Scientific Abstract from:
Geraldine Dawson, Ph.D.
University of Washington
Neurobiology and Genetics of Autism
The University of Washington autism program project has five objectives: (1) To deepen our understanding of the neurobiological bases of autism by investigating the relations among brain function, structure, and chemistry over time; (2) To determine whether the syndrome of autism is comprised of meaningful and valid subtypes characterized by distinct etiologies, structural and chemical brain abnormalities, neurocognitive profiles, developmental courses, patterns of symptom expression and outcome; (3) To improve methods of early identification; (4) To identify early behavioral and biological predictors of outcome in autism, including early precursors of language and social development; and (5) To investigate the genetic basis of autism by determining the chromosomal location of autism susceptibility genes, and to enhance this effort by developing quantitative autism phenotypic measures, and using information regarding genetic heterogeneity/subtypes. There are two major parts of this program project: (1) The first part consists of a longitudinal, multi-disciplinary study of 75 children with autism spectrum disorder (ASD) and 40 with developmental delay (DD) who are being followed from infancy to age 9 and comparison groups of CA- and MA-matched typically developing children. Projects I - IV comprise the longitudinal study. (2) The second part is a genetic linkage study of multiplex autism families (Project V). Information gained in the longitudinal study (Projects 1 - IV) is being used to model genetic heterogeneity and refine phenotypic measures used in the genetic linkage study (Project V). Thus, findings from all five-research projects are being integrated in a synergistic way to offer a deeper understanding of the neurobiological and genetic basis of autism.
Project I: Brain-Behavior Relations in Autism
Co-Principal Investigators: Andrew N. Meltzoff, Ph.D., and Geraldine Dawson, Ph.D.
Our primary aims are to clarify the nature of brain dysfunction in autism and elucidate factors that explain the substantial variability in outcome in autism. We will examine whether early measures of brain function are useful in explaining the variability in developmental trajectories found among individuals with autism. Our data demonstrate that degree of medial temporal lobe (MTL) impairment at age 3-4 is predictive of rate of social development during the preschool years in children with autism. Here, we plan to examine whether neuropsychological indices MTL function taken at age 3-4 years predict rate of social development and symptom expression across the preschool and elementary school ages in children with ASD versus children with DD without autism. We will also examine the relation between variations in social development from age 3 to 9 and patterns of brain electrical activity during face processing at age 9. Our data show that, at age 3-4 years, children with ASD exhibit specific impairments in the ability to recognize faces and facial expressions of emotion, as evidenced by high-density event-related brain potentials (ERPs). In the proposed ERP research, we will examine whether those children who show higher rates of social development from age 3 to 9 are more likely to show normal patterns of brain electrical activity during face processing at age 9. This study will shed light on brain plasticity in autism and offer insights into the nature of information processing impairments in autism. Finally, we plan to investigate continuity between early-emerging impairments in social cognition (i.e., social orienting, motor imitation, joint attention, and responses to distress) and later impairments in social cognition (theory of mind, empathy, and peer interaction) and language ability in autism. This work helps elucidate early behavioral predictors of outcome, and explain the nature of early autism impairments and their relations with later symptoms.
Project II: Language deficits in Autism
Principal Investigator: Patricia Kuhl, Ph.D
Language and communication impairments are key components of autism. We previously examined early measures of language in 3-4 year old children with autism spectrum disorder (ASD), and children with developmental delay (DD) and typical development (TD). We examined specific speech processing abilities, aspects of social communication, and cross-modal measures (auditory-visual and imitation) of speech processing. Results revealed critical differences on several measures between preschool age children with ASD and those with DD and TD. We now propose to evaluate the same children with ASD and DD at age 9, examining the stability and predictive utility of our early language measures, and assessing other aspects of language function relevant to older children. We will focus on: (1) Language processing -- Event-related brain potential measures of phonetic perception revealed that 3-4 year old children with ASD exhibit deficits in the capacity to differentiate phonetic units of speech. We will assess the longitudinal stability of this basic capacity and the predictive relation between early deficits and later language ability at age 9. In those ASD children who have spoken language, we will conduct ERP studies of word and sentence processing to assess impairment. (2) Social communication - Our work showed that listening preferences in children with ASD differ from those with DD and TD. Children with ASD preferred listening to mechanical-sounding auditory signals rather than speech. We will further examine this preference, varying the voice from human to nonhuman, and from highly inflected to monotone. New research suggests that adults with autism focus their visual attention on the mouth of the speaker, not the eyes, and our cross-modal and imitation studies show that children with ASD often cover their eyes when confronted with a talking face. We will examine how visual fixation patterns differ between children with ASD, and those with DD and TD when viewing a speaker. (3) Speech imitation and cross-modal speech perception - We found that children with ASD were more likely to vocally imitate than children with TD, and vocal imitation was correlated with higher language scores. We will further examine vocal imitation and cross-modal speech perception in auditory-only versus auditory-visual situations, varying complexity and prosody. This work will shed light on the nature of language impairment in autism.
