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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active taVNS | Experimental | 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. |
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| Sham taVNS | Sham Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transauricular vagus nerve stimulation (taVNS) | Device | 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). |
| 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. |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
Pregnancy.
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.
History of alcohol or drug abuse within the past 6 months as self-reported.
Presence of the following contraindication to transauricular vagus nerve stimulation
Unstable medical conditions (e.g. uncontrolled diabetes, uncompensated cardiac issues, heart failure, or chronic obstructive pulmonary disease).
Uncontrolled epilepsy, as defined by previous clinical seizures in the past 3 months in patients with treatment for epilepsy.
Suffering from severe depression (as defined by a score of >30 in the Beck Depression Inventory).
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| Name | Affiliation | Role |
|---|---|---|
| Felipe Fregni, MD, PhD, MPH | Spaulding Rehabilitation Hospital/Harvard Medical School | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spaulding Hospital Cambridge | Cambridge | Massachusetts | 02138 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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). |
| FG001 | 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. 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). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | Difference in alpha asymmetry (µV²). | Change from baseline to 60 minutes post-intervention. |
|
Side effects were assessed on the same day, immediately after the stimulation.
No serious or unforeseen adverse events were documented. Only one participant in the active group reported transient tingling behind their left ear at the onset of stimulation, dissipating within the subsequent five minutes.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Expected side effect | Ear and labyrinth disorders | Systematic Assessment | Transient tingling behind their left |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Felipe Fregni, PI | Spaulding Rehabilitation Hospital | 6179526158 | fregni.felipe@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 1, 2023 | Oct 24, 2025 | Prot_SAP_002.pdf |
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|
| BG001 | 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. 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). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 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. 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). |
|
|
| Primary | 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. | Posted | Mean | Standard Deviation | Unit on a scale (NPS 0-10) | Change from baseline to 60 minutes post-taVNS. |
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| Secondary | 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. | Posted | Mean | Standard Deviation | ms² | Post-intervention (after 60 minutes of taVNS) |
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| 0 |
| 22 |
| 0 |
| 22 |
| 1 |
| 22 |
| EG001 | 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. 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). | 0 | 22 | 0 | 22 | 0 | 22 |
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