Clinical trial NCT06954844: tVNS and Obesity-related Mechanisms
Official title: tVNS to Provide Mechanistic Insights Into the Relationship Between Systemic Inflammation and Altered Motivation and Mood in Healthy Individuals Who Are Overweight or Obese
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Overweight/Obesity (BMI: 27 and 35 kg/m2)
Keywords: Inflammation
Metaflammation
tVNS
Motivation
Lead sponsor: University of Bonn
Sponsor class: OTHER
First posted: 2025-05-02
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Stimulation-induced mid-term changes in a multiplex panel of different inflammatory biomarkers (peripheral inflammation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in circulating immune cells (peripheral inflammation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in tissue edema as assessed using non-restricted fraction (isotropic DBSI-NRF (f(D), D = 0.3 - 3.0 μm2/ms))
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in tissue cellularity as assessed using restricted fraction (isotropic DBSI-RF (f(D), D ≤ 0.3 μm2/ms))
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in PANAS items (mood)
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in Invigoration (motivation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in maintenance (motivation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in anticipatory neural reward response (motivation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in neural motor response (motivation)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Correlation of Stimulation-induced changes in peripheral and central inflammation with changes in mood and motivation
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
Secondary outcomes:
measure: Stimulation-induced mid-term changes in ratings of reward wanting and exertion
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in utility slope
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced changes in mood and motivation in daily life
timeFrame: During intervention phase: 14 days
measure: Stimulation-induced mid-term changes in anhedonia
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in depressive symptoms
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in apathy
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
Other outcomes:
measure: BMI
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Percentage of body-fat
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Waist-to-hip ratio
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Eating behaviour
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Physical activity (1)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Physical activity (2)
timeFrame: During intervention phase: 14 days
measure: Stimulation-induced mid-term changes in fat metabolism
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in triglycerides
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in insulin sensitivity
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes of HbA1c
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in resting heart rate
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in blood pressure
timeFrame: Baseline (immediately before each stimulation phase), immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in blood leptin levels
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in blood adiponectin levels
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in blood ghrelin levels
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in the levels of Glucagon-like Peptide-1 in the blood
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in dendrite density as assessed using fiber fraction (anisotropic DBSI-FF)
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced changes in subjective control over eating behaviour
timeFrame: During intervention phase: 14 days
measure: Stimulation-induced mid-term changes in neural response to feedback
timeFrame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
measure: Stimulation-induced mid-term changes in decision-making between two options of food
timeFrame: During intervention phase: 14 days
Locations:
city: Bonn
country: Germany
facility: Section of Medical Psychology, Department of Psychiatry & Psychotherapy, Faculty of Medicine, University of Bonn
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.