Project Summary In the resubmission of this K01 application, we propose to conduct a hybrid cross-sectional and longitudinal multi-modal neuroimaging study aimed at understanding the biological nature and time course of an acute brain response previously observed in first-episode schizophrenia patients. The acute brain response, characterized by a global increase in extracellular free water in first-episode patients, has been previously linked to neuroinflammation. Recent evidence suggests that the acute brain response may be part of a compensatory immune-related action related to recovery or resiliency. In this proposal, we suggest and investigate the hypothesis that this compensatory response may be related to the increased expression of Group I subtype metabotropic glutamate receptor 5 (mGluR5), which have been shown to serve a beneficial immunomodulatory role in the central nervous system. The central scientific goal of this K01 proposal is to utilize a comprehensive data collection paradigm to 1) understand the biological nature and trajectory of the acute brain response in early psychosis by investigating its connection to mGluR5 and 2) investigate the hypothesis that these markers of cerebral immune activation in FEP are linked to resiliency. To achieve this goal, we will leverage the state-of-the-art, simultaneous collection of structural, diffusion, and positron emission tomography (PET) images utilizing the mGluR5 radioligand [18F] FPEB. With our hybrid, cross-sectional and longitudinal study design, we will collect multi-modal imaging, blood, neurocognitive, and clinical data from a cohort of first-episode patients and healthy matched controls. We hypothesize that patients with greater acute brain responses and mGluR5 expression will exhibit less structural damage and better clinical and cognitive performance after 6 months. This will be the first study to investigate the role of mGluR5 in early psychosis and the results of this pilot study will be valuable for gaining a greater understanding of the neurobiological components underlying resiliency after illness onset. To carry out the proposed scientific aims, I identified four principal areas of training and associated mentors/advisors: 1) PET image acquisition and analysis under the mentorship of Dr. Jacob Hooker (primary mentor) and advisors Drs. Julie Price and Ciprian Catana; 2) clinical and neurocognitive assessments under the mentorship of Dr. William Stone (co-mentor) and advisor Dr. Matcheri Keshavan; 3) biostatistics with advisor Dr. Mark Vangel; 4) professional development under the mentorship of Dr. Marek Kubicki (co-mentor). This project will take place at multiple institutions within Harvard Medical School, which, combined, create an ideal environment for the execution of the scientific aims and proposed training plan. Upon completion of this K01, I will have acquired the expertise to become an independent researcher and the preliminary data for a future R01.

Project Narrative Schizophrenia (SZ) is a debilitating psychiatric disorder that affects almost 1% of the world's population. This proposal investigates that alternative hypothesis that the ability to mount an immune response at the onset of psychosis may portend a better outcome in early course SZ patients. We will employ a comprehensive cross- sectional and longitudinal multi-modal imaging paradigm combined with physiological, cognitive, and clinical data collection to construct a more complete picture of potential underlying biological factors related to resiliency in SZ patients.