PROJECT SUMMARY Schizophrenia (SZ), and related psychotic disorders, affects about 1% of the global population and is associated with highly increased rates of cardiovascular disease, diabetes, and cancer compared to the general population. Greater obesity severity and prevalence in this population are the primary contributors to these increased risks. While antipsychotic (AP) treatment is a known contributor to weight gain, the neurobiology underlying this and other contributing factors are largely unknown. Without an improved understanding of the neurobiology of obesity in SZ, developing targeted treatments remains challenging. A framework that may be useful in understanding this neurobiology is the "Triple Network Theory" of SZ, which postulates that disruptions in three brain networks (default mode, executive control, and salience networks) heavily contribute to SZ pathophysiology. Disruption of these networks are similarly strongly associated with obesity severity in the general population. This proposal, therefore, aims to determine how disruptions in the “triple network” in SZ contributes to the observed increased obesity risk. Associations between triple-network disruptions and obesity in SZ will be assessed with functional magnetic resonance imaging (fMRI) measurements of brain connectivity within the “triple network” in individuals with and without SZ. Connectivity will be measured at rest and during visual food cues, both before and after consuming a meal. Machine learning analyses will measure how AP-related weight gain correlates with disruptions in the triple network in SZ, how obesity relates to these disruptions in individuals with and without SZ, and how other factors (i.e., appetite-related hormones, eating behaviors, and mood ratings) may influence these relationships. Mr. Dodd’s training plan focuses on the neurobiology of obesity and psychiatric disorders, advanced neuroimaging analysis, and professional development (see Training Plan). He will be supported by mentors with relevant expertise, as well as state-of-the-art resources in obesity, neuroimaging, and psychiatry research at the University of Colorado Anschutz Medical Campus. This training will support both this proposal and his career goal to become a neuroimaging physician-scientist investigating the neurobiology of psychiatric conditions and their comorbidities. The research conducted during this training has the potential for high clinical impact. Determining how the Triple Network Theory relates to obesity in SZ, and related psychotic disorders, may lead to improved treatment development and targeting for obesity and obesity-related comorbidities for this population.