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STAART Network Centers: University of North Carolina, Chapel Hill

Project Descriptions

Gene-Brain Relationships in Autism

Primary Site: University of North Carolina, Chapel Hill
Joseph Piven, M.D., Director
James Bodfish, Ph.D., Co-director


The Neuropsychological Basis of the Broad Autism Phenotype
Principal Investigator: Piven; sites: UNC-Chapel Hill, King's College & University of Iowa

This study examines the neuropsychological basis of autism and the broad autism phenotype (BAP) in 50 individuals with high-functioning autism (HFA) and their parents in comparison to two contrast groups -- community controls (for both HFA and parent groups and, individuals with focal brain lesions in the amygdala, orbital-frontal cortex and right somatosensory cortex, drawn from a brain injury registry at the University of Iowa. The sample of autism parents will also be enriched for autism parents with the BAP from subjects identified in previous studies by our group. Subjects will be examined on selected neuropsychological measures of social cognition, central coherence and executive function, three principal cognitive frameworks proposed as theories to explain the neuropsychological basis of autism. Deficits in social cognition and executive function have also been found in individuals with the focal brain injuries being examined in this study. These neuropsychological characteristics will be examined in relationship to our clinically-based measures of the BAP, in autism parents, in order to both elucidate the neuropsychological basis of the BAP and to provide efficient, valid and reliable measures for future studies of the BAP. Neuropsycholgoical profiles in HFA and parents of autistic individuals (with and without the BAP) will also be compared to those seen in the neurological-lesion subjects drawn from a brain injury registry at the University of Iowa, to provide insights into the neural basis of the behavioral and neuropsychological characteristics of autism and the BAP. Finally, patterns of co-occurrence of these neuropsychological characteristics will be examined in autistic individuals and their parents for evidence of familial patterns. HFA subjects in this study will be the same subjects examined in Project II below. This project brings together a unique group of experienced researchers with complementary expertise in family-genetic (Piven) and neuropsychological studies of autism (Happe), and in the neural basis of social cognition (Adolphs), to study the neuropsychological basis of the broad autism phenotype.

Specific Aims:

  1. To examine whether autistic individuals and their relatives differ from typically-developing individuals on selected neuropsychological measures of social cognition, central coherence and executive function.
  2. To elucidate the neuropsychological basis of the broad autism phenotype by examining the relationship of clinically-based measures of the broad autism phenotype (that we have used in family studies of autism for 15 years) to selected neuropsychological measures.
  3. To compare performance of autistic individuals and their parents to that of individuals known brain lesions on measures of social cognition, executive function and central coherence, to gain insights into the neural basis of these deficits.
  4. To examine the pattern of co-occurrence of components of the broad autism phenotype and related neuropsychological deficits, in autistic individuals and their relatives.

Neuroimaging of Cognitive and Social Deficits in Autism
Principal Investigator: Belger; sites UNC_Chapel Hill & Duke University

This project will employ structural (MRI) and functional (fMRI) neuroimaging techniques to examine the neural basis of selected social cognitive, affective, and executive functioning deficits, and ritualistic-repetitive behaviors, in autism. Social deficits and ritualisticrepetitive behaviors are defining features of autism, and deficits in social cognition (e.g., processing emotional and social cues reflected in facial expressions) and executive function (e.g., generating flexible task-appropriate actions while inhibiting task-inappropriate ones) are considered key neuropsychological processes underlying these behaviors. Despite progress in describing these deficits, their neurobiological bases are still largely unknown. We propose to explore the neural circuitry of social cognitive, affective, and executive function processes and ritualistic-repetitive behaviors in autism in four studies designed to: (1) characterize the neural circuitry underlying inferences of social intentionality in autism, (2) examine neural circuitry underlying the processing and appreciation of facial expressions in autism, (3) explore the neural circuitry supporting the initiation and inhibition of taskappropriate/inappropriate behaviors in autism, and (4) characterize the structural integrity and development of frontal-striatal tracts, which we hypothesize to be involved in ritualistic-repetitive behaviors associated with autism. These aims will be addressed in three fMRI studies involving high functioning autistic adolescent and adult males, and in one longitudinal study employing diffusion tensor imaging in a sample of autistic children (ages 2- to 4-years). This project links conceptually to Family Study Project, Mouse Genetics Project, Fragile X Project, and Treatment Project, where these same processes are examined, as well as to a companion, separately funded study of these neuropsychological processes in this same sample of autistic individuals. This project brings together several experienced neuroimaging researchers, new to autism, forming the basis for the development of an integrated program of neuroimaging research to characterize key elements in the neural circuitry of autism. This information should further our understanding of the neural mechanisms as well as refine our notions of the brain and behavioral phenotypes in this disorder.

