Overview
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.
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.
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)