The proposed project will examine the basis of autism in the developing brain. The primary hypothesis of the Program Project is that developmental impairment of the orbitofrontal-limbic circuit of the brain, including the mesial-orbitofrontal cortex (M-ORB) and amygdala, is a biological marker for autism and that the characteristic socio- emotional deficits of persons with autism are related to developmental impairment of this circuit. A secondary hypothesis will also be addressed that the mental retardation in individuals with autism results from impairment of the dorsolateral prefrontal-hippocampal circuit (DL/HIPPO) of the brain. Together, these hypotheses have the potential to help explain the clinical features of autism as well as the range of outcomes seen. Four research projects and three core modules are proposed. Project I will use neuropsychological measures to determine whether developmental impairment is present in the hypothesized brain systems, and will relate performance on these measures to socioemotional development, and to clinical measures of autism. A group of children and adolescents with Autistic Disorder (DSM-IV) (N=72) aged 7 to 18 at entry and a comparison group of children and adolescents of comparable ages and IQs without autism (N=72) will be tested. Project II will examine structural magnetic resonance neuroimaging and magnetic resonance spectroscopy of the participants seen in Project I. Because Projects I & II share the same participants and design, comparisons between their results are facilitated. Project III will examine the effects of early lesions of the orbitofrontal cortex or amygdaloid nuclei on development of cognition and social behavior in rhesus monkeys. Because these monkeys will receive structural neuroimaging and the same neuropsychological tasks as the human participants, comparison of results between humans and animals will be possible. Project IV will explore the neuroanatomical and neurochemical reorganization of the brain in response to early lesions of the orbitofrontal cortex or amygdaloid nuclei in the monkeys from Project III. Core A will provide administrative oversight, scientific leadership and project coordination for the Program Project. Core B will provide patient coordination and assessment for Projects I and II. Core C will provide methodology, statistics and data management support for Projects I, II, III and IV.
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