Overweight/Obesity (BMI: 27 and 35 kg/m2)NCT06954844
tVNS and Obesity-related Mechanisms
A study testing Transcutaneous non-invasive vagus nerve stimulation (tVNS) and Low intensity stimulation in people with Overweight/Obesity (BMI: 27 and 35 kg/m2), run by University of Bonn at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Overweight/Obesity (BMI: 27 and 35 kg/m2)
- What is being tested?
- Transcutaneous non-invasive vagus nerve stimulation (tVNS) and Low intensity stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 60 participants
- Where
- 1 siteGermany
- Study dates
- 8 Apr 2025to 31 Mar 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Between 18 and 40 years of age
- BMI between 27 and 35.0 kg/m2
- Legally valid declaration of consent
Who cannot join
- 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
Show all 10Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Germany1 site
Section of Medical Psychology, Department of Psychiatry & Psychotherapy, Faculty of Medicine, University of Bonn
Bonn, 53127
About this study
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
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.
Read the 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.
- Being tested
- Transcutaneous non-invasive vagus nerve stimulation (tVNS), Low intensity stimulation
- Keywords
- Inflammation, Metaflammation, tVNS, Motivation
- Medical subject headings
- Overweight, Obesity, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
Low intensity stimulationDevice
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).
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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). Receives: Device: Low intensity stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Ratings of wanting and exertion after each trial (after the effort exertion phase) in the effort allocation task will be assessed on a visual analogue scale ranging from 0 (lowest rating) to 100 (highest rating). Stimulation-induced changes in ratings will be compared between high and low intensity stimulation.
Note: Exertion and wanting ratings are only assessed while participants perform the EAT outside the MRI, prior to the MRI task.
Measured: 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
To investigate the correspondence between effort and wanting, the investigators will calculate "utility slopes" as the correlation between trial-wise wanting ratings and trial-wise effort maintenance. Stimulation-induced changes in utility slopes will be compared between high and low intensity stimulation.
Note: Exertion and wanting ratings are only assessed while participants perform the EAT outside the MRI, prior to the MRI task.
Measured: 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
Mood and motivation will be assessed daily during the intervention phase via visual analogue scales ranging from 0 (lowest rating) to 100 (highest rating) using EMA. The main outcomes include mood assessed using mood state: (Happy - Sad)/100 and motivation (single item).
List of items:
How happy do you feel at the moment? How sad do you feel at the moment? How motivated do you feel right now?
Stimulation-induced changes in mood and motivation ratings during the intervention phase will be compared between high and low intensity stimulation.
Measured: During intervention phase: 14 days
Stimulation-induced mid-term changes in anhedonia
The German version of the Snaith Hamilton Pleasure Scale (SHAPS-D) will be used to assess anhedonia at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). The questionnaire consists of four domains. The investigators will determine an overall outcome measure "anhedonia" using the sum score across all items (0-14), with higher scores indicating more severe anhedonia. This sum score will be used to compare changes induced by high vs low intensity stimulation.
Measured: 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
The Beck's Depression Inventory (BDI-II) will be used to assess changes in depressive symptoms at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). The items of the score will be summed up to a total score (0-63), with higher scores indicating more severe depression. This score will be used to compare changes induced by high vs. low intensity stimulation.
Measured: 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 apathy
The Apathy Motivation Index (AMI) will be used to assess apathy at baseline and after each stimulation phase (high and low intensity; 14 days stimulation each). The questionnaire consists of three subscales that can be combined to a total score (0-72), with higher scores indicating more severe apathy. The investigators will determine an overall outcome measure "apathy" using the sum score across all items to compare changes induced by high vs. low intensity stimulation.
Measured: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2025
- Study start8 Apr 2025
- Primary completion31 Mar 2027 (estimated)
- Study completion31 Mar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Overweight/Obesity (BMI: 27 and 35 kg/m2)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Bonn
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Nils B. Kroemer, University Hospital, Bonn
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06954844
- Sponsor's protocol ID
- BON006
- Other IDs
- 493623632
- Status last verified
- Apr 2025
- First submitted
- 21 Mar 2025
- Last updated
- 2 May 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: After the publication of the key results of the study, all anonymized imaging data will be made publicly available (e.g., at openfmri.org)
Publications
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.
