Vagus Nerve Stimulation for Alzheimer's Disease

Overseen By Andy Bolender, B.A.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Massachusetts General Hospital

Disqualifiers: FmrI contraindications, 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: 3

Duration: 3 sessions

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for Alzheimer's disease using noninvasive nerve stimulation to observe its effects on the brain, stomach, and autonomic activity (such as heartbeat and digestion). The treatment stimulates the vagus nerve through the skin of the ear, potentially helping manage symptoms. This method is known as active auricular transcutaneous Vagus Nerve Stimulation (tVNS). Participants are divided into two groups based on different expectations of how the stimulation affects digestion. The trial seeks individuals aged 18 to 65 who experience ongoing stomach discomfort (functional dyspepsia). As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative therapy.

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications.

What prior data suggests that this nerve stimulation technique is safe for humans?

Research has shown that active auricular transcutaneous vagus nerve stimulation (taVNS) is generally safe. One study found that taVNS users did not face a higher risk of unwanted side effects compared to non-users. The overall rate of these side effects was 12.84%, indicating that most people handled the treatment well without major problems. Additionally, taVNS has been shown to improve certain mental functions, such as memory, in individuals with mild memory issues, suggesting it is well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Researchers are excited about the trial of active auricular transcutaneous Vagus Nerve Stimulation (tVNS) for Alzheimer's Disease because it offers a novel approach to managing the condition. Unlike traditional treatments that primarily focus on slowing the progression of symptoms through medication, auricular tVNS is a non-invasive technique that aims to stimulate the vagus nerve via the ear to potentially improve cognitive function. This method is particularly intriguing because it taps into the body's own nerve pathways to influence brain health, offering a different route than medications. Additionally, the trial explores how expectations of treatment effects—both congruent and incongruent with existing literature—may impact outcomes, providing valuable insights into the psychological aspects of therapy.

What evidence suggests that active auricular tVNS might be an effective treatment for Alzheimer's?

Research has shown that using a device to gently stimulate the ear can enhance thinking and memory. One study found that two weeks of this treatment improved immediate recall and short-term memory. Other studies suggest this treatment might also benefit brain areas affected by Alzheimer's disease. In this trial, participants will receive either active or inactive auricular tVNS. Evidence also indicates that this method is safe and may alleviate anxiety and headaches. These findings suggest that ear stimulation could be a useful way to improve brain function in people with Alzheimer's disease. ^{1 2 6 7 8}

Who Is on the Research Team?

Vitaly Napadow, PhD

Principal Investigator

Harvard University

Are You a Good Fit for This Trial?

This trial is for right-handed, healthy individuals without any neurological or psychiatric disorders, pain syndromes, or conditions that would make an fMRI brain scan unsafe.

Inclusion Criteria

You must be right-handed.

Exclusion Criteria

You have any problems related to your brain or mental health.

You have any type of pain condition.

You have a medical condition that prevents you from undergoing an fMRI brain scan.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 3 fMRI brain-gut scans with neuromodulation and physiological monitoring

3 sessions

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• active auricular tVNS
• inactive auricular tVNS

Trial Overview The study tests how active Transcutaneous Electrical Acupoint Stimulation (TEAS) affects the brain, stomach function, and autonomic nervous system activity in healthy subjects.

How Is the Trial Designed?

Group I: Incongruent Experimental Treatment 1 Intervention

Participants receive briefings on expectations of stimulation effects on gastric motility inconsistent with the literature.

Group II: Congruent Experimental Treatment 1 Intervention

Participants receive briefings on expectations of stimulation effects on gastric motility consistent with the literature.

active auricular tVNS is already approved in European Union, United States for the following indications:

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

• Epilepsy
• Migraine
• Depression
• Chronic Pain
• Autoimmune Diseases

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

• Epilepsy
• Migraine
• Depression
• Chronic Pain

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a pilot study involving 10 patients with Alzheimer's disease, vagus nerve stimulation (VNS) showed a positive effect on cognitive function, with 70% of patients improving on the Alzheimer's Disease Assessment Scale (ADAS-cog) and 90% on the Mini-Mental State Examination (MMSE) after 3 months.

VNS was well tolerated by patients, with only mild and transient side effects reported, suggesting it is a safe intervention for cognitive enhancement in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study. Sjögren, MJ., Hellström, PT., Jonsson, MA., et al.[2022]

Transcutaneous vagus nerve stimulation (tVNS) was shown to alter brain connectivity in patients with mild cognitive impairment (MCI), suggesting it may positively impact cognitive functions related to Alzheimer's disease.

