The goal of this project is to map the maturation of cortical circuits and higher-order cognitive functions inchildren and adolescents at genetic risk for schizophrenia. Executive function and social-affective processingdeficits are present in both individuals with schizophrenia and in those at genetic-high-risk (GHR) for theillness, and as such they represent cognitive endophenotypes of schizophrenia. Nevertheless, theircharacteristics in younger GHR individuals, the timing of their onset, and the specific neurodevelopmentalmechanisms that accompany them are not known. Puberty is a critical period both for the maturation ofthese functions, and for the onset of psychosis. The proposed study will probe functional and structuralchange that accompany peripubertal brain maturation in genetic high risk individuals, and will investigateexecutive control and social-affective processes in GHR children and adolescents. We' will probe attentionand executive and affective processing in fronto-striate-limbic regions in 60 GHR and 60 healthy subjectsaged 9-18 using. We will use a multimodal assessment protocol, including (a) neurocognitive testing (b)functional magnetic resonance imaging (fMRI), (c) electrophysiological recordings (ERPs), and (d) structuraland diffusion imaging (sMR| and DTI). In Specifc Aim 1, we will compare the neurocognitive profile of genetichigh risk (GHR) children and adolescents to healthy subjects cross-sectionally, and further assess groupdifferences in their maturational trajectory with longitudinal follow-ups.
Specific Aim 2 will characterize thefunctional profile of fronto-striate-limbic regions in GHR children and adolescents, using functional magneticresonance imaging and electrophysiological recordings. The structural profile of fronto-striate-limbic regionsin GHR adolescents, including both gray matter and white matter properties, will be assessed in SpecificAIMS. Finally, Specific AIM 4 will focus on network level integrative functioning of fronto-striate and fronto-limbic circuitry in GHR children and adolescents by exploring associations between functional connectivitymeasures, white matter properties and neurocognitive measures. By bringing together a strong clinical high-risk research program and a well established and diverse research infrastructure, this project promises tounveil critical knowledge about the neurodevelopmental changes associated with genetic risk forschizophrenia. The proposed experiments are novel, timely and highly significant for they focus on a uniquepopulation and probe a unique stage of cortical development that is critical for understanding thepathophysiology of core neurocognitive deficits in schizophrenia.
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