tVNS and Obesity-related Mechanisms

NCT ID: NCT06954844

Last Updated: 2025-05-02

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-08
• Study Completion Date: 2027-03-31

Brief Summary

The overarching goal of the project is to assess whether transcutaneous Vagus Nerve Stimulation (tVNS) induced reduction of central and peripheral inflammation is associated with tVNS induced changes in mood and motivation in a sample of healthy participants with overweight and obesity.

Detailed Description

Participants will receive high intensity or low intensity tVNS in a single-blind, randomized, crossover design. Each stimulation (high and low intensity) will be applied over 14 days (effective minimum duration) at home by the participants, with a 7-day (effective minimum duration) washout period in between the conditions. To assess the effect of high (vs. low intensity) stimulation on inflammation and mood/motivation, the investigators plan to use a combination of blood analysis, ecological momentary assessments (EMA), and neuroimaging sessions. To this end, the investigators will apply functional Magnetic Resonance Imaging (fMRI), diffusion basis spectrum imaging (DBSI), and a behavioural task capturing different facets of motivation. During the study, participants will be invited for four lab-based sessions (t0-t3). The first visit before the start of the stimulation (t0) will be used to measure baseline levels of mood, motivation, and inflammation, as well as body measures, and metabolic blood parameter. Additionally, participants will be asked to rate standardized food pictures for liking, wanting, healthiness, and environmental sustainability during the first lab-based session (t0). These ratings will be used for a food choice task during the intervention phase, which is described in more detail below. To track changes induced by the intervention, the second (t1) and fourth visits (t3) will take place after 14 days of daily stimulation with high or low intensity stimulation, respectively. There will be a 7-day washout period in between the end of the first stimulation phase and the start of the second. In the third session (t2), participants will be instructed how to use the tVNS device in the crossover condition at home and mood, body measures, and metabolic blood parameter will be measured again before the second intervention phase. The third session will take place after the 7-day washout period.

Sessions at t0, t1, and t3: Participants will be asked to come in a fasted (12h) state. After a short mood and metabolic state survey (Positive and Negative Affect Schedule (PANAS) items presented on a visual analogue scale (VAS) on a computer), the investigators will determine resting heart rate, blood pressure, and body measures (such as body height, weight and percentage of body fat). A blood sample will then be taken to measure peripheral inflammation (cytokines, circulating blood cells) and metabolic parameter (insulin sensitivity, blood lipid levels). Subsequently, the participants will perform an effort allocation task (EAT) during fMRI. In the EAT, participants are asked to move a ball above a drawn line (representing the difficulty) by exerting effort (e.g., by rapidly pressing a button or a grip force handle inside the scanner) to collect different types of reward (food and money). Trials within the task vary in difficulty, reward type (food vs. money), and reward magnitude (1 point vs. 10 points). After each trial, participants are asked to rate how much they wanted the reward and how much they exerted effort during the trial. In addition, a diffusion-weighted sequence is acquired in the MRI to measure central inflammation. The investigators will then assess mood (PANAS items) again and participants will be instructed to use the device for >30 min per day at home (stimulation use will be logged by the devices). After the session participants will be paid out the rewards gained during the task. 80% of the calories are paid out as breakfast (muesli with milk) and 20% of the calories as snacks (e.g. chocolate, wine gums). After paying out the rewards gained during the task, the investigators will again assess mood, using the PANAS items.

Sessions at t2: Participants will be asked to come in a fasted (12h) state. After a short mood and metabolic state survey (PANAS items presented on a visual analogue scale (VAS) on a computer), the investigators will determine resting heart rate, blood pressure, and body measures. A blood sample will then be taken to measure metabolic parameter (insulin sensitivity, blood lipid levels). Participants will then be instructed how to use the tVNS device in the crossover condition at home. Afterwards, the investigators will again assess mood, using the PANAS items.

