Research Abstracts from CPEA Investigators

Overall description: This Program Project aims to discover the biological bases of and environmental influences on the social communication deficits in autism. The first two projects propose experimental interventions and longitudinal follow-ups to test the extent to which joint attention, symbolic play, and language can be modified. Based on results showing that particular caregiver behaviors lead to gains in language skills over a 15-year period of development, the first project will test an experimental approach to modifying caregiver behaviors and measuring the consequences. The second project will follow a group of children whose nonverbal communication and play skills were improved through intervention and will also attempt to generalize the intervention from skilled clinicians to paraprofessionals with a new sample of children.

In order to understand the basis for the deficits associated with autism, the third project aims to explicate the role that duplication of chromosome 15q plays in autism by assessing the phenotypic sequelae in probands with known duplications. The proposed project also plans to define the autism critical region by detailed examination of rearrangements in probands with unusual breakpoints or imprinting errors. Lastly, the extent of cryptic duplication in the population of idiopathic autism will be investigated with newly developed mapping techniques. The fourth project focuses on the neuroanatomical bases of social communication deficits in autism. The proposed project will use fMRI to investigate fundamental aspects of information processing: imitation, joint attention, and referencing. These studies will test the hypothesis that deficits in the response properties of specific neural populations, such as mirror neurons, and deficits in the brain's reward systems underlie impairments in perception of referencing and joint attention, which give rise to the social communication deficits in autism.

Project I: Contributors to Communication Skills in Autism
Principal Investigator: Marian Sigman, Ph.D.

No description available at this time.

Project II: Longitudinal Follow-Up and Extension of Joint Attention Intervention
Principal Investigator: Connie Kasari, Ph.D.
Co-Investigators: Stephanny F.N. Freeman, Ph.D., and Tanya Paparella, Ph.D.

The proposed research project aims to better understand the effects of interventions aimed at core deficits of young children with autism, joint attention and symbolic play. Two studies are proposed. The first is a longitudinal follow-up of children with autism who participated in our previously funded intervention study. In this study, 60 children with autism, aged 3 to 4 years, were randomly assigned to a joint attention intervention, symbolic play intervention or a control group. These children will be followed up 4 years post-intervention when the children are between 6 and 8 years of age. Follow-up measures will include social, cognitive and language measures that are standardized, experimental and observational. Longitudinal outcome and aptitude by treatment interactions will be examined using growth-modeling techniques.

In the second proposed study, we will generalize our intervention approach from skilled clinicians to paraprofessional teachers. Paraprofessionals will be recruited to teach in an early childhood program for children with autism, and will be taught to implement a combined joint attention and symbolic play intervention. Paraprofessionals will be assessed for fidelity of treatment implementation, and generalization of skills to other professionals. Forty-eight paraprofessionals will be taught over 2 years, along with forty-eight newly recruited preschool-aged children with autism. Children will be assessed with standardized measures of cognition and language, and joint attention and symbolic play skills will be assessed pre and post intervention. Children's generalization of skills across adults, contexts, and peers will be assessed.

The goals of the proposed research are twofold. A first goal is to determine the long-term effect of a targeted intervention aimed at changing joint attention and symbolic play skills in young children with autism. A second goal is to determine the extent to which an intervention successfully implemented by skilled clinicians can be translated and implemented by less skilled and educated paraprofessionals.

Project III: Analysis of Chromosome 15 Duplications in Autism
Principal Investigator: Carolyn Schanen, Ph.D.

Duplication of the maternally-derived copy of the imprinted region on chromosome 15q is associated with a major risk for autism or autism spectrum disorders. The duplications arise by homologous but unequal recombination through series of transcribed repeats in the region and variation in the alignment at crossing over lead to difference in the content and origin of the chromatin involved. Our laboratory has focused on defining the range of the phenotypes of probands with 15q duplications and determining the molecular and cytogenetic correlates for various aspects of the phenotype, with particular focus on autism and language development. Since initiating this work in 1999, we have ascertained over 60 families with probands carrying duplications, including several subjects with atypical rearrangements that may be uniquely valuable for identification of the autism critical region. Our goals are directed toward understanding the role that duplication of chromosome 15q plays in autism by examining the phenotypic sequelae in probands with known duplications. We also propose to define the autism critical region by detailed examination of rearrangements in probands with unusual breakpoints or imprinting errors. We are developing a comparative genomic hybridization based array to improve efficiency for mapping the duplications. Moreover, by using closely spaced array elements, we can apply this strategy to cases of idiopathic autism to determine whether cryptic duplications of the region underlie a fraction of the autism population. Finally, we will continue to collect samples from the subjects in the other studies in this program, to enter into cross CPEA site projects (regression, candidate gene testing, association, sib pair studies.). Since we began this work in 1999, we have made significant headway and believe that this work will ultimately resolve the molecular basis of the autism risk associated with duplications of 15q.

Project IV: Anatomical Bases of Social Communication Deficits in Autism
Principal Investigator: Susan Bookheimer, Ph.D.
Co-Investigators: Mirella Dapretto, Ph.D., Marco Iacoboni, Ph.D., Mark Cohen, Ph.D., and John Mazziotta, M.D., Ph.D.

This is a competing renewal of our fMRI project, which focuses on the neuroanatomical bases of social communication deficits in autism. In our prior cycle, we demonstrated that both visual (face processing) and verbal (prosodic) processing was impaired in autism relative to matched controls at several levels, from basic perception of affective features which were modality specific, to brain areas responsible for processing this information, which were modality independent. These studies suggest that fundamental impairments in processing sensory information relevant to social cognition produce deficits in a common, higher level neuroanatomic network that may contribute to behavioral phenotype in autism. In the current submission, we focus on four fundamental aspects of information processing that may give rise to modality specific deficits in social cognition. These are: 1) imitation, where we determine whether autistic children show evidence of preserved mirror neurons as demonstrated in recent fMRI studies of imitation performed in our lab; 2) joint attention, in which we determine whether autistic subjects show similar responses in the brain's emotion networks during eye-contact with listener vs. other in positive, negative or neutral affect; and 3) referencing, where we will determine whether high functioning autistic subjects show similar neural responses to gaze - directed referencing during acquisition of new object names. These fMRI studies will determine whether there are underlying deficits in some basic neural response properties that affect primary skills necessary for social communication, namely, referencing and joint attention, using responses to human face perception as a model. We hypothesize that deficits in functional activity of specific neural populations such as mirror neurons, and abnormalities in the brain's reward systems, underlie impairments in perception of gaze-directed referencing and joint attention, which in turn give rise to behavioral outcome of social communication deficits in autism. In so doing, these experiments aim to link neural responses in specific neuronal populations to basic cognitive operations that serve as foundation skills for social communication, and that, if impaired may underlie the core symptoms observed in autism.