The overall goal of this Program Project is to define more clearly what is both familial and specific in the autism phenotype at three levels of analysis """"""""brain, neuropsychology, and behavior"""""""" through a series of converging tests. The Program Project is designed to provide a rigorous set of converging tests of five competing neuropsychological explanations of autism: 1) a basic sensory deficit measured by means of magnetoencephalograph (MEG), 2) a praxis deficit, 3) an affective deficit, 4) an inter-subjectivity deficit, and 5) a deficit in executive functions. The converging tests of the latter four, higher level deficit/s are 1) Does the candidate deficits/appear early in the development of children with autism? (0003) 2) Is the deficit/s specific to autism? (Projects 0002 and 003) 3) Are sib pairs concordant for autism also concordant for the deficit/s? (Project 0002) 4) Is the deficit/s pervasive in the sense that it is part of the familial phenotype? (Project 0002) and 5) Is the deficit/s correlated with the brain phenotype, either at a structural (measured by MRI scans) or functional (measured by MEG) level? To permit this set of converging tests, we are studying the same behaviors and neuropsychological constructs in all the samples across Projects. The samples to be studied are 1) 25 multiplex families with idiopathic autism and 25 Down syndrome control families (Project 0002) 2) 40 adults with idiopathic autism, 40 adults with FXS, 40 adults with developmental disabilities (DD) but neither autism nor FXS, and 40 CA and 30 MA controls (Project 0001); and 3) 25 very young children with idiopathic autism, 25 MA and CA controls with DDs but neither autism nor FXS and 25 typically developing MA controls (Project 0003). In collaboration with Jeanette Holden, we will also test the hypothesis that lowered maternal serum dopamine betahydroxylase (DBH), secondary to allelic differences at the DBH locus, provides a uterine environment which is part of the etiology of autism and autistic features in both idiopathic autism and Fragile X syndrome (FXS). GRNT P01HD354680001 Autism is a devastating developmental disorder with an incidence of approximately 1 in 1,000 live birth. While strongly genetically determined, specific abnormalities remain to be determined, and the clinical picture is sufficiently diffuse to implicate pathology in multiple neural systems. Central to the syndrome is impaired social interaction, a severely restricted range of interests, and abnormalities of attention (a hyper-attentiveness), sensation (usually hyper-reactivity). We propose to utilize magnetoencephalographic (MEG) sensory evoked field (EF) data, EEG evoked potential (EP) data, and MRI anatomical data to specifically address early cortical processing of sensory information. We will study 1) 40 high functioning (IQ>50) autistic adults, 2) 40 IQ and age matched FraX patients, 3) 40 age matched MR subjects, and 4) 40 age matched normal adults. We will specifically: 1) Using MEG and EEG, we will quantify reactivity of primary auditory and somatosensory cortex to stimuli of varying intensity; 2) By localizing and quantifying very high frequency (VHF) MEG activity (600 Hz) from primary somato-sensory cortex we will directly measure cortical GABA-ergic inhibitory interneurone activity, which we hypothesize will be deficient in autistic subjects (and correlated with cortical hyper-reactivity); 3) Using an MEG auditory EF based goodness of fit metric, we will quantify the ability of autistic subjects to shirt attention from one hemisphere to the other during a binaural auditory oddball task; 4) Using the amplitude of the 100 msec latency auditory EF (termed M100) as a function of auditory interstimulus interval (ISI) we will calculate tau (t), the time constant of the decay of the echoic memory trace, generated in Heschl's gyri. We hypothesize this will be prolonged in autistic subjects, relative to normals, Fra-X or MR groups; 5) Using the EEG EP based metric termed mis-match negativity (MMN) we hypothesize that autistic subjects will demonstrate evidence of an accentuated pre-attentive, automatic cortical feature detection processes; 6) Using and MEG EF metric of auditory cortex MEG alpha suppression during a tonal memory task, we hypothesize that autistic subjects will demonstrate evidence of greater alpha suppression than normals, supporting enhanced should term auditory memory storage, scanning and retrieval; 7) using high resolution MR images of the brain we will quantify volume and relate MEG EF sources to specific cortical areas to determined is MEG and EEG based functional abnormalities are related to observed anatomical deficits in the cortex generating those signals.
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