During the intervention phases, Ecological momentary assessments (EMA) (e.g., "how happy do you feel at the moment?", "how sad do you feel at the moment?", and "how motivated do you feel right now?") will be completed daily. In addition, EMA questions will be used to assess subjective control over eating behaviour (e.g., "While you were eating, to what extent did you feel a sense of loss of control?" and physical activity ("How many minutes of moderate or strenuous physical activity did you do today?"). A food choice task will be used to assess changes in eating behaviour. Therefore, participants will be asked to rate standardized food pictures for liking, wanting, healthiness, and environmental sustainability during the first lab-based session (t0). A choice task will be used to assess changes in decision weights. Two pictures that have been rated similarly for one domain (e.g. liking) will be presented to the participants, who will be instructed to choose one of the pictures. Decisions will be used to estimate decision weights for the remaining three domains.

Standardized questionnaires will be used to characterize our sample. The investigators will e.g., assess symptoms of depression, anhedonia, and apathy (Becks Depression Inventory, (BDI-II), Snaith-Hamilton Please Scale in German (SHAPS-D), and Apathy Motivation Index (AMI)). Additionally, the investigators will assess eating behaviour (using a food frequency questionnaire from the "German Health Interview and Examination Survey for Adults 2008-2011" (DEGS)), as well as physical activity (International Physical Activity Questionnaire (IPAQ)).

Five major hypotheses will be tested:

Hypothesis 1: Participants will have lower levels of peripheral inflammation measured as reduced levels of pro-inflammatory cytokines, enhanced levels of anti-inflammatory cytokines, and changes in the circulating immune cells after high compared to low intensity stimulation.

Hypothesis 2: Participants will have reduced central inflammation reflected in reduced tissue edema and cellularity after high compared to low intensity stimulation.

Hypothesis 3: Participants will have improved mood (as measured by items of the Positive and Negative Affect Schedule; PANAS) after high compared to low intensity stimulation.

Hypothesis 4: Participants will have enhanced motivation to work for rewards after high compared to low intensity stimulation.

Hypothesis 5: The tVNS-induced (high vs. low intensity) reduction of central and peripheral inflammation is associated with tVNS-induced changes in mood and motivation.

Secondary hypotheses:

Hypothesis 6: Levels of peripheral and central inflammation are associated with mood and motivation

Hypothesis 7: Participants will have enhanced ratings of reward wanting during the EAT after high compared to low intensity stimulation.

Hypothesis 8: Participants will have decreased utility slopes in the EAT after high compared to low intensity stimulation.

Hypothesis 9: Participants will have improved mood and motivation measured using EMA questions during high intensity stimulation phases compared to low intensity stimulation phases.

Hypothesis 10: Participants will show reduced anhedonia after high compared to low intensity stimulation.

Hypothesis 11: Participants will show reduced depressive symptoms after high compared to low intensity stimulation.

Hypothesis 12: Participants will show reduced apathy after high compared to low intensity stimulation.

Conditions

Overweight/Obesity (BMI: 27 and 35 kg/m2)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

High intensity transcutaneous non-invasive vagus nerve stimulation (tVNS)

Participants will receive high intensity tVNS for \>30 min per day for 14 days at home. To stimulate vagal afferents, the electrode will be placed at the cymba conchae of the right ear using a previously established conventional stimulation protocol (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany). Stimulation intensity will be pre-set for each participant for the following stimulation period to correspond to a mild pricking sensation determined with a staircase procedure in the lab session.

Group Type: EXPERIMENTAL

Transcutaneous non-invasive vagus nerve stimulation (tVNS)

Intervention Type: DEVICE

To stimulate vagal afferents, the electrode will be placed at the cymba conchae of the right ear using a previously established conventional stimulation protocol (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany). Stimulation intensity will be pre-set for each participant for the following stimulation period to correspond to a mild pricking sensation determined with a staircase procedure in the lab session.

