Abstract (Project Summary) We propose to parse the clinical heterogeneity of psychotic disorders by studying the evolution of hippocampal dysfunction in the early stage of psychosis (ESOP). Smaller hippocampal volume is one of the most significant brain abnormalities in chronic schizophrenia, but is less pronounced in prodromal and early stages of psychosis. In contrast, hyperactivity of the anterior hippocampus has been observed in both early and chronic stages of psychosis. Clinical and preclinical studies have identified excitation/inhibition imbalance as a plausible mechanism for hippocampal hyperactivity in psychosis. Clarifying the timing and mechanism of hippocampal dysfunction will improve our ability to intervene and prevent the progression from early psychosis to schizophrenia. We propose to study 2 ESOP cohorts. ESOP-1 will be a new cohort of acutely ill psychotic patients who meet DSM-5 criteria A for schizophrenia for at least one month, but not more than 2 years (i.e., schizophreniform disorder or early schizophrenia). We expect that, at the end of the study, 2/3 of the ESOP-1 cohort will have progressed to schizophrenia, while the remaining 1/3 will be diagnosed with schizophreniform disorder. ESOP- 2 is a well-characterized sample of schizophrenia patients, who have participated in repeated assessments during the first two years of their illness. From ESOP-1 we will recruit 30 patients and 30 healthy control subjects for the restoration of hippocampal excitation/inhibition balance. We predict that the hippocampus is hyperactive in the ESOP-1 cohort, resulting in perturbations of relational, hippocampal-based memory. We expect to find structural changes of the anterior hippocampus only in those ESOP persons who will progress to schizophrenia. In the ESOP-2 cohort, we predict progressive hippocampal volume loss, advancing from the anterior to the posterior region, resulting in more significant memory deficits. We predict that restoring normal excitation/inhibition balance will improve hippocampal function in ESOP persons. To test our hypotheses, we will collect high-density, multi-dimensional assessments of psychosis. We will use high-resolution parcellation protocols of the hippocampus and functional imaging of resting-state and task-based activation. We will use single dose administration of levetiracetam, an anti-epileptic drug, to modulate excitation/inhibition balance. The proposed combination of longitudinal and pharmacological imaging will allow us to study the timing and mechanism of hippocampal dysfunction in psychotic disorders. The integration of these approaches aims to establish a staging model of psychotic disorders, with the ultimate goal to aid early detection, prevention and treatment.