Specific Aims:

  1. To characterize the neural circuitry underlying the ability to make socially relevant inferences of intentionality in autism.
  2. To examine the neural circuitry underlying the processing and appreciation of affective information from faces.
  3. To investigate the neural circuitry association with initiation and inhibition of task-appropriate/inappropriate actions and the emergence of ritualistic and repetitive behaviors.
  4. To characterize the structural integrity and development of frontal-striatal circuitry in a longitudinal sample of autistic children from 2 to 4 years of age and its relationship to ritualistic-repetitive behavior.
Novel Approaches for Finding Genes in Autism
Principal Investigator: Wassink; site: University of Iowa

The goal of this application is to identify and characterize autism susceptibility loci and genes. While numerous linked chromosomal regions of interest have been identified in autism, the traditional approaches to finding disease genes within those regions have encountered unforeseen difficulties. First, these linked regions tend to be large and difficult to narrow, thus the number of candidate genes can be overwhelming. Second, the genes we are looking for are likely to be genes of small effect with types of variability that may be difficult to detect using traditional gene screening methods. Countering these difficulties, however, are a number of significant recent technological advances. Foremost is the ready availability of draft and finished genomic sequence providing the raw material for gene discovery that in the past took months and years to generate. Genome analysis tools and annotation databases are rapidly accelerating our ability to delineate genomic structure and accurately describe a gene's pattern of expression, function, and potential relevance to the disease of interest. Lastly, we are increasingly able to identify functional domains within genes that may be more likely to harbor disease-causing mutations. Our application, therefore, attempts to skirt the obstacles while focusing on the advances. First, we streamline the gene examination process with sophisticated computational bioinformatics technology that automatically identifies, delineates, and extracts expression information for genes in linked regions of interest. Prioritized genes are then screened in multiple autism DNA samples using our high-throughput sequencing and genotyping capabilities, with a preferential focus on protein functional domains. We will also identify and refine linked regions of interest by extending our innovative research on the Broader Autism Phenotype. Laboratory resources that will support this project include 1) a prominent, highperformance computer laboratory dedicated to genomic research; 2) a molecular laboratory with dedicated genotyping and sequencing facilities that has extensive expertise and a track record of success in disease gene discovery; 3) a premier statistical genetics research center; and 4) a wealth of well characterized clinical resources.

Specific Aims:

  1. To identify and determine the genomic structure of, and prioritize for screening, all identifiable genes within autism regions of interest (ROI), and to identify functional domains within those genes.
  2. To assess 25 prioritized genes per year from linked Regions of Interest (ROI) for their involvement in autism.
  3. To rate characteristics of the BAP in first degree relatives of autistic probands and to use this information to help refine and extend evidence for linkage in our Iowa ASP families.

Gene Dissection of Autism-Related Behaviors in Mice
Principal Investigator: Magnuson; site: UNC-Chapel Hill

Autism is a neurodevelopmental disorder defined by the presence of social deficits, communication abnormalities and ritualistic-repetitive behaviors. Although the importance of hereditary factors is well established, no specific genes responsible for autism or autistic behaviors have been identified. In this project we propose an approach using mouse models and genome-scale gene expression profiling to discover clusters of genes whose expression profiles identify molecular signatures that are highly predictive of the natural variation in social behaviors and cognitive flexibility, behaviors of clear relevance to understanding the autistic phenotype. Our hypothesis is that variation in the social and cognitive behaviors manifested by autistic individuals are at the extreme of normal genetically controlled variation. Furthermore, we hypothesize that the genetic variation underlying a behavioral trait is a manifestation of unique, stable gene expression profiles within specific regions of the brain. This project will lead to the genetic dissection of novel genotype behavior correlations relevant to autism.

Specific Aims:

  1. Characterize social and cognitive behavior phenotypes in a diverse panel of mouse inbred strains and genetically engineered models
  2. Generate gene expression profiles for specific brain regions thought to control the targeted behaviors
  3. Identify associations between behavior and gene expression.

Citalopram Treatment in Children with Autism Spectrum Disorders and High Levels of Repetitive Behavior
Principal Investigator: Sikich; site: UNC- Chapel Hill
Multi-site study - see description under Social and Affective Processes in Autism Primary Site: Boston University School of Medicine

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