PROJECT SUMMARY The high prevalence, reduced quality of life and poor understanding of functional gastrointestinal disorders calls for development of better diagnostic modalities and novel therapies. Functional nausea (FN) is a particularly challenging subcategory as there is no knowledge of mechanisms to direct therapy. Due to close symptom overlap, patients with FN fall between the cracks of several subspecialties and other better defined disorders. Disorders of gastric motor function such as delayed stomach emptying (gastroparesis) and impaired gastric compliance share very similar symptom complex and are difficult to distinguish from FN based on available tests in children. The common co-occurrence of anxiety results in labeling many with undefined nausea with psychosomatic disease. Our prior descriptive studies point to autonomic nervous system (ANS) imbalance and high arousal in adolescents with “functional nausea.” Central brain pathways and the arousal neurocircuitry are closely integrated with ANS signals. The main purpose of this study is to investigate brain- gut mechanisms at play in adolescents with FN and the efficacy of a novel neurostimulation device for nausea. Two aims are proposed in this K23 award. The first aim attempts to classify nausea into defined subtypes based on clinical and physiologic parameters (gastric motor abnormalities and autonomic imbalance). No prior study has prospectively described pediatric FN. We will classify FN based on autonomic imbalance/low vagal tone and lack of gastric motor dysfunction. We will use non-invasive gastric function tests to categorize patients and heart rate variability measures as an index of autonomic balance/vagal tone to further define FN. The second aim focuses on response to neurostimulation therapy and hypothesized functional brain connectivity changes in patients with FN. Our group has recently demonstrated the ability to modulate central brain pathways in animals with a peripheral, non-invasive neurostimulation device. This novel, FDA-cleared neurostimulation device delivers percutaneous, electrical stimulation below sensation threshold to branches of several cranial nerves including the vagus, in the external ear. In animals, this therapy inhibits amygdala output and improves visceral hyperalgesia. In humans, we have shown safety and efficacy over placebo for adolescents with functional abdominal pain disorders. A subset with improvement in concurrent nausea had a notable increase in vagal tone with therapy. We hypothesize that neurostimulation improves FN by modulating ANS function and limbic brain areas (amygdala, hypothalamus). We will investigate vagal tone and functional brain connectivity changes induced by this therapy compared to baseline and healthy controls. Through this proposal, we hope to gather more knowledge on the brain-gut pathways underlying functional nausea and study a novel therapy with strong physiologic basis for this debilitating condition.