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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Aging

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham preceded by cross-over Sham-Stimulation<br>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<br>* Sham stimulation of vagus nerve in the outer ear<br>* Other names: Sham transcutaneous vagus nerve stimulation;|
| Sham Comparator: Sham preceded by cross-over Stimulation-Sham<br>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<br>* Sham stimulation of vagus nerve in the outer ear<br>* Other names: Sham transcutaneous vagus nerve stimulation;|
| Experimental: Stimulation preceded by cross-over Sham-Stimulation<br>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<br>* Stimulation of vagus nerve in the outer ear<br>* Other names: transcutaneous vagus nerve stimulation;|
| Experimental: Stimulation preceded by cross-over Stimulation-Sham<br>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<br>* Stimulation of vagus nerve in the outer ear<br>* Other names: transcutaneous vagus nerve stimulation;|
| Other: cross-over Stimulation-Sham<br>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<br>* Stimulation of vagus nerve in the outer ear<br>* Other names: transcutaneous vagus nerve stimulation;Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions<br>* Sham stimulation of vagus nerve in the outer ear<br>* Other names: Sham transcutaneous vagus nerve stimulation;|
| Other: cross-over Sham-Stimulation<br>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<br>* Stimulation of vagus nerve in the outer ear<br>* Other names: transcutaneous vagus nerve stimulation;Other: Sham transcutaneous vagus nerve stimulation respiratory-gated non-painful electrical stimulation of the auricle for 10 minute sessions<br>* Sham stimulation of vagus nerve in the outer ear<br>* Other names: Sham transcutaneous vagus nerve stimulation;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcutaneous vagus nerve stimulation, Memory, Brainstem, Aging, Preclinical Alzheimer's disease