ACE SCIENTIFIC ABSTRACTS

Overall ACE Abstract

This center focuses on explaining fundamental information processing and neurobiological mechanisms causing Autism.  It incorporates five themes:

1. Autism is a disorder of complex information processing abilities with intact or enhanced basic abilities.

2. Autism as a disturbance in cerebral connectivity with under-connectivity of long-distance connections and over-connectivity of compensatory local connections.

3. Autism as a developmental disorder whose brain-behavioral manifestations change with each stage of brain maturation from childhood to adulthood.

4. The pathognomonic social impairments are best understood in terms of underlying information processing mechanisms.

5. The emotional and affective impairments are a major component of the syndrome and significant contributor to impaired function and serious behavior issues.

These goals will be addressed using behavioral, cognitive, fMRI, DTI, DTT and neuro-pathologic studies of: 

• Infant Siblings

• First-Diagnosed Toddlers with Autism

• Children, Adolescents and Adults with and without Autism

Project I:  Development of Categorization & Facial Knowledge in Low & High Functioning Autism

Project I focuses on understanding the earliest manifestations of autism and the development of earlier diagnostic tools.  It also focuses on information processing mechanisms underlying social and cognitive symptoms.

The center of this proposal is on one of the most basic and critical aspects of information processing-categorization.  The term categorization is used in a broad sense to mean not only the grouping of similar objects, but also a process basic to our core perceptual recognition abilities.  Categorization is a process that begins within the first few months of life.  Infants quickly begin to categorize their world, significantly reducing demands on memory.  Once the infant can categorize and have a central representation of similar objects such as dogs, it is not necessary to remember every encountered instance unless the instance is unusual.  The ability to categorize is also critical to language development, and most theories assume it is a prerequisite for learning words.  Categorizing or prototyping is also central to face recognition abilities and problem solving.  This project will extend our current research on high functioning children and adults with autism (HFA) on processing categorical information about objects and facial information including gender, emotional expression, recognition and attractiveness.

Studies will take a more in-depth look at the mechanisms that underlie development of categorical expertise.  Extensions of this research will look into understanding individual differences in performance of HFA participants, and will provide important behavioral indices of autism that will be used by Projects II, III and IV as they attempt to characterize the neuro-anatomy of autism as reflected in brain structure and connectivity. Importantly, this research will be extended to two populations critical to our understanding of autism spectrum disorders (ASD) including its origin, early diagnosis, and the development of early intervention strategies. First, this project will longitudinally study a group of 6- to 16- month old infant siblings of older children diagnosed with autism. Second, the project will study a group of newly diagnosed ASD toddlers that are low functioning. Both of these populations will be tested with nonverbal methodologies originally designed for studying typically developing infants and toddlers. These methods will allow us to look at critical early information processing abilities such as attention, memory, and categorization. These methods represent well-designed experimental procedures that could easily be translated to clinical practice for early diagnosis if results support their use. These methods allow us to study underlying information processes currently not addressed by more standard observation studies of at risk infants. These basic information-processing mechanisms are more effective targets for changing outcome than behavior. This project will directly address the Autism Research Matrix goal #19 of developing “indices of risk for the development of autism” and #4 characterizing the autism phoneme.

Project II:  Disturbances of Affective Contact: Development of Brain Mechanisms for Emotion Processing

Project II focuses on elucidating emotion processing mechanisms and the maturational disturbances from childhood through adulthood; these studies will clarify how individual with autism experience, understand and regulate emotion, and will also examine their self-awareness of emotion.  Genetic modifiers of emotionality will also be determined.

Kanner’s (1943) original characterization of autism as a "Disturbance of Affective Contact" encompassed the lack of the capacity to connect from an early age emotionally to people, reflecting broad impairments in the experience, perception, regulation, and expression of emotion as well as in synchronizing and sharing it to form relationships. Since then, researchers have started to characterize these deficits at the behavioral level. In addition, a few studies have begun to explore the brain mechanisms underlying the deficits in adults with autism. Despite these important efforts, the characterization of the development of brain mechanisms for emotion processing remains a critical and largely unmet challenge, with few studies exploring this in individuals with and without autism throughout childhood.

