DESCRIPTION (provided by applicant): Psychotic spectrum disorders (PSD) are disabling severe mental syndromes with high prevalence. Among the PSD deficits, cognitive dysfunction represents a core characteristic shown to the best predictor of poor outcome and chronic disability. However, current therapies do not adequately address cognitive symptoms. This limitation reflects to a large degree the still incipient and incomplete understanding of the involved neural mechanisms. A significant predictor of cognitive ability in both healthy individuals and individuals on the psychotic spectrum is working memory capacity, a cognitive domain impaired in many forms of psychopathology. Our preliminary data, based on Diffusion Kurtosis Imaging (DKI) technique, suggest that a) in the healthy brain, interindividual variations in visual working memory capacity relates to a large degree to axonal density (measured by Axonal Water Fraction (faxon )) of the white matter pathways connecting brain regions known to be involved in working memory processes, b) white matter deficits in schizophrenia (SZ), a primary PSD syndrome, are driven by impairments in Extra-axonal Radial Diffusivity (RDextra), a putative marker of myelination, and c) visual working memory capacity associations to white matter microstructural properties are altered in SZ, a primary PSD disorder, with relationships with critical pathways connecting prefrontal and temporal brain regions no longer present or relating not to axonal density, but to RDextra, the putative marker of dysmyelination. Thus, supported by these preliminary data, the primary aims of this project are to test that: 1) visual working memory capacity and overall cognitive deficits in PSD are explained to a large degree by deficits in white matter microstructure and therefore 2) Diffusion Kurtosis Imaging (DKI) markers of dysmyelination are candidate neurobiological endophenotypes of PSD. The dysmyelination hypothesis will be validated using a corroborative approach that includes DKI, Magnetic Resonance Spectroscopy, and genetic assays. The results of this study may reveal more specific microstructural alterations of white matter and contribute to the understanding of the mechanisms underlying cognitive dysfunction in PSD. The proposed biomarkers may prove instrumental in characterizing treatment efficacy and identifying at risk individuals.

PUBLIC HEALTH RELEVANCE: Psychotic Spectrum Disorders (PSD) are severe mental syndromes associated with significant lifelong impairment and high prevalence. In this proposal we will test the hypothesis of dysmyelination as a substrate of cognitive dysfunction in PSD and evaluate imaging markers to characterize this deficit. The results of this study will provide a) targets for treatments aimed at restoring and preventing impaired cognition in PSD patients and b) biomarkers to assess individual response to such treatments.