tVNS, Motivation, and Insulin Sensitivity

NCT ID: NCT07198100

Last Updated: 2025-12-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-10
• Study Completion Date: 2027-12-31

Brief Summary

Disturbances in energy metabolism significantly increase the risk of developing major depressive disorder (MDD), especially in individuals with type 2 diabetes. Insulin sensitivity may particularly impair reward anticipation and motivational processes, contributing to anhedonia, a core symptom of depression. Preclinical and clinical studies highlight the vagus nerve as a critical pathway mediating metabolic signals between the body and the brain, influencing motivational and affective states.

The present study aims to evaluate whether acute transcutaneous auricular vagus nerve stimulation (taVNS) improves motivation and mood and whether individual differences in insulin sensitivity modulate these improvements.

The investigators plan to recruit 60 patients with MDD and 60 control participants matched for age, sex, and body mass index (BMI), covering a wide BMI range (up to 40 kg/m²) and insulin sensitivity (including patients with type 2 diabetes). Participants will undergo comprehensive metabolic assessments, behavioral testing of reward anticipation, motivation, consummation, and learning, and ecological momentary assessments (EMA) coupled with continuous glucose monitoring to assess real-world motivational behavior and glucose dynamics. Furthermore, participants will undergo two neuroimaging sessions, involving both task-free and task-based functional MRI, during concurrent taVNS or sham stimulation, implemented in a randomized, single-blinded, crossover design.

This study hypothesizes that individuals with lower insulin sensitivity, particularly those with MDD and pronounced anhedonic symptoms, will show greater motivational and neural responsiveness to taVNS.

H1A. Individuals with depression (vs. controls) and higher anhedonia show greater deficits in reward-related behavior and lower insulin sensitivity.

H1B. Across all participants, reduced reward-related behavior and higher anhedonia are associated with lower insulin sensitivity.

H2A. tVNS (vs. sham) increases motivation for rewards, brain responses to rewards, and body-brain interactions across participants.

H2B. These tVNS-induced effects are particularly pronounced in individuals with depression and stronger anhedonia who show reductions in these domains.

H3A. Greater tVNS-induced effects (behavioral, neural, body-brain) are associated with lower insulin sensitivity.

Detailed Description

To assess where individual reward deficits manifest, participants will undergo an intake session that includes clinical interviews, a fasting blood draw, and a battery of reward tasks (Reward Rating, Effort Allocation, Taste Test, Go-Nogo-Learning). Changes in symptoms and glucose levels will be evaluated using a wearable glucose sensor and ecological momentary assessments (EMA) over 2 weeks. To assess insulin sensitivity, the investigators will perform an oral glucose tolerance test, with concurrent stimulation (tVNS vs. sham; i.e., two sessions, randomized). Finally, in two neuroimaging sessions, the investigators will assess the effect of acute tVNS (vs. sham; randomized) on motivation and stomach-brain coupling using concurrent functional magnetic resonance imaging (fMRI) and electrogastrography (EGG). Washout between tVNS/sham days will be a minimum of 2 days. Condition order will be randomized, and the design is single-blind (participant).

To characterize our sample, the investigators will also collect information using standardized questionnaires assessing personality traits, eating behavior, psychiatric symptoms, and physical activity. To further characterize our sample metabolically, the investigators will also collect blood samples to determine metabolic parameters (e.g., acyl-ghrelin, des-acyl ghrelin, insulin, glucose, triglycerides, HDL, LDL), and participants can opt in to collect data for genetic analyses as part of a Biobank. These measures will be used to describe the sample and will be explored as predictors to explain inter-individual intervention effects.

• Personality traits related to reward and motivation: Behavioral Inhibition/Activation System
• Eating behavior: Three Factor Eating Questionnaire
• Psychiatric symptoms: depressive symptoms and anhedonia (BDI-II; Snaith-Hamilton Pleasure Scale, German version, SHAPS-D; Temporal Experience of Pleasure Scale, TEPS; Dimensional Anhedonia Rating Scale, DARS).
• Physical activity: International Physical Activity Questionnaire (IPAQ).

During the EMA period, participants will measure changes in glucose using a continuous glucose monitor (CGM) using the Freestyle Libre 3 sensor. Participants will answer questions with respect to:

• state ratings (e.g. hunger, mood)
• anticipated rewarding activities (wanting, time planned)
• consummated rewarding activities (liking, time spent)
• as well as complete a food choice task.

Conditions

Major Depressive Disorder (MDD)

Keywords

tVNS; motivation; insulin-sensitivity; depression; diabetes

Study Design

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

Study Groups

Patients with Major Depressive Disorder (MDD)

All participants will receive tVNS and sham stimulation in a randomized order.

Group Type: EXPERIMENTAL

Transcutaneous non-invasive vagus nerve stimulation (tVNS)

Intervention Type: DEVICE

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

Sham stimulation

Intervention Type: DEVICE

The control intervention consists of a sham stimulation. The electrode will be placed at the earlobe, which is not innervated by vagal afferent fibers. To improve blinding, the same stimulation protocol as for the tVNS will be applied (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany) and stimulation intensities will be adjusted to correspond to a mild pricking sensation.

