The long-term goal of the proposed study is to characterize the relationship between cerebello-prefrontal networks with respect to symptom severity and course of illness in individuals at ultra high-risk (UHR) for psychosis. UHR individuals are at much higher risk for the development of an Axis I psychotic disorder, and identifying neural differences associated with symptomatology and the course of illness is a key first step towards the development of predictive biomarkers for psychosis. Such biomarkers would open the door to more targeted preventative therapeutics. While movement abnormalities associated with striatal function are associated with the conversion to psychosis, we have also found evidence distinctly implicating the cerebellum in symptom severity in UHR individuals. While the cerebellum has been well studied in schizophrenia, and its networks, particularly networks associated with the prefrontal cortex, are implicated in the cognitive dysmetria framework for the dysfunction seen in schizophrenia, it has been relatively understudied in UHR populations. There is some evidence to indicate cerebellar volumetric decreases in UHR groups, and there is decreased resting state cerebello-cortical connectivity in first-degree relatives of schizophrenia patients, but the literature on this topic is generally sparse. Given ou recent finding of a relationship between cerebellar dysfunction and symptom severity, along with the contributions of the cerebellum to schizophrenia and cognitive dysmetria, cerebellar networks are an important target for research in UHR populations. Here, we aim to 1) investigate group differences in resting state functional cerebello-prefrontal cortical networks and 2) investigate group differences in brain structure and structural connectivity of cerebello-prefrontal cortical networks between UHR and healthy controls. Crucially, we will also investigate the relationship between the integrity of these networks (structural and functional), and the volume of cerebellar and prefrontal nodes in these networks, with respect to symptom severity, cognitive function, and the course of illness using a two year longitudinal design. Usingmulti-modal neuroimaging we will collect resting state connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) in conjunction with high-resolution anatomical scans annually. In addition, all participants will complete cognitive testing, along with clinical assessments to quantify symptom severity and disease progression in UHR individuals. I will receive key training in translational research and in both DTI and structural anatomical analysis methods. Knowledge of the relationships between cerebellar-prefrontal networks and the development of psychosis is crucial for gaining a complete picture of the etiology of schizophrenia. Doing so will help explainthe role of the cerebellum in schizophrenia, and its etiology. Furthermore, this may facilitate thedevelopment of targeted interventions that may improve disease course and treatment outcomes in at-risk populations.
The proposed research will investigate brain networks that may underlie the development of schizophrenia in at-risk individuals. Though schizophrenia affects only about 1% of the population; it has devastating personal and societal consequences. Identifying neural differences in these at-risk populations will aid in our understanding of the underlying factors causing schizophrenia; and importantly; may lead to preventative therapies that could ease some of the devastating effects of schizophrenia on the impacted individual; their family; and society as a whole.
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