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AgingWALLeNCT04908358

The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive Performance

A study testing Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions in people with Aging, run by Massachusetts General Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 60 to 85 yearsHealthy volunteers can take part
Conditions the study is for
Aging
What is being tested?
Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
126 participants
Where
1 siteUnited States
Study dates
24 Nov 2021to 25 Aug 2026
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 to 85 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Fluent in English
  • Willingness and ability to comply with scheduled visits, magnetic resonance imaging (MRI) scanning, laboratory tests, and other study procedures.
  • Subjects with well-controlled vascular risk factors, such as treated hypertension, treated hyperlipidemia or well controlled Type II diabetes will be included.
  • Stable medications for at least 30 days.
  • Mini Mental State Exam adjusted for age and education of 25 to 30, inclusive or a Telephone Interview for Cognitive Status score of at least 32
  • Perform within 1.5 S.D. of age and education matched norms on the Logical Memory Paragraph Delayed Recall
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  • Geriatric Depression Scale < 11
  • Aged 60-85, inclusive
  • Right-handed
  • Reduced vision is allowed if it can be corrected with MRI-goggles

Who cannot join

  • Prior known diagnosis of mild cognitive impairment (MCI) or dementia
  • Use of investigational drugs or devices within 60 days prior to screening
  • Subjects with contraindications to MRI cannot participate (i.e., implanted metal including pacemakers, cerebral spinal fluid shunts, aneurysm clips, artificial heart valves, ear implants or metal/foreign objects in the eyes and those with a history of claustrophobia)
  • Pregnant.
  • Major psychiatric disorders such as schizophrenia, schizoaffective disorder, major affective disorder in mid-life, or treatment with electroconvulsive therapy (ECT) (Mild depression that is well treated with stable dose of selective serotonergic reuptake inhibitor (SSRI) antidepressants will be allowed).
  • Have a history of major head trauma defined as a loss of consciousness and/or trauma requiring hospitalization
Show all 19Show fewer
  • Substance abuse within the past 2 years
  • Active hematological, renal, pulmonary, endocrine or hepatic disorders.
  • Evidence of cortical infarcts or strategically placed lacunar infarct (e.g. dorsal medial nucleus of thalamus). MRI evidence of mild white matter signal abnormalities will be allowed.
  • Active cancer, metabolic encephalopathy, infection
  • Active cardiovascular disease, stroke, congestive or severe heart failure
  • Huntington's disease, hydrocephalus or seizure disorder
  • Cataracts, glaucoma, detached retina's, eye surgery involving the muscles; droopy eyelids, penetrating eye wounds and use of anticholinergic eye drop use
  • Weight equal to or greater than 300 lbs (weight limit of the MRI table).
  • Recurrent vaso-vagal syncopal episodes
  • Unilateral or bilateral vagotomy
  • Severe valvular disorder (i.e. prosthetic valve or hemodynamically relevant valvular diseases)
  • Sick sinus syndrome
  • Hypotension due to autonomic dysfunction

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Massachusetts General Hospital

    Charlestown, Massachusetts, 02129

Other trials in United States

About this study

Official title: The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive

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.

Read the detailed description

The intervention will be studied in 140* older individuals using a randomized cross-over design of sham versus RAVANS stimulation (2 sessions separated by 4 weeks) during a functional magnetic resonance imaging (fMRI) task. Participants will then be randomized to daily tVNS or sham sessions during 10 visits within two weeks, and two follow-up cognitive assessments each after 2 months of the last intervention session. The face-name association task will be the main outcome measure. The investigators will also draw blood twice to examine whether the response on the outcome is dependent on Alzheimer's disease related biomarker, and whether RAVANS has effects on inflammatory responses.

  • Please note that the target accrual was revised to N = 126 due lower than expected drop-out rates. This change was approved by the Mass General Brigham IRB, DSMB, and NIH.
Conditions
Aging
Being tested
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
Keywords
Transcutaneous vagus nerve stimulation, Memory, Brainstem, Aging, Preclinical Alzheimer's disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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

    Also called Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), transcutaneous vagus nerve stimulation

    Stimulation of vagus nerve in the outer ear

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

    Also called Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), Sham transcutaneous vagus nerve stimulation

