Vagus Nerve Stimulation for Alzheimer's Disease

(WALLe Trial)

Overseen By Nina Engels, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Massachusetts General Hospital

Must not be taking: Investigational drugs

Disqualifiers: MCI, Dementia, Schizophrenia, Substance abuse, others

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

Compensation: Varies

Number of Visits: 14

Duration: 2 weeks

140 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that your medications be stable for at least 30 days before participating, so you may need to continue your current medications without changes.

What data supports the effectiveness of the treatment Vagus Nerve Stimulation for Alzheimer's Disease?

Transcutaneous vagus nerve stimulation (tVNS) has been shown to modulate brain activity and has been used successfully for conditions like epilepsy and depression, suggesting potential benefits for Alzheimer's Disease. It is a non-invasive method that stimulates the vagus nerve through the skin, which may help in managing symptoms by affecting brain function. ^{1 2 3 4 5}

Is transcutaneous auricular vagus nerve stimulation (taVNS) safe for humans?

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally considered safe, with mild and temporary side effects like ear pain, headache, and tingling. Studies show no significant risk of severe adverse events, making it a feasible option for clinical use. ^{2 5 6 7 8}

How does the treatment of transcutaneous vagus nerve stimulation for Alzheimer's disease differ from other treatments?

This treatment is unique because it uses non-invasive electrical stimulation of the ear to activate the vagus nerve, which may enhance cognitive function without the need for surgery or medication. Unlike traditional treatments, it offers a novel approach by potentially improving brain function through the modulation of neural pathways and cardiovascular stability. ^{9 10 11 12 13}

What is the purpose of this trial?

In this research study the investigators want to find out if a non-invasive electrical brain stimulation method called RAVANS (also called tVNS) can have a beneficial effect on cognition in older individuals. The investigators also want to understand whether certain individual factors contribute to the effect of RAVANS on cognition. RAVANS is only used in research studies.

Research Team

Heidi IL Jacobs, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for individuals aged 60-85 with mild Alzheimer's or aging-related cognitive decline, fluent in English, and have stable health conditions like controlled hypertension. They must score within certain limits on cognitive tests and be right-handed. Exclusions include metal implants incompatible with MRI, severe psychiatric disorders, active cancer or heart disease, major head trauma history, substance abuse within the past two years.

Inclusion Criteria

Fluent in English

Right-handed

Willingness and ability to comply with scheduled visits, magnetic resonance imaging (MRI) scanning, laboratory tests, and other study procedures

Exclusion Criteria

I have an active blood, kidney, lung, hormone, or liver disorder.

I have a serious heart condition or have had a stroke.

Substance abuse within the past 2 years

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cross-over Intervention

Participants undergo a cross-over design of sham versus RAVANS stimulation during a functional magnetic resonance imaging (fMRI) task

4 weeks

2 sessions

Treatment

Participants receive daily tVNS or sham sessions during 10 visits

2 weeks

10 visits (in-person)

Follow-up

Participants undergo two follow-up cognitive assessments to monitor changes in cognition and inflammatory responses

4 months

2 visits (in-person)

Treatment Details

Interventions

• Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
• Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

Trial Overview The study examines if RAVANS (non-invasive electrical brain stimulation) can improve cognition in older adults. Participants will receive either the actual tVNS treatment or a sham (fake) version during ten-minute sessions to compare effects on brain function.

Participant Groups

Group I: cross-over Stimulation-Sham Experimental Treatment 2 Interventions

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham One time RAVANS versus one time Sham Two weeks wash-out

Group II: cross-over Sham-Stimulation Experimental Treatment 2 Interventions

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out

Group III: Stimulation preceded by cross-over Stimulation-Sham Experimental Treatment 1 Intervention

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Group IV: Stimulation preceded by cross-over Sham-Stimulation Experimental Treatment 1 Intervention

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of RAVANS during 2 weeks

Group V: Sham preceded by cross-over Sham-Stimulation Placebo Group 1 Intervention

Cross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Group VI: Sham preceded by cross-over Stimulation-Sham Placebo Group 1 Intervention

Cross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by Sham Wash-out period of four weeks Ten daily sessions of sham during 2 weeks

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

A pilot study involving 24 patients with chronic tinnitus demonstrated that transcutaneous vagus nerve stimulation (tVNS) is a feasible and generally safe treatment method, with only two adverse cardiac events reported, which were unlikely linked to the device.

Preliminary data suggest that tVNS does not cause arrhythmic effects in patients without known heart conditions, indicating its potential safety for cardiac function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. Kreuzer, PM., Landgrebe, M., Husser, O., et al.[2022]

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]

In a study involving 15 patients with chronic pelvic pain due to endometriosis, respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) showed a trend towards reducing pain intensity and significantly decreased anxiety compared to nonvagal auricular stimulation (NVAS).

RAVANS demonstrated moderate to large effect sizes in reducing pain and anxiety, suggesting it could be a promising nonpharmacological treatment option for chronic pain disorders, warranting further investigation into its long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Napadow, V., Edwards, RR., Cahalan, CM., et al.[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]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and well-tolerated method for treating conditions like drug-resistant epilepsy, but a recent randomized double-blind trial found no significant difference in outcomes between high- and low-stimulation groups.

The most common side effect of taVNS is a tingling sensation or pain at the stimulation site, and while it shows promise, further research is needed to fully understand its efficacy and to potentially gain approval for insurance coverage in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation]. Yamamoto, T.[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 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) effectively normalized gastric dysrhythmias in healthy individuals during a water-load test, indicating its potential as a treatment for gastric symptoms.

The study found that TaVNS at 40 Hz improved heart rate variability and reduced bloating, suggesting it positively influences both parasympathetic and sympathetic nervous system pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. Du, P., Maharjan, A., Calder, S., 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]

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]

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]

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]

Vagus nerve stimulation (VNS) has been effectively used to treat conditions like intractable epilepsy and treatment-resistant depression, and new non-invasive methods like transcutaneous VNS (t-VNS) provide similar benefits without the risks associated with surgery.

t-VNS shows promise for improving cognitive function and neurocardiovascular stability, particularly in aging populations, by enhancing cerebral blood flow and regulating the body's parasympathetic responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance. Dolphin, H., Dukelow, T., Finucane, C., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study. [2022]

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

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. [2023]

5. Japan pubmed.ncbi.nlm.nih.gov

[Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation]. [2022]

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

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

7. England pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. [2022]

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

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

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

10. 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]

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

Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study. [2022]

12. United States 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. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

"The Wandering Nerve Linking Heart and Mind" - The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance. [2022]