Healthy Volunteers
Conditions
Keywords
vagal nerve stimulation, healthy subjects, biomarkers
Brief summary
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.
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.
Interventions
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).
Sponsors
Spaulding Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resting-state Electroencephalogram (EEG) | Change from baseline to 60 minutes post-intervention. | 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. |
| Conditioned Pain Modulation (CPM) Response - Change in Pain Ratings on the Pain-6 Scale (0-10) | Change from baseline to 60 minutes post-taVNS. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart Rate Variability (HRV) | Post-intervention (after 60 minutes of taVNS) | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFelipe Fregni, MD, PhD, MPH
Spaulding Rehabilitation Hospital/Harvard Medical School
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 22 |
| 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). | 22 |
| Total | 44 |
Baseline characteristics
| Characteristic | Active taVNS | Sham taVNS | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 20 Participants | 37 Participants |
| Age, Continuous | 41.7 years STANDARD_DEVIATION 68.2 | 40.8 years STANDARD_DEVIATION 17.8 | 41.3 years STANDARD_DEVIATION 20.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 17 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 14 Participants | 11 Participants | 25 Participants |
| Region of Enrollment United States | 22 participants | 22 participants | 44 participants |
| Sex: Female, Male Female | 15 Participants | 12 Participants | 27 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 1 / 22 | 0 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 |
Outcome results
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.
Time frame: Change from baseline to 60 minutes post-taVNS.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active taVNS | Conditioned Pain Modulation (CPM) Response - Change in Pain Ratings on the Pain-6 Scale (0-10) | 0.34 Unit on a scale (NPS 0-10) | Standard Deviation 0.6 |
| Sham taVNS | Conditioned Pain Modulation (CPM) Response - Change in Pain Ratings on the Pain-6 Scale (0-10) | -0.53 Unit on a scale (NPS 0-10) | Standard Deviation 1.14 |
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.
Time frame: Change from baseline to 60 minutes post-intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active taVNS | Resting-state Electroencephalogram (EEG) | 0.016 Difference in alpha asymmetry (µV²). | Standard Deviation 0.012 |
| Sham taVNS | Resting-state Electroencephalogram (EEG) | -0.025 Difference in alpha asymmetry (µV²). | Standard Deviation 0.016 |
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.
Time frame: Post-intervention (after 60 minutes of taVNS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active taVNS | Heart Rate Variability (HRV) | 0.6 ms² | Standard Deviation 0.3 |
| Sham taVNS | Heart Rate Variability (HRV) | 0.1 ms² | Standard Deviation 0.2 |