    Sham stimulation of vagus nerve in the outer ear

Study groups in NCT04908358
Study groupRoleWhat they receive
Sham preceded by cross-over Sham-StimulationSham comparatorCross-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
Receives: Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
Sham preceded by cross-over Stimulation-ShamSham comparatorCross-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
Receives: Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
Stimulation preceded by cross-over Sham-StimulationExperimentalCross-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
Receives: Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
Stimulation preceded by cross-over Stimulation-ShamExperimentalCross-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
Receives: Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
cross-over Stimulation-ShamOtherCross-over: experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) followed by sham One time RAVANS versus one time Sham Two weeks wash-out
Receives: Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions
cross-over Sham-StimulationOtherCross-over: Sham followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out
Receives: Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Performance on the Face-name association memory task (FNAME)

    Change from baseline at each visit where FNAME is completed: Scores are z-scores with a mean of zero. Higher scores are better (there is no minimum/maximum).

    Measured: Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25

  2. Being a responder as determined by Face-name association memory task (FNAME) change scores

    Participants are grouped in being a responder (1) or non-responder (0).

    Measured: Based on data from the first 4 weeks (cross-over)

Secondary outcomes (8)

  1. Performance on other cognitive composite scores: this includes a composite score of memory, a composite score of executive function and the Preclinical Alzheimer's disease cognitive composite.

    Change from baseline at each visit where neuropsychological data is collected. Composites are calculated following a confirmatory factor analyses. All scores (correct answers) will be expressed in z-scores and higher scores are better (there is no minimum/maximum).

    Measured: Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25

  2. Change in inflammatory responses (aggregated)

    Change from baseline to after intervention, these markers will be analyzed from blood:

    • Interleukins (IL): IL-1β, IL-2, IL-6, IL-8
    • Tumor necreose factor alpha (TNF-α)
    • Macrophage inflammatory protein (MIP1B)
    • Monocyte chemoattractant protein (MCP-1)
    • Complement components: C1q and C3
    • soluble triggering receptor expressed on myeloid cells (TREM2).

    Following stability analyses, specific markers will be selected (with advise by Dr. Arnold) and analysed individually (see outcome measures 5-10) and in aggregated form (here). Markers will be combined following a principal component analyses and will be normalised. Values will be expressed in z-scores.

    Measured: Assessed during the first week and during week 9

  3. Change in inflammatory responses (interleukins)

    Change from baseline to after intervention:

    • Interleukins (IL): IL-1β, IL-2, IL-6, IL-8 (expressed in IU, international units)

    Measured: Assessed during the first week and during week 9

  4. Change in inflammatory responses (TNF)

    Change from baseline to after intervention:

    • Tumor necreose factor alpha (TNF-α) (units/ml)

    Measured: Assessed during the first week and during week 9

  5. Change in inflammatory responses (MIP)

    Change from baseline to after intervention:

    • Macrophage inflammatory protein (MIP1B) (units/ml)

    Measured: Assessed during the first week and during week 9

  6. Change in inflammatory responses (MCP)

    Change from baseline to after intervention:

    -Monocyte chemoattractant protein (MCP-1) (units/ml)

    Measured: Assessed during the first week and during week 9

  7. Change in inflammatory responses (C)

    Change from baseline to after intervention:

    • Complement components: C1q and C3 (units/ml)

    Measured: Assessed during the first week and during week 9

  8. Change in inflammatory responses (TREM)

    Change from baseline to after intervention:

    • soluble triggering receptor expressed on myeloid cells (sTREM2) (units/ml)

    Measured: Assessed during the first week and during week 9

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jun 2021
  2. Study start24 Nov 2021
  3. Primary completion25 Aug 2026
  4. Study completion25 Aug 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Other
Allocation
Randomised
Intervention model
Sequential
Model description
Randomized cross-over followed by placebo-controlled study (allocation to placebo or control condition takes APOE-E4 status into account and the previous ordering of the cross-over design)
Masking
Single blind
Who is masked
Participant
Enrolment
126 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04908358
Sponsor's protocol ID
2021P000498
Other IDs
1R01AG068062-01A1
Acronym
WALLe
Status last verified
Sep 2026
First submitted
4 May 2021
Last updated
9 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Consistent with NIH regulations, as provided in the manual of the NIH (SF424 (R\&R)), data will be made available at the time of publication of the primary results or within 9 months of database lock, whichever comes first. A more detailed plan for sharing data and a data user agreement procedure will be set up during the study.

Questions about this trial

What is this clinical trial studying?

A study testing Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions in people with Aging, run by Massachusetts General Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Performance on the Face-name association memory task (FNAME) (time frame: Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04908358.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2026.

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