tVNS and Obesity-related Mechanisms

NCT06954844 | Enrolling By Invitation

• 2 other identifiers: BON006493623632
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Inflammation; Metaflammation; tVNS; Motivation

Outcome Measures

Primary Outcomes (10)

• Stimulation-induced mid-term changes in a multiplex panel of different inflammatory biomarkers (peripheral inflammation)

  To measure peripheral inflammation, the investigators will assess plasma levels of pro- and anti-inflammatory cytokines, chemokines, and other biomarker of inflammation (e.g. Growth Factors) using highly sensitive immunoassays (e.g. NULISA). The investigators will select the specific panel after data collection is complete and before data analysis begins, based on the literature and the analysis methods available at that time. Blood levels will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Multivariate analysis will be used to compare stimulation-induced changes in plasma levels between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in circulating immune cells (peripheral inflammation)

  To measure peripheral inflammation, the investigators will measure the following circulating immune cells using fluorescence flow cytometry: Leukocytes, lymphocytes, neutrophil granulocytes, T-cells, (Cluster of Differentiation (CD)4+, CD8+), naïve T cells (CD4+, CD8+), central memory T-cells (CD4+, CD8+), effector memory T-cells (CD4+, CD8+), terminal effector memory re-expressing CD45RA T cells, regulatory T cells (Treg) (activated, resting), conventional T cells, cytotoxic T-cells, T helper cells (Th), Th1 cells, Th2 cells, Th1/17 cells, Th17 cells, effector T-cells, mononuclear phagocytes, monocytes (classical, Intermediate, non-classical), dendritic cells (type 1 conventional, type 2 conventional, plasmacytoid). Cells will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Multivariate analysis will be used to compare stimulation-induced changes in circulating immune cells between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• 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))

  One measure of central inflammation will be the non-restricted fraction in the brain. This will be calculated with diffusion tensor imaging (DTI) measurement acquired with a 3 Tesla (3T) Siemens Scanner. Non-restricted fraction is calculated as the isotropic DBSI-NRF (f(D), D = 0.3 - 3.0 μm2/ms) and indicates tissue edema. Regions of interest (ROI) will be defined using the Harvard Oxford extended Atlas and include the putamen, caudate, pallidum, and nucleus accumbens (NAcc) as well as the hypothalamus. Non-restricted fraction will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each) and compared in predefined ROIs between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in tissue cellularity as assessed using restricted fraction (isotropic DBSI-RF (f(D), D ≤ 0.3 μm2/ms))

  Another measure of central inflammation will be restricted fraction indicating tissue cellularity. This will be calculated with diffusion tensor imaging (DTI) measurement acquired with a 3T Siemens Scanner. Restricted fraction will be calculated as the isotropic DBSI-RF (f(D), D ≤ 0.3 μm2/ms) and indicates tissue edema. Regions of interest (ROI) will be defined using the Harvard Oxford extended Atlas and include the putamen, caudate, pallidum, and NAcc as well as the hypothalamus. Restricted fraction will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each) and compared in predefined ROIs between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in PANAS items (mood)

  To measure mood, the investigators will use items from the PANAS, rated on visual analogue scales (VAS) ranging from 0 (lowest rating) to 100 (highest rating). These items will be assessed at baseline (before each stimulation phase) and after each stimulation phase (high and low intensity; 14 days stimulation each). Values from the Positive and Negative Affect Schedule will be analysed as repeated measures assessing either positive (PA) or negative (NA) affect. Stimulation-induced changes in mood state (PA - NA) will be compared between high and low intensity stimulation.

  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

• Stimulation-induced mid-term changes in Invigoration (motivation)

  Invigoration will be assessed using the effort allocation task and is captured by the slope of the initial approach (i.e., the increase of force until a first plateau is reached). Invigoration will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Stimulation-induced changes in Invigoration will be compared between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in maintenance (motivation)

  Maintenance will be assessed using the effort allocation task and reflects the average relative force/frequency across the whole trial. Maintenance will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Stimulation-induced changes in maintenance will be compared between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in anticipatory neural reward response (motivation)

  To evaluate anticipatory neural reward response, the investigators will assess fMRI bold signals during cue presentation prior to exerting effort during the effort allocation task using a 3T Siemens Scanner. The contrast of interest will be the modulation of the anticipatory response by the reward magnitude (high vs. low) combining responses to food and monetary rewards. Other contrasts (cue response itself and contrasts specific for food or monetary rewards are exploratory). Regions of Interest (ROI) will be defined using the Harvard Oxford extended Atlas. Primary ROIs will be the NAcc and ventromedial prefrontal cortex (vmPFC) and secondary ROIs will be ventral tegmental area (VTA)/substantia nigra (SN), and caudate, and putamen. fMRI metrics will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Stimulation-induced changes in bold signals in predefined ROI will be compared between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in neural motor response (motivation)

  To evaluate neural motor response, the investigators will assess fMRI bold signals while the participants exert effort (work phase) during the effort allocation task using a 3T Siemens Scanner. The contrasts of interest will be force/repetition time (TR) to assess motor work during the task and the first derivative of force/TR (temporal relative = d(force)/d(TR)) estimating the drive to work. Region of Interest (ROI) will be defined using the Harvard Oxford extended Atlas and include the supplementary motor area (SMA) and pre-SMA, as well as VTA/SN, and caudate, putamen, and NAcc. fMRI metrics will be assessed at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). Stimulation-induced changes in bold signals in predefined ROI will be compared between high and low intensity stimulation.

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Correlation of Stimulation-induced changes in peripheral and central inflammation with changes in mood and motivation

  The investigators will correlate changes (i.e., random effect estimates of high intensity stimulation slopes relative to low intensity stimulation) in peripheral and central inflammation markers with tVNS-induced (high vs. low intensity) changes in mood and motivation.

  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 (6)

• Stimulation-induced mid-term changes in ratings of reward wanting and exertion

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in utility slope

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced changes in mood and motivation in daily life

  During intervention phase: 14 days

• Stimulation-induced mid-term changes in anhedonia

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Stimulation-induced mid-term changes in depressive symptoms

  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 (20)

• BMI

  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

• Percentage of body-fat

  Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase

• Waist-to-hip ratio

  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

Study Arms (2)

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

EXPERIMENTAL

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.

Device: Transcutaneous non-invasive vagus nerve stimulation (tVNS)

Low intensity stimulation

SHAM COMPARATOR

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).

Device: Low intensity stimulation

Interventions

Transcutaneous non-invasive vagus nerve stimulation (tVNS) 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.

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

Low intensity stimulation 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).

Low intensity stimulation

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Bonn: lead

Study Sites (1)

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

Bonn, 53127, Germany

Location

Related Publications (3)

• 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.

  PMID: 34227242 BACKGROUND

• 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.

  PMID: 32678082 BACKGROUND

• 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.

  PMID: 26344127 BACKGROUND

MeSH Terms

Conditions

Overweight; Obesity; Inflammation

Condition Hierarchy (Ancestors)

Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. rer. nat.

Study Record Dates

• First Submitted: March 21, 2025
• First Posted: May 2, 2025
• Study Start: April 8, 2025
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027
• Last Updated: May 2, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data will become available after an embargo period of 12 months after completion of the study
• Access Criteria: Until the data is publicly available, researchers may contact the lead PI to gain access.

Locations

DE (1)