The research outlined in this application is devoted to a uniquely multi-disciplinary approach toward determining the bases, consequences, and mutability of social communication deficits in autism. Project I (Sigman) proposes a longitudinal study of over 300 infants at risk for autism based on their family history of having older siblings who are diagnosed with the autism syndrome. We will describe the developmental trajectories of subgroups of children who manifest varying patterns of symptoms ranging from full autism to the broader autism phenotype to non-affected siblings, thus developing the tools for earlier diagnosis and better determination of prognosis, an issue of critical importance to families. A unique feature of this research is that Project II (Geschwind) will use the same sample to investigate the extent to which the variability in the children's language gains is attributable to genetic factors that have previously been tied to the acquisition of language skills in children with autism. Project II improves upon earlier genetic studies in that genetic contributions to the trajectory of language acquisition can be investigated for the first time due to the availability of a broad range of phenotypic measures of language skills over the course of the children's early lives. Project III (Dapretto) examines the extent to which the social communication deficits in autism are due to specific neurophysiological patterns in brain systems, particularly to disorders of the mirror neuron and brain reward systems. Project III will examine the plasticity of the mirror neuron system in a sample of children who participated in a therapeutic intervention (Kasari) that succeeded in improving their communicative abilities, a path-breaking study to connect brain circuit activation with treatment outcome. Project IV (Kasari) will significantly extend our previous work demonstrating the remarkable consequences of successfully intervening with social communicative deficits of children with autism. Project IV investigates whether the treatment of very young children with autism can be carried out by parents rather than trained interventionists, thereby making such treatment more accessible. Project V (McCracken) researches the effects of risperidone on repetitive behaviors in children as well as the mediators of these effects by using fMRI to identify functional patterns that differentiate treated and non-treated children with autism. In summary, these projects represent a set of carefully interwoven designs, providing synergy by studying overlapping subject populations with complimentary methods that identify the nature and determinants of core deficits in autism. Information from these studies will lead to a better understanding of the relationships between these deficits in autism and their specific genetic risk factors and brain circuitry, as well as improved early diagnosis and treatment of autism. ? ? ?
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