taVNS Effects on Neural Networks in Healthy Subjects

Overseen By Felipe Fregni, MD, PhD, MPH

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Spaulding Rehabilitation Hospital

Disqualifiers: Neuropsychiatric, Cardiac, Alcohol, Drug, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

44 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, if you have been treated for a neuropsychiatric or cardiac disorder with chronic medication in the past six months, you are not eligible to participate.

What safety data exists for transcutaneous auricular vagus nerve stimulation (taVNS)?

A systematic review and meta-analysis of 177 studies involving 6322 subjects found that taVNS is generally safe, with mild and transient adverse effects such as ear pain, headache, and tingling. The incidence of adverse events was low, at 12.84 per 100,000 person-minutes-days of stimulation, and there was no increased risk of adverse events compared to controls. No severe adverse events were causally linked to taVNS, making it a safe and feasible option for clinical intervention. ^{1 2 3 4 5}

Is transauricular vagus nerve stimulation (taVNS) a promising treatment?

Yes, taVNS is a promising treatment because it can increase heart rate variability, which is good for heart health, and it has shown positive effects in reducing symptoms of depression in some studies. ^{2 3 5 6 7}

What data supports the idea that taVNS Effects on Neural Networks in Healthy Subjects is an effective treatment?

The available research shows that transauricular vagus nerve stimulation (taVNS) is being explored for various conditions like heart failure, migraines, and inflammatory bowel disease. It is a non-invasive alternative to surgically implanted devices, making it more accessible and less expensive. Studies have shown that taVNS can activate brain areas involved in autonomic and emotional regulation, which might help in conditions like depression and epilepsy. However, the research is still developing, and more studies are needed to determine the best ways to use this treatment effectively. ^{2 3 4 8 9}

Who Is on the Research Team?

Felipe Fregni, MD, PhD, MPH

Principal Investigator

Spaulding Rehabilitation Hospital/Harvard Medical School

Are You a Good Fit for This Trial?

This trial is for healthy adults over 18 who have never tried transauricular vagus nerve stimulation (taVNS) and can consent to participate. It's not for pregnant individuals, those with recent neuropsychiatric or cardiac disorders, metal in the head, implanted medical devices, uncontrolled health conditions like diabetes or epilepsy, or a history of substance abuse.

Inclusion Criteria

Able to provide informed consent to participate in the study

I am older than 18 years.

I have never undergone taVNS therapy.

Exclusion Criteria

Presence of the following contraindication to transauricular vagus nerve stimulation: Ferromagnetic metal in the head and in the cranium (e.g., plates or pins, bullets, shrapnel), Implanted cranial electronic medical devices (e.g., cochlear implants), Implanted cardiac devices (e.g., pacemaker), 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)

Pregnancy

I have been treated for a heart or mental health issue in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single 60-minute session of bilateral taVNS or sham stimulation

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in EEG, QST, and HRV after the stimulation session

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Transauricular vagus nerve stimulation (taVNS)

Trial Overview The study is testing how a single 60-minute session of taVNS affects brain networks and body regulation systems in healthy people. Participants are randomly assigned to receive either real taVNS or a sham (fake) treatment without knowing which one they get.

How Is the Trial Designed?

Group I: Active taVNS Experimental Treatment 1 Intervention

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.

Group II: Sham taVNS Placebo Group 1 Intervention

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) is already approved in United States, European Union for the following indications:

Approved in United States as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Refractory Depression
• Chronic Obesity

Approved in European Union as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Tinnitus
• Post-stroke upper limb function

Who Is Running the Clinical Trial?

Spaulding Rehabilitation Hospital

Lead Sponsor

Trials

143

Recruited

11,200+

Published Research Related to This Trial

Vagus nerve stimulation (VNS), particularly through non-invasive methods like transcutaneous VNS (tVNS), shows promise for treating various clinical disorders, including heart failure and migraines, by stimulating the auricular branch of the vagus nerve without the need for surgical implantation.

