Project Summary There is an overwhelming belief that schizophrenia (SZ) is a neurodevelopmental disorder, due to evidence that structural and cognitive changes emerge at different illness stages. The timeline of structural abnormalities and their relationship to cognitive pathologies, however, is poorly understood. Neurocognitive impairments, most prominently language and working memory deficits, are considered core features of SZ, but the developmental progression of these deficits varies. Language abilities appear to be reduced very early in those at genetic risk for SZ, and they remain stably reduced thereafter, whereas working memory abilities diverge from a healthy trajectory shortly before the onset of psychosis and further deteriorate with illness progression. The differential trajectories of language and working memory capabilities in SZ strongly suggest there are distinct underlying pathophysiological mechanisms. Evidence suggests that white matter plays a crucial role in brain development and maturation, and studies have linked microstructural abnormalities in white matter tracts to deficits in cognitive abilities in at-risk individuals and SZ patients. In order to elucidate the developmental timeline of the structure-function relationship between white matter and cognitive abilities in at risk individuals, we aim to characterize pathological alterations in white matter that correspond to neurocognitive deficits in SZ risk individuals. The proposed project will analyze already collected data from three genetic high risk cohorts that represent three key developmental stages of SZ risk: infancy, childhood, and early adulthood. This study will therefore provide insight into both early and late neurodevelopmental changes associated with SZ risk and enable the characterization of structural deficits within specific developmental windows. We plan to apply advanced diffusion tensor imaging methodologies along with tract geometry and free water imaging to the datasets, allowing for the identification and differentiation of localized white matter abnormalities that may be related to aberrant early neurodevelopmental or later maturational pathologies in vivo. This project has two primary hypotheses: 1) We hypothesize that deficits in language are related to stable structural differences originating in aberrant early neurodevelopmental processes, reflected by changes in fiber architecture (geometry) in white matter language tracts; 2) We hypothesize that the deterioration of working memory abilities is related to a transient or reactive pathology to the presence of a possible insult, and this is reflected by deviations from normal maturational trajectories in tracts underlying working memory.. This will be the first study to analyze white matter from genetically at-risk individuals across the range of neurodevelopment. This study will significantly impact our understanding of the timeline of biological mechanisms that underlie functional correlates associated with SZ risk while uncovering biomarkers linked to functional vulnerabilities and identifying windows when therapeutic interventions would be most effective.

Project Narrative This application aims to understand the neurodevelopmental timeline of structural aberrations in white matter tracts that may be related to specific neurocognitive deficits in individuals at genetic high risk for schizophrenia. The PI and investigators of this proposal will apply cutting-edge image analysis methodologies to already collected diffusion weighted images and relate it to neurocognitive data from three unique cohorts of genetic high-risk for schizophrenia individuals and matched healthy controls with ages which span the course of early development: Infancy, Childhood, Early Adulthood. This research will have a significant impact on the field because it will provide a first step toward the identification of biomarkers in white matter related to vulnerability for developing schizophrenia and isolate optimal windows in development for therapeutic interventions.