Modulating the Locus Coeruleus Function

Boosting a Neuromodulatory System Relevant to Alzheimer's Disease to Enhance Memory

The purpose of this study is to investigate the impact of transcutaneous vagus nerve stimulation (tVNS) on specific brain regions involved in memory and attention processes.

tVNS is a non-invasive and non-pharmacological technique known for targeting the locus coeruleus, a small subcortical nucleus in the brain thought to be involved in the earliest stages of Alzheimer's disease. This nucleus also plays a role in numerous cognitive functions, comprising memory and attention.

Study Overview

• Status: Completed
• Conditions: Healthy Aging
• Intervention / Treatment: Device: Transcutaneous vagus verne stimulation

Detailed Description

This study is an observational MRI study with a pseudo-randomized single blind cross-over design. The population consists of 30 healthy human volunteers from 60 to 80 years old. These healthy older individuals will be recruited from the community.

After being informed about the study protocol and the potential risks, subjects will be given 1 week to consider their participation.

All participants giving written informed consent will be included in the study. The first session will consist in neuropsychological assessments and a task practice session in the dummy scanner in order to get familiar with the environment. Participants meeting the eligibility criteria will be included for the next sessions.

The second and third sessions are MRI scanning sessions including transcutaneous vagus nerve stimulation. Both the placebo and experimental stimulation conditions will be randomized in a single-blind manner across scanning sessions.

About 7 to 10 weeks after each scanning session and at least 4 days previous to the next MRI session, participant will be asked to fill in an online memory test for assessing potential outlasting effects of the stimulation technique.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6229 ET
    • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Healthy older individuals participating in the study will be recruited from the community.

Description

Inclusion Criteria:

• Average neuropsychological test results in accordance with normative data corrected for age, education and sex
• No substantial memory complaints according to the participant
• Body mass index < 28
• Non-smoking
• Right handedness
• Average/high level of education (minimum 12 years of education)

Exclusion Criteria:

• Psychoactive medication use
• Abuse of alcohol and drugs
• Cognitive impairment due to alcohol/drug or other substances abuse
• Recent trans-meridian travel (<2months)
• Night shift work (<1year)
• Diabetes if not stable
• Hypo-/hyper-tension, hypo-/hyper-thyroid if not stable
• Hypo-tension due to autonomic dysfunction
• Recent (<5years) or present psychiatric or neurological disorders (anxiety, major depression, schizophrenia, bipolar disorder, psychotic disorder -or treatment for it-, epilepsy, stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, brain surgery, brain trauma, electroshock therapy, kidney dialysis, Ménière's disease, brain infections)
• Major vascular disorders (e.g. stroke)
• History of cardiovascular disorders (e.g., severe heart failure, recurrent vasovagal syncopal episodes)
• Major valvular disorders (e.g., prosthetic valve or hemodynamically relevant valvular disease, unilateral or bilateral vagotomy)
• Contraindications for scanning (e.g., brain surgery, cardiac pacemaker, metal implants, claustrophobia, body tattoos, reduced vision even after appropriate optical correction)
• Contraindications for pupil measurements and light exposure (e.g., Cataracts, Glaucoma, detached retina's, eye surgery involving the muscle, penetrating eye wounds, use of cholinesterase inhibitors, anticholinergic eye drop use, droopy eyelids preventing eye measurement).

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy older participants; Healthy older participants receiving both stimulation conditions (experimental and placebo) randomized across scanning sessions.	Device: Transcutaneous vagus verne stimulation; Non-invasive and short electrical stimulation by placing the stimulating electrode at the cymba conchae of the left ear. The reference electrode is placed near the left cymba conchae. It provides a light tingling, massaging feeling in the ear.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pupillometry - Scan session 1	Measure of pupil size variations during functional tasks. It can be used as a proxy for measuring arousal-related state transitions in brain activity and it allows for a reliable detection of the locus coeruleus activity.	During the first MRI scanning session (55 minutes)
Pupillometry - Scan session 2	Measure of pupil size variations during functional tasks. It can be used as a proxy for measuring arousal-related state transitions in brain activity and it allows for a reliable detection of the locus coeruleus activity.	During the second MRI scanning session (55 minutes)
Blood oxygen level dependent (BOLD) response - Scan session 1	This BOLD signal reflects brain activity during the functional tasks. The study focuses on the BOLD-signal in the locus coeruleus and task-relevant networks during the memory and the vigilance tasks.	During the first MRI scanning session (55 minutes)
Blood oxygen level dependent (BOLD) response - Scan session 2	This BOLD signal reflects brain activity during the functional tasks. The study focuses on the BOLD-signal in the locus coeruleus and task-relevant networks during the memory and the vigilance tasks.	During the second MRI scanning session (55 minutes)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Performance on the online memory task - Post-session 1	Total accuracy on the face-name association task (from 0 to 100%); Mean reaction time on the face-name association task (from 0 to 4 seconds). The higher the total accuracy and the lower the mean reaction time, the better the outcome measure.	Performed from home, 7 to 10 days after the first MRI session and at least 4 days prior to the second session.
Performance on the online memory task - Post-session 2	Total accuracy on the face-name association task (from 0 to 100%); Mean reaction time on the face-name association task (from 0 to 4 seconds). The higher the total accuracy and the lower the mean reaction time, the better the outcome measure.	Performed from home, 7 to 10 days after the second MRI session.

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: University of Liege
• Investigators: Principal Investigator: Heidi IL Jacobs, Dr., Maastricht University

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Actual): September 25, 2023
• Study Completion (Actual): October 5, 2023

Study Registration Dates

• First Submitted: April 20, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 7, 2021

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Healthy aging; Transcutaneous vagus nerve stimulation; Locus coeruleus; Memory and attention
• Other Study ID Numbers: NL77066.068.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD during the study are to be shared with the lab's members and according to the pre-defined agreements between Maastricht University and the University of Liège.
• IPD Sharing Time Frame: Previously mentioned IPD and additional supporting information will be shared from the end of the study ad will be available for a time period of 15 years.

IPD Sharing Access Criteria

Data will be accessible only by lab members, through an access to the encrypted server where all data are stored.

All kind of analyses might be performed on the available data.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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