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.

Eligibility

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)

Conditions3

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