e.g. uncontrolled diabetes, uncompensated cardiac issues, heart failure, or chronic obstructive pulmonary disease).
6. Uncontrolled epilepsy, as defined by previous clinical seizures in the past 3 months in patients with treatment for epilepsy.
7. Suffering from severe depression (as defined by a score of >30 in the Beck Depression Inventory).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active taVNS; TaVNS will be administered by an earset, with conductive eartips placed on the auricular concha of the ears, connected to a stimulator, and during active stimulation, we stimulate both the cymba conchae and external auditory canal of both left and right ears with the following parameters: 30Hz, 200-250 us, and with adjustable intensity for 60 min.	Device: Transauricular vagus nerve stimulation (taVNS); Transauricular vagus nerve stimulation (taVNS) is a simple technique in which small surface electrodes are placed over the skin of the ear that are thought to be innervated by the auricular branch of the vagus nerve (ABVN).
Sham Comparator: Sham taVNS; Sham condition will have the same device, with an earset, and conductive eartips placed in the same location of the active stimulation; however during 60 min there will be no current and the device will be turned off.	Device: Transauricular vagus nerve stimulation (taVNS); Transauricular vagus nerve stimulation (taVNS) is a simple technique in which small surface electrodes are placed over the skin of the ear that are thought to be innervated by the auricular branch of the vagus nerve (ABVN).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting-state Electroencephalogram (EEG)	Resting-state EEG was recorded using a 64-channel high-density EGI system (Electrical Geodesics, Inc., Eugene, USA) under the eyes closed condition. Data was filtered into standard frequency bands using short-time Fourier transformation (STFT): delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-80 Hz). Frontal asymmetry was computed as the difference in power between homologous left and right frontal electrodes (e.g., F3-F4) in the alpha band.	Change from baseline to 60 minutes post-intervention.
Conditioned Pain Modulation (CPM) Response - Change in Pain Ratings on the Pain-6 Scale (0-10)	Pain intensity was measured using the Numeric Pain Scale (NPS; 0 = no pain, 10 = worst pain). Higher scores indicate worse pain. A "pain-6 temperature" was first identified (temperature that elicits NPS = 6). Test stimulus: Pain-6 temperature applied for 30s; participants rated pain at 10, 20, and 30s. The test-stimulus score is the average of the three NPS ratings. Conditioned stimulus: After 5 minutes, the left hand was immersed in 10-12°C water for 30s while the same pain-6 temperature was applied again. Pain was rated the same way, and the conditioned-stimulus score is the average of the three NPS ratings. CPM calculation = (test-stimulus average) - (conditioned-stimulus average). Positive values = better endogenous pain inhibition; negative values = worse.	Change from baseline to 60 minutes post-taVNS.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Rate Variability (HRV)	HRV from ECG on non-dominant hand. High-frequency HRV calculated from 5-min resting recordings; higher values indicate greater parasympathetic activity. Post-stimulation values (60 min) were analyzed.	Post-intervention (after 60 minutes of taVNS)

Collaborators and Investigators

• Sponsor: Spaulding Rehabilitation Hospital
• Investigators: Principal Investigator: Felipe Fregni, MD, PhD, MPH, Spaulding Rehabilitation Hospital/Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Actual): September 23, 2023
• Study Completion (Actual): March 1, 2026

Study Registration Dates

• First Submitted: February 27, 2023
• First Submitted That Met QC Criteria: March 24, 2023
• First Posted (Actual): April 6, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: biomarkers; healthy subjects; vagal nerve stimulation
• Other Study ID Numbers: 2022P003200

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: Yes
• product manufactured in and exported from the U.S.: No