Oral glucose tolerance test (oGTT)

Intervention Type: DIAGNOSTIC_TEST

The oGTT will be conducted as a standardized metabolic challenge to assess glucose metabolism and insulin sensitivity. After an overnight fast, participants ingest a 75 g glucose solution. Venous blood samples are collected at five time points (0, 30, 60, 90, and 120 minutes) to measure plasma glucose and insulin concentrations. The primary variable of interest will be the peripheral insulin sensitivity index (ISI) according to Matsuda and DeFronzo as 10,000/(G0 × I0 × Gmean × Imean)1/2 with G = glucose and I = insulin.

Additionally we will investigate the correspondence of ISI with other measures of insulin sensitivity (HOMA-IR), and Insulin secretion indices (Insulinogenic index (IGI), Corrected insulin response (CIR), Areas under the curve (AUC)), and HbA1c.

Control Participants (CPs)

All participants will receive tVNS and sham stimulation in a randomized order.

Group Type: EXPERIMENTAL

Transcutaneous non-invasive vagus nerve stimulation (tVNS)

Intervention Type: DEVICE

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

Sham stimulation

Intervention Type: DEVICE

The control intervention consists of a sham stimulation. The electrode will be placed at the earlobe, which is not innervated by vagal afferent fibers. To improve blinding, the same stimulation protocol as for the tVNS will be applied (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany) and stimulation intensities will be adjusted to correspond to a mild pricking sensation.

Oral glucose tolerance test (oGTT)

Intervention Type: DIAGNOSTIC_TEST

The oGTT will be conducted as a standardized metabolic challenge to assess glucose metabolism and insulin sensitivity. After an overnight fast, participants ingest a 75 g glucose solution. Venous blood samples are collected at five time points (0, 30, 60, 90, and 120 minutes) to measure plasma glucose and insulin concentrations. The primary variable of interest will be the peripheral insulin sensitivity index (ISI) according to Matsuda and DeFronzo as 10,000/(G0 × I0 × Gmean × Imean)1/2 with G = glucose and I = insulin.

Additionally we will investigate the correspondence of ISI with other measures of insulin sensitivity (HOMA-IR), and Insulin secretion indices (Insulinogenic index (IGI), Corrected insulin response (CIR), Areas under the curve (AUC)), and HbA1c.

Interventions

Transcutaneous non-invasive vagus nerve stimulation (tVNS)

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

Intervention Type: DEVICE

Sham stimulation

The control intervention consists of a sham stimulation. The electrode will be placed at the earlobe, which is not innervated by vagal afferent fibers. To improve blinding, the same stimulation protocol as for the tVNS will be applied (30 s ON, 30s OFF, 25 Hz frequency, 250 µs pulse widths; tVNS R device, tVNS Technologies GmbH, Erlangen, Germany) and stimulation intensities will be adjusted to correspond to a mild pricking sensation.

Intervention Type: DEVICE

Oral glucose tolerance test (oGTT)

The oGTT will be conducted as a standardized metabolic challenge to assess glucose metabolism and insulin sensitivity. After an overnight fast, participants ingest a 75 g glucose solution. Venous blood samples are collected at five time points (0, 30, 60, 90, and 120 minutes) to measure plasma glucose and insulin concentrations. The primary variable of interest will be the peripheral insulin sensitivity index (ISI) according to Matsuda and DeFronzo as 10,000/(G0 × I0 × Gmean × Imean)1/2 with G = glucose and I = insulin.

Additionally we will investigate the correspondence of ISI with other measures of insulin sensitivity (HOMA-IR), and Insulin secretion indices (Insulinogenic index (IGI), Corrected insulin response (CIR), Areas under the curve (AUC)), and HbA1c.

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Participants with depression (DSM-5 diagnosis) or participants without depression (no DSM-5 diagnosis, lifetime)
• BMI between 18.5 and 40 kg/m²
• Age between 18 and 60 years
• Legally valid informed consent

Exclusion Criteria

The following diagnoses in medical history:

• Brain injury
• Schizophrenia
• Bipolar disorder
• Severe substance use disorder
• Coronary heart disease
• Stroke
• Epilepsy
• Chronic inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, etc.)
• Type I diabetes

The following diagnoses within 12 months prior to the experiment:

• Obsessive-compulsive disorder
• Somatic symptom disorder
• Eating disorder

The following diagnoses in medical history for control participants:

• Depression
• Anxiety disorders (except specific phobias)

Generally:

• Contraindications for MRI (e.g., metal implants, claustrophobia) or taVNS (e.g., piercings, sore or diseased skin on the outer right ear)
• Pregnant and breastfeeding women will not be included
• Unclear capacity to consent
• Stomach surgeries affecting body weight (e.g., bypass surgeries)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Bonn

OTHER

Sponsor Role: lead

Responsible Party

Dr. Nils B. Kroemer

Prof. Dr. rer. nat.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nils B Kroemer, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Section of Medical Psychology, Department of Psychiatry & Psychotherapy, Faculty of Medicine, University of Bonn, 53127 Bonn, Germany

Locations

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

Bonn, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Nils B Kroemer, Prof. Dr.

Role: CONTACT

Phone: +49 228 287 11151

Email: nkroemer@uni-bonn.de

Facility Contacts

Nils B Kroemer, Prof. Dr.

Role: primary

Other Identifiers

82DZD23H03

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

BON007

Identifier Type: -

Identifier Source: org_study_id