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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Aging
• Intervention / Treatment: Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions

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.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Charlestown, Massachusetts, United States, 02129
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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
• Geriatric Depression Scale < 11
• Aged 60-85, inclusive
• Right-handed
• Reduced vision is allowed if it can be corrected with MRI-goggles

Exclusion Criteria:

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham preceded by cross-over Sham-Stimulation; 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	Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Sham stimulation of vagus nerve in the outer ear; Other Names: Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS); Sham transcutaneous vagus nerve stimulation
Sham Comparator: Sham preceded by cross-over Stimulation-Sham; 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	Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Sham stimulation of vagus nerve in the outer ear; Other Names: Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS); Sham transcutaneous vagus nerve stimulation
Experimental: Stimulation preceded by cross-over Sham-Stimulation; 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	Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Stimulation of vagus nerve in the outer ear; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Experimental: Stimulation preceded by cross-over Stimulation-Sham; 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	Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Stimulation of vagus nerve in the outer ear; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Other: cross-over Stimulation-Sham; 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	Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Sham stimulation of vagus nerve in the outer ear; Other Names: Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS); Sham transcutaneous vagus nerve stimulation; Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Stimulation of vagus nerve in the outer ear; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)
Other: cross-over Sham-Stimulation; 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	Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Sham stimulation of vagus nerve in the outer ear; Other Names: Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS); Sham transcutaneous vagus nerve stimulation; Other: Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions; Stimulation of vagus nerve in the outer ear; Other Names: transcutaneous vagus nerve stimulation; Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25
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).	Based on data from the first 4 weeks (cross-over)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 25 weeks: assessed during week 1, week 2, week 8,week 9, week 17 and week 25
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.	Assessed during the first week and during week 9
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)	Assessed during the first week and during week 9
Change in inflammatory responses (TNF)	Change from baseline to after intervention: - Tumor necreose factor alpha (TNF-α) (units/ml)	Assessed during the first week and during week 9
Change in inflammatory responses (MIP)	Change from baseline to after intervention: - Macrophage inflammatory protein (MIP1B) (units/ml)	Assessed during the first week and during week 9
Change in inflammatory responses (MCP)	Change from baseline to after intervention: -Monocyte chemoattractant protein (MCP-1) (units/ml)	Assessed during the first week and during week 9
Change in inflammatory responses (C)	Change from baseline to after intervention: - Complement components: C1q and C3 (units/ml)	Assessed during the first week and during week 9
Change in inflammatory responses (TREM)	Change from baseline to after intervention: - soluble triggering receptor expressed on myeloid cells (sTREM2) (units/ml)	Assessed during the first week and during week 9

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Heidi IL Jacobs, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 24, 2021
• Primary Completion (Estimated): August 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: May 4, 2021
• First Submitted That Met QC Criteria: May 21, 2021
• First Posted (Actual): June 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Aging; Memory; Transcutaneous vagus nerve stimulation; Brainstem; Preclinical Alzheimer's disease
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: 2021P000498; 1R01AG068062-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: 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, and will be available for at least 3 years or until the sharing platform is no longer available. A more detailed plan for sharing data and a data user agreement procedure will be set up during the study.
• IPD Sharing Access Criteria: Access to the clinical trial IPD can be requested by qualified scientists affiliated a research institutions, and will be provided following review and approval of a research proposal, statistical analysis plan and after signing a data user agreement. Requests can be submitted to wallestudy@mgh.harvard.edu from the first publication date of the primary results or within 9 months of database lock, whichever comes first. In the future, more information on data requests can be found on http://www.heidijacobs.org/. A more detailed plan for sharing data and a data user agreement procedure will be set up during the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No