Project III: Early Recognition and Outcome in Autism
Principal Investigator: Geraldine Dawson, Ph.D.
The goal of this research is two-fold: (1) to identify behavioral symptom markers for early identification of autism and (2) to determine early predictors of language outcome in autism. During the previous budget period, we collected and catalogued 1st and 2nd year home videotapes from matched groups of well-characterized children with autism spectrum disorder (ASD), developmental delay (DD), and typical development, and conducted detailed coding of a variety of social, communicative, and motor behaviors from these tapes. Based on these data, we have identified several behaviors that characterize infants with autism at 1 year of age. We now propose to use these same home videotapes to more comprehensively examine prelinguistic vocalizations in 1 and 2 year olds with ASD, DD, and typical development. We believe that atypical prelinguistic behaviors might represent early-appearing positive symptom markers of autism. If so, such markers might improve early identification of infants with autism. In addition, we aim to code prelinguistic vocalizations and verbalizations from language samples collected from these same children at ages 3, 6 and 9 years to allow for longitudinal analyses of language development in children with autism as compared to children with DD and typical development, and to examine whether early measures of prelinguistic vocalizations/verbalizations are useful in predicting level of language acquisition in autism.
Project IV: Neuroimaging in Autism
Principal Investigator: Stephen Dager, M.D.
Previous work in our laboratory demonstrated that 3-4 year-old children with autism spectrum disorder (ASD) have cerebral enlargement, as well as proportional enlargement of subcortical regions (cerebellum, hippocampi and amygdalae), compared to age-matched children with developmental delay (DD) and typical development (TD). Children with strictly-defined autistic disorder (AD) showed enlargement of the amygdalae, in excess of overall cerebral enlargement. From the same groups of children, proton echo-planar spectroscopic imaging (PEPSI) revealed widespread regional decreases in neurochemical concentrations in the ASD children, as well as abnormal metabolite relaxation, indicative of abnormal brain cellular composition. We currently are investigating the longitudinal progression of these findings, reimaging the children at 6 years of age.
In the proposed research, we plan to extend our longitudinal investigation of brain development in ASD. Brain structure and chemistry, and their relationships with neurocognitive and symptom measures, will be reevaluated in the children with ASD (N=45) at age 9, in comparison to age-matched children with DD (N=25) and TD (N=25). The goals of this research are to characterize patterns of brain anatomical and chemical abnormalities in autism over the developmental time course from pre-school to pre-adolescence and to examine the relation between individual differences in brain development and clinical outcome at age 9. This research will be important for understanding brain developmental processes involved in the clinical expression of autism.
Project V: Genetic Linkage Study of Autism
Principal Investigator: Gerard Schellenberg, Ph.D
Autism is a common developmental disorder with a prevalence of 2-10 per 10,000. Characteristic impairments include difficulty processing social and emotional information, language abnormalities, and repetitive or stereotyped behaviors. Additionally, 75% of autistic persons are mentally retarded. The etiology of autism is unknown, but evidence for inherited factors is strong. Monozygotic twins are frequently both affected while dizygotic twins have a lower concordance rate. Autism family studies show an elevated risk in sibs of probands relative to the general population. Genetic modeling suggests that the genetic component of autism is the result of multiple genes, which interact (epistatic multigenic inheritance). Some unaffected parents and sibs exhibit some subclinical features related to autism, which may reflect inheritance of some, but not all of the aberrant genes required for the full autism phenotype. Presently we have identified and fully characterized 159 families with 2 or more affected sibs with autism spectrum disorder. We are proposing to collect additional families to bring the total sample size to 350-400 families. The autistic probands, unaffected sibs and parents are being rigorously evaluated using diagnostic, neurocognitive, and broader phenotype assessments. DNA will be obtained from 2 affected sibs, 1 unaffected sib, and both parents. Markers covering all chromosomes will be genotyped. The data will be analyzed by sib-pair analysis methods. Recently, we developed a new statistical technique for Quantitative Trait Locus (QTL) analysis that permits us to analyze genetic linkage data using continuous variables (e.g. results from neurocognitive and broader phenotype assessments) under a model that allows for simultaneous analysis of multiple underlying trait loci. QTL analysis will be used to analyze the genotype data. The use of phenotypic data from the entire family should greatly increase the power to detect autism loci. The ultimate goal is to identify all the chromosomal locations of genetic loci contributing to autism with the eventual goal of cloning these genes.