Despite the wealth of magnetic resonance imaging (MRI) studies supporting the dysconnectivity model of schizophrenia, our understanding of the underlying neurophysiological mechanisms remains limited. Abnormalities in myelination are a plausible candidate as myelination is essential for the coordinated activity of neural networks that support cognitive function and behaviour. Moreover, myelin-related pathology has long been postulated in schizophrenia on the basis of post-mortem and gene expression evidence. Dys-myelination is also a key component of neurodevelopment theories of schizophrenia because myelination of cortical association areas in late adolescence and early adulthood coincides with the peak period of risk for disease onset. This application will harness the power of ultra-high-field MRI coupled with advanced analyses algorithms to detect and quantify cortical myelin in a way that has never been possible before and test the relevance of myelination for schizophrenia-related dysconnectivity. We provide initial evidence for intracortical myelin abnormalities in patients with recent onset schizophrenia and demonstrate their impact on connectivity and disease severity. In this application, we propose a series of experiments with three specific aims. First, we aim to demonstrate the reproducibility of our initial findings on schizophrenia-related intracortical myelin changes in an independent sample of patients with recent onset psychosis and relate these changes to the topological properties of the functional and structural connectome; we will also examine the functional correlates of compromised myelin integrity on clinical features and cognition (Aim 1). Second, we plan to test for longitudinal changes in myelination in patients with schizophrenia over a 2-year follow-up period and investigate their relevance to disease severity and course (Aim 2). Third, we will test whether abnormalities in myelination are related to familial risk of schizophrenia by investigating intracortical myelin and its effect on the functional and structural connectome and cognition in unaffected siblings of patients, both cross-sectionally and over a 2-year follow-up period (Aim 3). The inclusion of unaffected siblings will also allow for the investigation of myelin-related abnormalities relevant to schizophrenia without the confounding effect of medication. The results of this study will provide novel evidence for unlocking the mechanistic ?black box? in schizophrenia and will open new avenues for treatment using interventions that may target myelin pathology.

Public Health Relevance

Dysconnectivity between brain regions is the leading systems-level model for psychosis, but the neurobiological origins of this dysconnectivity are poorly understood. This proposal tests the hypothesis that psychotic dysconnectivity arises from abnormalities in cortical myelination that alter the topological role of brain regions in the structural and functional connectome. We will thus provide crucial mechanist insights into the origins of dysconnectivity in psychosis and potential new targets for novel interventions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Zalcman, Steven J
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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