2014 — 2017 |
Frangou, Sophia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deconstructing Psychoses Based On Patterns of Abnormal Brain Activity @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): The main psychotic disorders, schizophrenia (SZ) and bipolar disorder (BD), continue to rank amongst the leading causes of disability worldwide largely because current clinical syndromal definitions are insufficient for treatment and prognosis because they are inadequately aligned with underlying pathophysiology. This proposal uses the Research Domains Criteria (RDoC) framework in order to define and validate biologically informed and clinically relevant neural phenotypes for psychotic disorders. Specifically, neuroimaging studies in patients with SZ and BD suggest that dysconnectivity within neural networks linked to the RDoC domains of perception, cognitive control and facial affect processing is central to the pathophysiology of psychosis. Further, abnormalities in these domains have been proposed to explain the clinical symptoms and cognitive deficits associated with psychotic disorders. Accordingly, our overall hypothesis is that abnormalities in effective connectivity, within domain-general neural networks of perception, cognitive control and facial affect identification, will detect biologically and clinically relevant neural phenotypes for psychosis. We present preliminary data that show that patients with SZ or BD can be classified into subgroups defined by their neural network architecture and that these neural phenotypes can be mapped onto clinical dimensions. Our results are based on estimates of effective connectivity from a dynamic causal model of the domain-general networks engaged in perception and cognitive control during working memory. The neural phenotypes we identified showed partial overlap between SZ and BD and were associated with symptom severity and clinical course. Based on this evidence, the aims of this proposal are (a) to expand our preliminary results in order to identify neural phenotypes for psychosis based on effective connectivity parameters derived from dynamic causal models of domain-general networks of perception, cognitive control and facial affect processing and test their reproducibility in two independent samples, (b) to define the association between the identified neural phenotypes and clinical dimensions of symptomatology and course, and (c) to determine their predictive value for treatment response. The proposal benefits from the use of dynamic causal modelling, which can infer causal interactions between brain regions underlying altered network dynamics, from testing the validity of our results based on their reproducibility and from assessing the therapeutic relevance of the identified neural phenotypes. Successful completion of the studies proposed in this application will improve our understanding of the clinical and prognostic significance of abnormal brain connectivity in psychosis, provide a scientific basis for therapeutic planning, and facilitate targeted etiological investigations and the development of new therapeutic approaches.
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2018 — 2021 |
Frangou, Sophia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Connectivity and the Role of Myelin in Psychosis @ Icahn School of Medicine At Mount Sinai
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.
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