Low intensity stimulation

The control intervention consists of low intensity stimulation. Participants will receive low intensity stimulation for \>30 min per day for 14 days at home. The electrode will be placed at the cymba conchae, but only receive a low-intensity stimulation below the perception threshold (0.1mA, 1s ON, 30s OFF, 1 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany).

Group Type: SHAM_COMPARATOR

Low intensity stimulation

Intervention Type: DEVICE

The electrode will be placed at the cymba conchae, but only receive a low-intensity stimulation below the perception threshold (0.1mA, 1s ON, 30s OFF, 1 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany).

Interventions

Transcutaneous non-invasive vagus nerve stimulation (tVNS)

To stimulate vagal afferents, the electrode will be placed at the cymba conchae of the right ear using a previously established conventional stimulation protocol (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany). Stimulation intensity will be pre-set for each participant for the following stimulation period to correspond to a mild pricking sensation determined with a staircase procedure in the lab session.

Intervention Type: DEVICE

Low intensity stimulation

The electrode will be placed at the cymba conchae, but only receive a low-intensity stimulation below the perception threshold (0.1mA, 1s ON, 30s OFF, 1 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany).

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Between 18 and 40 years of age
• BMI between 27 and 35.0 kg/m2
• Legally valid declaration of consent

Exclusion Criteria

• Current or past diagnosis of brain injury/surgery or neurological condition with permanent effects, epilepsy, stroke, schizophrenia, bipolar disorder, severe substance use disorder, heart disease that precludes use of tVNS, diabetes (type 1 or 2), chronic inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, etc.)
• Following diagnosis within 12 months before start of experiment: obsessive compulsive disorder, somatic symptom disorder, eating disorder
• Considerable weight change (>10%) within the last 6 months before the experiment
• Elevated BMI is due to fat-free mass (e.g., in athletes)
• Medication or Electroconvulsive therapy to treat a mental, metabolic, or neurological disorder (e.g., selective serotonin reuptake inhibitors, Glucagon-like Peptide-1 agonists) currently or in the last 3 months (hormone treatments that normalize function are not excluded)
• Anti-inflammatory medication currently or in the last 3 month
• Contraindications for MRI (e.g., metal implants, claustrophobia)
• Contraindications for tVNS (e.g., piercings, sore or diseased skin areas on the outer right ear)
• active implants (e.g., pacemaker), cerebral shunt
• Pregnant and breastfeeding women

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Bonn

OTHER

Sponsor Role: lead

Responsible Party

Dr. Nils B. Kroemer

Prof. Dr. rer. nat.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Section of Medical Psychology, Department of Psychiatry & Psychotherapy, Faculty of Medicine, University of Bonn

Bonn, , Germany

Countries

Germany

References

Samara A, Li Z, Rutlin J, Raji CA, Sun P, Song SK, Hershey T, Eisenstein SA. Nucleus accumbens microstructure mediates the relationship between obesity and eating behavior in adults. Obesity (Silver Spring). 2021 Aug;29(8):1328-1337. doi: 10.1002/oby.23201. Epub 2021 Jul 5.

Reference Type: BACKGROUND

PMID: 34227242 (View on PubMed)

Neuser MP, Teckentrup V, Kuhnel A, Hallschmid M, Walter M, Kroemer NB. Vagus nerve stimulation boosts the drive to work for rewards. Nat Commun. 2020 Jul 16;11(1):3555. doi: 10.1038/s41467-020-17344-9.

Reference Type: BACKGROUND

PMID: 32678082 (View on PubMed)

Charbonnier L, van Meer F, van der Laan LN, Viergever MA, Smeets PAM. Standardized food images: A photographing protocol and image database. Appetite. 2016 Jan 1;96:166-173. doi: 10.1016/j.appet.2015.08.041. Epub 2015 Sep 4.

Reference Type: BACKGROUND

PMID: 26344127 (View on PubMed)

Other Identifiers

493623632

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

BON006

Identifier Type: -

Identifier Source: org_study_id