PROJECT SUMMARY/ABSTRACT Functional dyspepsia (FD) is one of the most common disorders of gut-brain interaction (DGBI), characterized by recurrent epigastric discomfort consisting of any one or a combination of postprandial fullness, early satiation, and/or epigastric pain or burning, in the absence of a clear structural etiology. Despite the high prevalence, there is a lack of treatment options available to patients for whom traditional pharmacological interventions have failed due to either lack of efficacy or uncontrollable side effects. While many non- pharmacological therapies have shown promise for DGBI, including FD, the efficacy of any single-modality treatment is typically modest. Finding a way to boost clinical outcomes for these therapeutic modalities is a crucially important goal. As FD is a multifactorial condition with visceral, affective, and cognitive components, we propose that multimodal neurophysiologically-informed strategies – e.g. combining bottom-up and top-down approaches - will enhance benefits by targeting different, but convergent, neural pathways that contribute to FD symptomatology. To date, however, better integration of bottom-up and top-down strategies has been hampered by a lack of mechanistic understanding of how they interact to improve FD symptoms, presenting a knowledge gap that, when filled, could help optimize care by illuminating approaches that are most likely to have a synergistic salubrious effect. Specifically, we propose a randomized, single-blinded, 2x2 sham- controlled trial to investigate the potential synergy of transcutaneous auricular vagus nerve stimulation (taVNS, bottom-up) with GI-targeted cognitive-behavioral therapy (GI-CBT, top-down). We will evaluate the longitudinal effects (8 weeks) of taVNS+CBT (or controls) on post-meal gut-brain physiology and clinical outcomes. Furthermore, we will examine the role of GI-specific anxiety in anticipating (i.e. change at 4 weeks) and thus predicting clinical improvements following 8 weeks of therapy, as well as mediating post-therapy changes in gut-brain physiology and clinical outcomes. In our study, we will exploit our fully non-invasive experimental framework including sequential gastric and brain Magnetic Resonance Imaging (MRI). The significance of our proposal is high as it will provide a mechanistic framework for how taVNS and CBT, both separately and synergistically, modulate FD pathophysiology, leading to future clinical trials to evaluate this integrated multimodal intervention for difficult to treat chronic GI disorders, such as FD.