PubMed 34227242Neuser 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.
PubMed 32678082Charbonnier 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.
PubMed 26344127Kaluza L, Kuhnel A, Picon-Galindo E, Hergenrother M, Alkhateeb H, Michalski S, Ribeiro DJS, Schmidt SV, Wachten D, Kroemer NB. tVNS and obesity-related inflammation: a prospective sham-controlled randomized crossover study protocol. BMC Psychol. 2026 Aug 4;14(1):1133. doi: 10.1186/s40359-026-05219-5.
PubMed 42552546
Study at a glance
From the registry record, last updated by the sponsor on 2 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT06954844
- Acronym / sponsor ID
- BON006
- Keywords
- Inflammation, Metaflammation, tVNS, Motivation
- Study type
- Interventional
- Recruitment status
- Enrolling by invitation
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- University of BonnUniversity, hospital or other
- Study start
- 8 Apr 2025 (actual)
- Primary completion
- 31 Mar 2027 (estimated)
- Study completion
- 31 Mar 2027 (estimated)
- First posted
- 2 May 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| High intensity transcutaneous non-invasive vagus nerve stimulation (tVNS) | Experimental | Device: 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. |
| Low intensity stimulation | Sham comparator | Device: Low intensity stimulationThe 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). |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Between 18 and 40 years of age
- BMI between 27 and 35.0 kg/m2
- Legally valid declaration of consent
Key exclusion criteria (10 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Device | High intensity transcutaneous non-invasive vagus nerve stimulation (tVNS) |
| Low intensity stimulationThe 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 |
Primary outcome
Stimulation-induced mid-term changes in a multiplex panel of different inflammatory biomarkers (peripheral inflammation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in circulating immune cells (peripheral inflammation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
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))
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in tissue cellularity as assessed using restricted fraction (isotropic DBSI-RF (f(D), D ≤ 0.3 μm2/ms))
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in PANAS items (mood)
Time frame: 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
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.
Stimulation-induced mid-term changes in Invigoration (motivation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in maintenance (motivation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in anticipatory neural reward response (motivation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Stimulation-induced mid-term changes in neural motor response (motivation)
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
Correlation of Stimulation-induced changes in peripheral and central inflammation with changes in mood and motivation
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
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.
6 secondary outcomes
Stimulation-induced mid-term changes in ratings of reward wanting and exertion
Time frame: 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
Time frame: 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
Time frame: During intervention phase: 14 days
Stimulation-induced mid-term changes in anhedonia
Time frame: 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
Time frame: 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 apathy
Time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 May 2025.
- Background: PubMed 34227242Samara 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.
- Background: PubMed 32678082Neuser 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.
- Background: PubMed 26344127Charbonnier 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.
- Derived from this study: PubMed 42552546Kaluza L, Kuhnel A, Picon-Galindo E, Hergenrother M, Alkhateeb H, Michalski S, Ribeiro DJS, Schmidt SV, Wachten D, Kroemer NB. tVNS and obesity-related inflammation: a prospective sham-controlled randomized crossover study protocol. BMC Psychol. 2026 Aug 4;14(1):1133. doi: 10.1186/s40359-026-05219-5.
- Individual participant dataSharing planned: Yes. After the publication of the key results of the study, all anonymized imaging data will be made publicly available (e.g., at openfmri.org)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcutaneous non-invasive vagus nerve stimulation (tVNS) and Low intensity stimulation in people with Overweight/Obesity (BMI: 27 and 35 kg/m2), run by University of Bonn at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: enrolling by invitation, as of the sponsor's last update on 2 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Stimulation-induced mid-term changes in a multiplex panel of different inflammatory biomarkers (peripheral inflammation) (time frame: Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06954844, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 May 2025; AzTrials last refreshed its copy on 6 Nov 2026.