tVNS, Motivation, and Insulin Sensitivity

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.

Conditions

• Major Depressive Disorder (MDD)

Interventions

DEVICE

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

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.

DIAGNOSTIC_TEST

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.

Sponsors & Collaborators

• University of Bonn

  lead OTHER

Principal Investigators

• Nils B Kroemer, Prof. Dr. · Section of Medical Psychology, Department of Psychiatry & Psychotherapy, Faculty of Medicine, University of Bonn, 53127 Bonn, Germany

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-10-10

Primary Completion

2027-12-31

Completion

2027-12-31

Countries

• Germany

Study Locations