tVNS to Provide Mechanistic Insights Into the Relationship Between Systemic Inflammation and Altered Motivation and Mood in Healthy Individuals Who Are Overweight or Obese
Trial Snapshot
- Phase
- Not Applicable
- Status
- Enrolling By Invitation
- Sponsor
- University of Bonn
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Stimulation-induced mid-term changes in a multiplex panel of different inflammatory biomarkers (peripheral inflammation)
Study Overview
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)).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
Eligibility Criteria
- Ages
- 18 Years to 40 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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
Arms & Interventions
High intensity transcutaneous non-invasive vagus nerve stimulation (tVNS)
Participants will receive high intensity tVNS for >30 min per day for 14 days at home. To stimulate vagal afferents, the electrode will be placed at the cymba conchae of the right ear using a previously established conventional stimulation protocol (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany). Stimulation intensity will be pre-set for each participant for the following stimulation period to correspond to a mild pricking sensation determined with a staircase procedure in the lab session.
Intervention: Transcutaneous non-invasive vagus nerve stimulation (tVNS) (Device)
Low intensity stimulation
The control intervention consists of low intensity stimulation. Participants will receive low intensity stimulation for >30 min per day for 14 days at home. The electrode will be placed at the cymba conchae, but only receive a low-intensity stimulation below the perception threshold (0.1mA, 1s ON, 30s OFF, 1 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany).
Intervention: Low intensity stimulation (Device)
Outcomes
Primary Outcomes
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 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.
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.
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.
Secondary Outcomes
- 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 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 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)
- Stimulation-induced mid-term changes in apathy(Baseline, immediately after the first 14-day stimulation phase and before a 7-day washout, immediately after the second 14-day stimulation phase)
Investigators
Dr. Nils B. Kroemer
Prof. Dr. rer. nat.
University Hospital, Bonn