PROJECT SUMMARY/ABSTRACT This application for a K23 mentored patient-oriented research career development award will provide the applicant, a clinical neuroscientist with a broad background in translational neuroscience, with advanced training, an impactful mentored research experience, and protected research time. My long-term goal is to become an independent physician-scientist, focused on identifying neurobiological correlates and predictors of the therapeutic effects of novel treatments, especially those with acute effects. By applying such insights, I aim to develop individualized treatment strategies for mood and anxiety disorders. In line with these goals, I propose a training plan to gain expertise in translational clinical investigations and neuroimaging methods. This will be achieved through an integrated career development plan, overseen by a mentoring team with expertise in drug development, neuroimaging, and neurobiology. This proposed study will be the first to examine the neural correlates of the effects of psilocybin in obsessive- Numerous recent studies have reported acute, and sometimes persisting, clinical benefit after the administration of a single dose of psilocybin in mood and anxiety disorders, addiction, and OCD. The persistence of clinical effects long after acute intoxication has worn off implies lasting brain changes, but the mechanisms underlying these lasting therapeutic effects remain poorly understood. We propose to use connectivity analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data to probe the neuronal correlates of clinical change after a single dose of psilocybin in OCD, in the context of an independently funded randomized, placebo-controlled pilot efficacy and tolerability trial that we have just begun at Yale. Consistent with the experimental therapeutics framework, we here examine the hypothesized brain effects of psilocybin; while we predict that these will be associated with symptom improvement, our analyses will be informative whether or not psilocybin proves to have a beneficial clinical effect in this controlled trial. We focus on the default mode network (DMN), a network known to be involved in the evaluation of internal states, disrupted in OCD, and affected by psilocybin in other populations. We hypothesize that psilocybin will result in increased (i.e. normalized) intra-DMN functional connectivity in OCD, and that this will correlate with any clinical change (Aim 1). Baseline DMN connectivity is anticipated to predict subsequent neural and clinical change (Aim 2). Finally, we will examine connectivity within the corticostriatal circuitry (Aim 3); while this circuitry has not previously been investigated in the context of psilocybin, it is robustly implicated in OCD. This work will shed light on the neurobiological underpinnings of lasting clinical and behavioral effects effects of psilocybin in neuropsychiatric disease, with potential implications for other rapid-acting p...