An interventional study of Active transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions and Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions in Aging, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to participants aged 60 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-09.
Sponsored by Massachusetts General Hospital · Not applicable, Interventional, and Other
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.
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.
Massachusetts General Hospital is the lead sponsor of 2,536 studies on the registry; 446 are open to participants now.
Of its 214 completed or terminated interventional studies of FDA-regulated products, 161 (75%) have results posted.
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Exclusion Criteria:
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
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
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
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
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: 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 followed by experimental Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) One time RAVANS versus one time Sham Two weeks wash-out
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
Stimulation of vagus nerve in the outer ear
Also known as: Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), transcutaneous vagus nerve stimulation
Sham stimulation of vagus nerve in the outer ear
Also known as: Sham Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), Sham transcutaneous vagus nerve stimulation
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).
Time frame: 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).
Time frame: Based on data from the first 4 weeks (cross-over)
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).
Time frame: 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.
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Assessed during the first week and during week 9
Plan to share: 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.
Supporting information: Study protocol, Icf
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