Non-invasive Vagus Nerve Stimulation as a Tool to Modulate Stomach-Brain Coupling in Depression

The overarching goal of the project is to determine whether differences in stomach-brain coupling contribute to key symptoms of major depressive disorder (MDD) and whether transcutaneous non-invasive vagus nerve stimulation (tVNS) may serve as a non-invasive intervention to improve aberrant interoceptive signaling in participants suffering from MDD.

It is planned to conduct a randomized cross-over study including two neuroimaging sessions to assess the effect of acute tVNS (vs. sham) on stomach-brain coupling using concurrent fMRI and EGG. Furthermore, to evaluate potential medium-term effects of repeated applications of tVNS (vs. sham), changes across two weeks in gastric myoelectric frequency and interoception/somatic sensations as well as metabolic and mood states will be evaluated using a combination of lab-based with ecological momentary assessments (EMA).

Consequently, three major hypotheses will be tested:

Hypothesis 1: Participants suffering from MDD show altered stomach-brain coupling compared to matched healthy control participants; inter-individual differences in interoceptive measures/somatic sensations correlate with stomach-brain coupling.

Hypothesis 2: tVNS enhances stomach-brain coupling in a vagal afferent network.

Hypothesis 3: In participants suffering from MDD, tVNS influences interoception/somatic sensations and normalizes gastric myoelectric frequency over an extended stimulation period.

In addition to these main outcomes, tNVS effects on value-based decision-making will be investigated. In detail, participants will be invited to two neuroimaging sessions (T1 and T2) including tVNS or a sham stimulation. At the beginning of each of these sessions, blood will be drawn to determine concentrations of circulating hormones. Afterwards, participants will undergo MRI and complete the following tasks: 1.) Watching an Inscape movie specifically designed to improve imaging at rest. After a 10-minutes baseline scan, tVNS/sham stimulation will start and the Inscape scan is repeated. 2.) Food bidding task to assess neural food cue reactivity as well as bidding behavior and its neural correlates when participants are asked to bid for accessing the presented food. 3.) Foraging task to assess value-based decision-making and its neural correlates with the goal to maximize points in different environments (poor and rich environment). After completing the food bidding and foraging task, the Inscape movie is presented once more to assess tVNS effects after a prolonged stimulation. Throughout all MRI tasks, stomach activity will be assessed by an EGG. Both neuroimaging sessions end with an additional blood draw.

Following the neuroimaging sessions, participants will be invited to two extended stimulation periods (tVNS vs. sham), each lasting approximately two weeks. At the beginning of the extended stimulation periods, participants will be invited to the lab and blood will be drawn (T3). Gastric myoelectric frequency using EGG and value-based decision-making will be assessed at baseline and during stimulation (tVNS or sham). After completing the session, participants are given a tVNS device and are asked to stimulate their vagus nerve for 1.5h at least on four days during the following two weeks. During this time period, participants complete further tasks on value-based decision-making and questionnaires using ecological momentary assessments. In detail, four tasks will cover different aspects of value-based decision making: 1.) Effort allocation task (motivation to work for rewards; completed at T3-T6), 2.) temporal discounting (completed during the whole extended stimulation period), 3.) social discounting (completed during the whole extended stimulation period), and 4.) Influenca (gamified reinforcement learning; completed during the whole extended stimulation period).

After two weeks, participants will again come to the lab and EGG recordings and value-based decision-making tasks will be repeated (T4). Likewise, another blood sample will be collected. The extended stimulation period will then be repeated in the same way for the other stimulation type (tVNS or sham), including both sessions in the lab (T5 and T6). The order of tVNS and sham stimulation is randomized for both neuroimaging sessions as well as the extended stimulation period.

Eligibility Criteria:
Inclusion Criteria:

* Between 18 and 55 years of age
* BMI between 18.5 and 30kg/m\^2
* Legally valid declaration of consent
* MDD group: current major depressive episode based on DSM V criteria

Exclusion Criteria:

* Current or past diagnosis of brain injury, epilepsy, schizophrenia, bipolar disorder, severe substance use disorder (exception: tobacco), coronary heart disease, stroke
* Following diagnosis within 12 months before start of experiment: obsessive compulsive disorder, somatic symptom disorder, eating disorder
* Contraindications for MRI (e.g. metal implants, claustrophobia) or tVNS (e.g. piercings, sore or diseased skin areas on the outer right ear)
* Pregnant and breastfeeding women are not included
* Unclear ability to give consent