Identifying multidimensional signatures of gastric interoception in functional dyspepsia

About This Grant

PROJECT SUMMARY/ABSTRACT Functional dyspepsia (FD) is common, affecting 12% of adults in the United States with high morbidity (e.g., work absenteeism, malnutrition) and healthcare costs. FD symptoms most commonly include early satiation and epigastric pain, worsened by meal ingestion in the absence of clear structural etiology. Precision medicine is lacking due to the complex pathophysiology thought to underlie gut-brain axis dysfunction in FD. Identification of maintenance mechanisms is necessary to determine which existing and new treatments work for whom and why. Gut interoception—how the gut and brain communicate to sense (i.e., attend to), interpret, and integrate gut signals at both conscious and unconscious levels—may be a useful model for understanding dynamic body-to-brain (‘bottom up’) and brain-to-body (‘top down’) processing in FD. This proposal uses multi- disciplinary methods (i.e., functional magnetic resonance imaging: fMRI, resting state functional connectivity, gut connectivity, self-report). We will examine three dimensions of interoceptive processing: gastric attention, interpretation of gastric signals, and gut-brain signal integration. We will contrast gut interoception in adults with FD (n=50) to healthy controls (n=50) and a clinically relevant comparator (anorexia nervosa; n=50) to test our central hypothesis: FD is linked to neural hyper-attention to gastric signals, neural fear-based interpretation of gastric signals, and poor bi-directional gut-brain integration. First, we hypothesize FD will exhibit fasting and pre-meal neural hyper-attention to gastric cues in primary interoceptive regions (insula, anterior cingulate cortex) of the Salience Network (involved in interoception and cognitive/emotional integration). We expect hyperactivation to correlate with a trait-level gut interoceptive awareness. Second, we hypothesize that FD will show pre-and post-meal resting state hyperconnectivity in the primary hub of interoception—the mid insula— and the amygdala (primary limbic region of the Salience Network) alongside hypoconnectivity with the orbital frontal cortex (a primary food-reward region of the Salience Network). Finally, we expect FD to show greater connectivity than controls and AN between the nucleus tractus solitarius (key brain stem region involved in processing interoceptive signals) and the Salience Network, which we expect will correlate with slower gastric motility. Conceptualizing FD pathophysiology within an interoceptive framework has strong potential to advance precision medicine for FD by identifying neural mechanistic targets—hyper-attention (e.g., attention re-training), dysregulated interpretation (e.g., behavioral exposure therapy), and altered integration (e.g., vagal nerve stimulation).