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New approaches that bridge knowledge across genes and proteins to cells to whole-brain networks and to behaviour are beginning to transform our understanding of how the brain works in health and disease. Translation of neuroimaging results depend on this mechanistic understanding and is critical for discovery of new druggable targets. This talk will provide an overview of recent work using in our lab combining multimodal brain imaging methods to ask questions about the interactions between neurochemistry, neurophysiology, and neuroanatomy in psychosis vulnerability with a focus on brain excitation-inhibition balance. I will discuss our recent research using preclinical models and bioinformatic approaches to delineate with increased precision in the biological mechanisms involved in the human neuroimaging observations. We will also apply experimental medicine approaches to probe how to intervene on those mechanisms early to prevent or delay the development of psychosis. Finally, and in parallel, we work to integrate this mechanistic understanding with large-scale approaches to neuroimaging data (ENIGMA Schizotypy) and real-world clinical outcomes using electronic health records.