Further studies are required to examine the relationship between the development of emotion processing and that of underlying neural systems, particularly sub-cortical, temporal, and prefrontal cortical structures and their interactions. Such studies will inform the understanding of the neural bases of atypical emotional development in children with autism and of normal emotional development in children without autism, and the results will aid the development of earlier and better behavioral interventions and management for children and adults with autism.

 In this application, we propose to study samples of 6- to 11-year-old children with and without autism and adults with and without autism using a multiple methodology approach to characterize the development of brain mechanisms for emotion processing. We will investigate the perception, understanding, experience, and expression of emotion using eye tracking and behavioral measurements. We will also chart the functional development of the underlying neural substrates for emotion processing using functional magnetic resonance imaging (fMRI) and paradigms designed to probe atypical patterns in autism both in the functioning of specific brain regions and in the functional connectivity between key emotional brain structures. Finally, we will adopt an imaging genetics approach to examine gene-brain-behavior interactions in shaping the development of the emotional brain and as inter-individual modifiers of behavioral expression. Specifically, we will examine the role of the 5-HTTLPR S allele in the development of amygdala dysfunction and in reduced functional connectivity between limbic and prefrontal structures in autism.

 Research on the behavioral and neural mechanisms underlying the development of emotion processing deficits in autism, as proposed in this application, will provide important new insights into the development of the emotional brain in autism. It will also provide behavioral and brain phenotypes for genetics studies to investigate important genetic modifiers of behavioral expression that may be amenable to rational pharmacotherapy. Improved understanding of the behavioral, cognitive, and neural mechanisms of emotional processing in autism will improve the recognition and treatment of the profound emotional immaturity in ASD that is associated with problematic behavior at all ages and contributes to poor function in adulthood. This research addresses Autism Research Matrix goals # 16, 19, 22, 23, 26, 31, and 34.

Project III:  Systems Connectivity &Brain Activation: Imaging Studies of Language & Perception

Project III focuses on understanding disturbances in functional brain connectivity that underlie the impaired processing of information and in turn the cognitive and behavioral impairments in autism.  The project also includes innovation machine-learning studies of how the brain identifies and categorizes words and computational modeling of cortical function.

The overriding aim of this project is to relate the major symptoms of autism to abnormalities in their neural substrates, providing a neural systems-level analysis of autism, and focusing on neural systems connectivity. The primary method will be to perform fMRI studies of several different types of thinking to obtain information about underlying brain function, and to simultaneously acquire information about the size and integrity of brain tissues. The fMRI studies will provide information about cortical activation, but also about functional connectivity or the synchronization of the activation between areas.

The project has developed the beginnings of a theory proposing that autism is marked by disordered connectivity among regions, particularly affecting the connectivity between frontal areas and more posterior areas. The connectivity framework is being used to formulate and test hypotheses and then integrate the new findings into a coherent theory. The new studies will deepen and broaden the understanding of the underlying neural disorder. The deepening will include the integration of several imaging modalities, so that the connectivity can be understood at more levels and in more detail. The broadening will consist of examining a wider range of tasks, to include conceptual comprehension, high-level perceptual tasks, and social tasks. This broadening is essential for determining the generality or specificity of the brain function characteristics of autism. The specifics aims are:

1. To characterize brain function in the processing of higher conceptual levels of language comprehension, visual cognition, and dynamic social cognition.

2. To characterize the semantic representation of single words in individual participants with autism applying innovative machine learning techniques to fMRI data. Autism as a disturbance in

3. To relate functional characteristics of the brain to anatomical characteristics at the individual participant level.

4. To further develop the theory of disordered connectivity in autism, integrating functional (fMRI) and anatomical (MRI and DTI) characteristics of autism and using computational modeling as a theory-building tool.

This research will continue to build an understanding of the relationship between the behavioral impairments that characterize autism and their neural basis. The connectivity model for autism advanced on the basis of this research has significantly influenced the field and validates the complex information processing development by Minshew, Goldstein and Williams. The combined model is proving to be promising in altering conceptualizations of autism and opening the way for new intervention methods (see deception learning for example). This research addresses Autism Research Matrix Goals # 2, 6, 22, 23, 26, and 34.

 
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© 2006 CeFAR at the University of Pittsburgh • Site last updated November, 2008