Brain Function and Structure in Young Children at Familial Risk for Schizophrenia

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DESCRIPTION (provided by applicant): The identification of markers for the prediction of psychosis is central to the development of early intervention and prevention strategies for schizophrenia. Primary or secondary prevention strategies oriented to the pre-psychosis and pre-prodromal periods have not been attempted because of an absence of biomarkers or solid knowledge of pathophysiology in the period before adolescence prior to the emergence of mild psychotic symptoms (i.e., prior to the putative "prodrome"). Because there is consistent evidence of significant neuropsychological and social deficits beginning in early childhood of people who later develop schizophrenia, there is strong reason to believe that brain abnormalities are present in the preteen years, but there is no evidence as yet about such abnormalities in that period. The present proposal aims to begin to fill that critical gap of knowledge. Indeed, some of the earliest symptoms of schizophrenia such as disturbances in the sense of self, and those that reflect impaired metacognition such as impaired self-other boundaries are frequently present in those at risk for schizophrenia (ARS) in the age range we intend to study. We hypothesize that the neurobiology of the "early premorbid" period, is characterized by brain dysmaturation, reflected in altered cortical thickness, volume reduction in hippocampus and medial prefrontal cortex, abnormal information processing and dysfunctional connectivity. This preliminary study, focused on children at risk for schizophrenia, ages 8- 11, is designed to test hypotheses about brain function, structure, and cognition in a cross-sectional design that will lay a foundation for subsequent grants designed to study the longitudinal evolution of brain structure and function in prepubertal ARS children. This project will focus on a novel, but highly promising area of new research; the neural substrates of the inner experience of the child at risk, by evaluating (using functional MRI): 1). the "default mode" of brain function and; 2). the neural network underlying 'self reflection' (reflection about oneself or others). Moreover, we will extend to childhood our previous work in adolescents demonstrating; 3). altered brain function during working memory and 4). structural abnormalities. The study goals are consistent with the R21 guidelines emphasizing novelty and innovation, in regard to the feasibility of conducting these imaging studies in young children. Moreover, the study is consistent with the 2008 NIMH Strategic Plan in which prediction and prevention of schizophrenia and disability in those at risk for the illness are key NIH priorities. PUBLIC HEALTH RELEVANCE: This preliminary study, focused on children at risk for schizophrenia, ages 8-11, is designed to begin to fill a critical gap of knowledge regarding brain function and structure in the pre-teen period. The identification of markers for the prediction of psychosis is central to the development of early intervention and prevention strategies for schizophrenia. Primary prevention strategies oriented to the pre-psychosis and pre-prodromal periods have not been attempted because of an absence of biomarkers or solid knowledge of pathophysiology in the period before adolescence prior to the emergence of mild psychotic symptoms (i.e., putative "prodrome"). The information gathered from the project is of significant public health relevance, in that it will characterize the neural and cognitive capacities of the pre-teen child who is at familial risk for schizophrenia.