Current research highlights the need for more detailed studies on the neuroanatomy of the auricular branch of the vagus nerve (ABVN) to better understand its therapeutic effects and optimize stimulation parameters, as existing literature lacks consensus on the most effective stimulation sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. Butt, MF., Albusoda, A., Farmer, AD., et al.[2022]

In a study involving 17 healthy adults, transcutaneous auricular vagus nerve stimulation (taVNS) at the left tragus significantly increased brain activity in areas associated with the vagal pathway, indicating its potential efficacy in neuromodulation.

Compared to control stimulation at the earlobe, tragus stimulation resulted in greater activation in key brain regions, suggesting that taVNS could be a promising therapeutic approach for influencing brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. Badran, BW., Dowdle, LT., Mithoefer, OJ., et al.[2020]

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive and less expensive alternative to invasive vagus nerve stimulation (VNS), which is used to treat conditions like epilepsy and depression, but requires further research to optimize stimulation sites and parameters.

tVNS has the potential to activate various brain areas and may be effective for a wide range of conditions, including medication-refractory epilepsy, depression, migraines, and more, suggesting it could become a standard treatment for enhancing autonomic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation - A brief introduction and overview. Hilz, MJ.[2022]

In a study involving 26 subjects, simultaneous stimulation of the cymba and concha (CC) areas of the ear using extra-large electrodes was found to be the most effective for eliciting vagus somatosensory evoked potentials (VSEP), indicating strong neuromodulation effects.

The research demonstrated that the earlobe is not an effective target for taVNS, and using larger electrodes not only increased the amplitude of the response but also made the stimulation more comfortable for participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. de Gurtubay, IG., Bermejo, P., Lopez, M., et al.[2021]

Transcutaneous vagus nerve stimulation (tVNS) applied to different areas of the ear (tragus, cymba conchae, and earlobe) did not show significant differences in cognitive effects or neurophysiological responses, indicating a non-specific effect of tVNS on error processing and autonomic regulation.

The study found that norepinephrine activity increased after errors, and cardiac vagal activity rose over time, suggesting that while tVNS may not target specific areas effectively, it still influences important neural pathways related to cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation via tragus or cymba conchae: Are its psychophysiological effects dependent on the stimulation area? Borges, U., Pfannenstiel, M., Tsukahara, J., et al.[2021]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) effectively increases heart rate variability (HRV), indicating a shift towards parasympathetic dominance, with the most significant effects observed at the cymba conchae and fossa triangularis targets.

The study found that HRV increases in a charge-dependent manner, with optimal stimulation parameters being bursts of taVNS at a pulse duration of 100 μs and a current intensity of 2 mA, suggesting these parameters are both comfortable and effective for enhancing HRV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. Machetanz, K., Berelidze, L., Guggenberger, R., et al.[2021]

A pilot study involving 37 patients with major depression showed that non-invasive auricular transcutaneous electric nerve stimulation (tVNS) resulted in a significant improvement in depression symptoms as measured by the Beck Depression Inventory, with an average score decrease of 12.6 points compared to 4.4 points in the sham group.

While the Hamilton Depression Rating Scale did not show significant changes, this study is the first to suggest an antidepressant effect of tVNS, indicating potential for further research despite limitations like small sample size and the need for more robust testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. Hein, E., Nowak, M., Kiess, O., et al.[2021]

In a study with 66 healthy participants, transcutaneous auricular vagus nerve stimulation (taVNS) did not significantly affect markers of noradrenergic activity, despite expectations that it would enhance this activity.

The results indicated that continuous taVNS stimulation at the tested parameters was ineffective in modulating both phasic and tonic noradrenergic responses, suggesting that this method may not be a viable approach for increasing noradrenergic activity through vagal pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity. D'Agostini, M., Burger, AM., Villca Ponce, G., et al.[2022]

Citations

1. England pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation - A brief introduction and overview. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation via tragus or cymba conchae: Are its psychophysiological effects dependent on the stimulation area? [2021]

6. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. [2021]

8. Austria pubmed.ncbi.nlm.nih.gov

Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity. [2022]