Keeping mind and body in sync: Non-invasive vagus nerve stimulation as a tool to modulate stomach-brain coupling in depression

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Bodily signals ensure long-term survival of an organism by tuning goal-directed behavior according to homeostatic demands. These bodily signals from peripheral organs, such as the stomach and the gut, are primarily routed via the vagus nerve, which can be stimulated non-invasively with electrodes placed at the ear to target afferent fibers projecting to the brainstem. Although somatic symptoms characterize many common mental disorders, such as major depressive disorder (MDD), it is currently not sufficiently understood if mechanistic treatments modulating brain-body signaling could fundamentally improve the effectiveness of interventions.To close this crucial knowledge gap, we propose to investigate the coupling between gastric myoelectic activity (as measured by an electrogastrogram, EGG) and brain signals at rest and during food reward tasks (as measured by fMRI) in a sample of 80 participants, including 40 patients who are suffering from MDD. Importantly, to alter the correspondence between signals of the body and the brain, we propose to use transcutaneous vagus nerve stimulation (tVNS). To better resolve the intricate link between the stomach and the brain and its evolution over time, we will use a randomized cross-over design. First, we will conduct two fMRI sessions with concurrent tVNS or sham and recordings of bodily signals (EGG and electrocardiography, ECG). Second, to investigate changes over an extended period, participants will receive six additional sessions with stimulation (tVNS and sham, randomized order) while we will track potential changes in value-based decision-making and metabolic as well as mood states using a gamified reward task with ecological momentary assessments (EMA). Each repeated stimulation period will be flanked by sessions in the lab, where we will record bodily signals and collect data on symptoms to evaluate mid-term changes. Based on preclinical findings and our preliminary data, we expect that tVNS will acutely alter stomach-brain synchrony within the vagal afferent network. We theorize that extended administration of tVNS will help improve symptoms in patients suffering from MDD and hypothesize that this will be reflected in changes of gastric myoelectic frequency. Lastly, we will explore whether inter-individual differences in circulating hormones, such as ghrelin, are associated with stomach-brain coupling, which would help embed the emerging work on the gastric network in the larger literature on interoceptive signals regulating energy homeostasis.To conclude, by focusing on a pathway that plays a vital role in eating behavior as well as energy and mood homeostasis, the proposed project may pave new avenues for mechanistic therapies that help target diverse symptoms of psychopathology more rapidly and, ultimately, more effectively.