tVNS, Motivation, and Insulin Sensitivity

Condition(s) studied

Investigational drug(s) / intervention(s)

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.

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.

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.

Study 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.

Eligibility

Primary outcome measure(s)

• tVNS-induced behavioral changes in invigoration — During MRI scan of effort allocation task (20 minutes), tVNS vs. sham session
  The primary outcome of interest is the invigoration related to monetary and food rewards, which will be operationalized via the relative effort exerted on a grip force device using the effort allocation task. Invigoration is captured by the slope of the initial approach (i.e., the increase of force until a first plateau is reached). Invigoration will be compared between groups (CP, MDD) and stimulation conditions (tVNS, sham), and will be associated with insulin sensitivity. We will also investigate how effects on invigoration compare to effects on effort maintenance as well as on the association between ratings (i.e., wanting and exertion) during the effort task from the Intake session and effort (i.e., their correspondence expressed as slopes).
• tVNS-induced changes in brain responses — During MRI scan of effort allocation task (20 minutes), tVNS vs. sham session
  Brain activity (BOLD signal) in response to monetary and food rewards and during exerting effort on a grip force device will be analyzed by focusing on brain regions associated with the vagal afferent pathway. Brain activity will be compared between groups (CP, MDD) and stimulation conditions (tVNS, sham), and will be associated with insulin sensitivity.
• Association of insulin sensitivity with anhedonia severity — oGTT (120 minutes)
  Here, insulin sensitivity (Matsuda ISI) is considered a predictor variable, and the primary outcome is the association coefficient with anhedonia (SHAPS).
• Association of insulin sensitivity with motivation during an effort allocation task — ~40 minutes during Intake Session
  Here, insulin sensitivity (Matsuda ISI) is considered a predictor variable, and the primary outcome is the association coefficient with invigoration, which will be operationalized via the relative effort (frequency button presses, controller) using the effort allocation task. Invigoration is captured by the slope of the initial approach (i.e., the increase of force until a first plateau is reached). Motivation will be compared between groups (CP, MDD), and in association with anhedonia, insulin-sensitivity. We will also investigate effects on effort maintenance and subjective ratings during the effort task (i.e., wanting and exertion) as well as the association between ratings and effort (slopes).

Trial sites (1)

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