In a study of 50 MCI patients using resting state fMRI, tVNS led to changes in functional connectivity in brain regions associated with semantic and salience functions, indicating its potential as a noninvasive therapeutic intervention for improving brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of Transcutaneous Vagus Nerve Stimulation on Functional Connectivity Within Semantic and Hippocampal Networks in Mild Cognitive Impairment. Murphy, AJ., O'Neal, AG., Cohen, RA., et al.[2023]

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]

Transcutaneous auricular vagus nerve stimulation (taVNS) showed promising results in two patients with structural focal epilepsy, leading to seizure freedom in one patient after 4 weeks and significant reduction in seizures for the other after 20 weeks.

Both patients experienced improved quality of life with no significant adverse events reported, suggesting that taVNS could be a safe and effective treatment option for individuals with focal epilepsy and preserved cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. Shiraishi, H., Egawa, K., Murakami, K., et al.[2023]

Vagus nerve stimulation (VNS) was well tolerated over one year in a study of 17 patients with Alzheimer's disease, showing promising cognitive-enhancing effects with 41.2% of patients improving on the ADAS-cog scale.

After one year, there was no significant decline in mood, behavior, or quality of life, suggesting that VNS may be a safe long-term treatment option for cognitive decline in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year. Merrill, CA., Jonsson, MA., Minthon, L., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly improved visual memory performance in a study of 60 healthy individuals aged 18 to 24, compared to a control group that did not receive taVNS.

Despite the positive effects on visual memory, taVNS did not show a significant impact on fatigue levels, indicating that while it may enhance cognitive function, it does not alleviate feelings of tiredness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of transcutaneous auricular vagus nerve stimulation on visual memory performance and fatigue. Yıldız, R., Özden, AV., Nişancı, OS., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) shows potential as a treatment for disorders of consciousness, particularly in patients with a minimally conscious state (MCS), as it significantly alters brain activity measured by EEG.

In patients with MCS, taVNS led to notable changes in both delta and beta brain wave energy across multiple regions, suggesting it may enhance brain connectivity and promote awakening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vague nerve stimulation improved brain connection activity on patients of disorders of consciousness: a pilot study. Yifei, W., Yi, Y., Yu, W., et al.[2023]

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]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and effective neuromodulation therapy for a variety of conditions, including epilepsy, depression, and anxiety, indicating its broad therapeutic potential.

Despite its effectiveness, there is currently no standardization among taVNS devices, and further research is needed to clarify the relationship between stimulation parameters and therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Wang, L., Wang, Y., Wang, Y., et al.[2022]

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) is a non-invasive and cost-effective method for modulating the vagus nerve, making it a promising alternative to traditional surgical vagus nerve stimulation.

taVNS allows for easy and safe administration, with considerations for proper electrode placement and individual dosing based on perception thresholds, which enhances its potential for treating various central and peripheral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. Badran, BW., Yu, AB., Adair, D., et al.[2020]

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly improves depression symptoms, as evidenced by reduced scores on the Hamilton Depression Scale in a review of 12 studies involving 838 participants.

taVNS shows comparable response rates to traditional antidepressants and has fewer side effects, suggesting it could be a safe alternative or complementary treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. Tan, C., Qiao, M., Ma, Y., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11732881/

Influence of a 2-week transcutaneous auricular vagus ... Results. Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups.

2. nature.com nature.com/articles/s41598-022-25864-1

Safety of transcutaneous auricular vagus nerve stimulation ... Further studies have shown promising results that VNS can treat disorders such as anxiety disorder, Alzheimer's disease, cluster headache, heart ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X22002078

The efficacy and safety of transcutaneous auricular vagus ... Both vagus nerve stimulation and auriculotherapy are effective in improving cognitive functions. •. It demonstrates that taVNS can improve cognitive performance ...

4. nature.com nature.com/articles/s41598-025-11363-6

Transcutaneous auricular vagus nerve stimulation ... This study is the first attempt to investigate taVNS effects on WM in the older adults with hearing impairment (HI) and with typical hearing (TH) ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1878747923000892

The Effects of Transcutaneous Vagus Nerve Stimulation on ... Transcutaneous vagus nerve stimulation (tVNS) may impact brain networks relevant to AD through multiple mechanisms.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10394887/

Safety and feasibility of transcutaneous vagus nerve ... VINCI-AD is an investigator-led, single-site, single-blind, sham-controlled crossover pilot study which aims to assess the safety and feasibility of tVNS in 40 ...

7. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1334887/full

Transcutaneous vagus nerve stimulation: a new strategy ... This review explores the interaction between percutaneous vagus nerve stimulation and the BGM axis, emphasizing its potential effects on AD.

8. link.springer.com link.springer.com/article/10.1007/s10286-024-01053-0

Influence of a 2-week transcutaneous auricular vagus ... Results. Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups.