Geraldine Dawson - US grants

The specific aims of the project are (1) to determine the types of impairments of emotional expression and perception that are found in autism, and (2) to investigate the neuropsychological bases of these impairments. Measures will be taken on three groups of subjects: autistic children ranging from 6 to 18 years of age, and developmentally-matched normal and mentally retarded children. These three groups will be compared in terms of their ability to perceptually discriminate and categorize facial expressions, and in terms of their spontaneous expression of various emotions. Measures of spontaneous emotional behavior will be taken in both a controlled laboratory setting and in naturalistic school situations. Parents will also provide information about their child's emotional behavior in a questionnaire The above measures will be used to investigate whether individual differences in affective and social ability are related to specific patterns of frontal and parietal lobe functioning. Electroencephalographic (EEG) recordings of right and left frontal and parietal activity will be taken in response to a variety of affective and cognitive stimuli. EEG will be subjected to power spectrum analysis to yield measures of alpha band power frequency (8-13 Hz). Measures of right and left parietal and frontal integrated alpha will be used to infer differential cortical activation during affective and cognitive processing. Comparisons of patterns of brain activity will be made among autistic, and matched mentally retarded and normal subjects. Specific predictions regarding the pattern of brain dysfunction expected in autistic subjects are based on current neuropsychological models of emotion. The long term objectives of the research program are to shed light on the neuropsychological bases of early infantile autism and to use this information to develop more effective diagnostic and treatment methods for autistic persons.

The purpose of this project is to identify, and explore the nature of, psychophysiological characteristics that are related to depression. In particular, we are interested in the frontal lobe and its role in affective expression and regulation in depressed and non-depressed adolescent mothers and their infants. We seek to replicate our previous finding that infants of depressed and non-depressed mothers differ in their patterns of frontal EEG activity during emotional situations. Furthermore, we plan to extend this research by examining the contemporaneous and predictive relationships between measures of frontal lobe EEG activity and autonomic arousal, and "depressed" behavior in mothers and their infants. Participants will be 120 infants and their adolescent mothers, approximately half of whom will be depressed as reflected in their scores on the Center for Epidemiological Studies-Depression Scale. Infants' patterns of frontal EEG and autonomic arousal in resting and emotion-eliciting conditions will be studied longitudinally at 10, 20 and 30 months of age, along with measures of maternal depression and maternal affective and interactive style with her infant. Infants' social and affective behavior, and cognitive and language abilities also will be assessed longitudinally. A central question to be addressed by the longitudinal study is whether it is the case that infants' psychophysiological responses are relatively stable over time despite changes in maternal report of depression and/or maternal behavior toward the infant (Model 1), or, alternatively, that infants' psychophysiological responses are closely linked at any given time to mother's current report of depressive symptoms and/or her behavior toward her infant (Model 2). Finally, when infants are 10 and 30 months of age, frontal EEG activity and autonomic arousal also will be measured in the depressed and non-depressed adults were found to differ in their patterns of resting frontal EEG activity, and also allow us to examine more closely the linkage between infants' and mothers' affective and physiological responses.

Among the early impairments typically shown by children with autism is a failure to imitate the motor actions of other people. Imitation plays a central role in both in both social and cognitive development. Thus, autistic children's deficient imitation ability may help to explain many of the core symptoms of autism. Although impaired motor imitation is considered a diagnostic criterion for autism, very little is known about the nature or cause of this impairment. The primary aim of this research project is to explore the psychological nature and neurophysiological basis of autistic children's deficit in motor imitation. Three possible reasons for autistic children's impairment in motor imitation will be investigated using rigorous experimental methods that have been designed to assess imitation in normally-developing infants. Subjects will consist of developmentally-matched samples of young autistic, mentally-retarded, and normally-developing children. The first experiment is designed to determine whether the autistic child has difficulty recognizing the similarity between actions of the self and other, a possibility that has been raised by investigators in the field but has never been directly tested. The second experiment is designed to assess whether the autistic child, although recognizing the similarity between actions of self and other, is unable to translate this perceptual information into motor actions (immediate imitation). The third experiment is designed to assess whether the autistic child's failure to imitate is related to a general deficit in the ability to store and later act on internal representations of absent events (deferred imitation). Such a representational capability has been linked to the prefrontal cortex. To further explore the relations between frontal lobe functioning and motor imitation in autism, both behavioral and electrophysiological (EEG) measures of frontal lobe functioning will be obtained to examine whether these measures are predictive of children's level of imitation and social ability.

There are three aims of this project. The first aim is to demonstrate that autism can be distinghished from mental retardation in infants one year of age. This will be accomplished by observing 1st birthday home videotapes of 75 3-4 year old children later diagnosed with autism, and comparing them to 1st birthday party videotapes obtained from 50 3-4 year children with idiopathic mential retardation and from 75 children with typical development. The second aim is to determine whether variations in early course of development in autism (early vs late onset) are related to individual differences in later symptom expression and brain function. It is believed that approximately 25 percent of children with autism show a pattern of normal development followed by regression in the second or third year of life. Such patterns likely reflect different underlying brain mechanisms in autism and may index subtypes of the disorder. To investigate this possibility, children with early versus later onset of autistic symptoms, as reflected in observations from 1st and 2nd year videotapes, will be compared to determine whether they differ in terms of their patterns of symptom expression and neurocognitive profiles at 3-4 years of age. The third aim is to study more broadly the longitudinal development of children with autism from infancy through early childhood with the goal of identifying key factors related to outcome in autism. Children with autism and the comparison group of children with mental retardation will be followed longitudinally during the preschool period. Analyses will examine how three primary factors - age of symptom onset, early neurocognitive profile, and intensity of early intervention - are related to outcome by early elementary school age (6-7 years).

DESCRIPTION (provided by applicant): The primary purpose of the Behavioral Science Core is to facilitate high quality, creative, and cost-effective research and to provide research facilities and consultation to support behavioral scientists investigating normal and atypical human development. Providing core facilities and a forum for behavioral scientists to communicate ideas, specific knowledge, and techniques regarding common conceptual and methodological issues involved in behavioral research accomplish this. Such issues include methodological techniques pertaining to behavioral observation and psychophysiology, and conceptual issues pertaining to measurement of specific constructs (e.g., parent-child interaction, peer relations, attachment) and the interface between behavioral and neurophysiological measures.

The overall UW ACE theme centers on a comprehensive developmental model of risk, risk processes, symptom emergence, and adaptation in autism spectrum disorder (ASD). According to this model, early autism risk factors (genetic/familial and environmental) lead to risk processes, namely altered patterns of interaction between the child and his/her environment, which contribute to the abnormal development of neural circuitry and atypical behaviors. By identifying infants at risk at an early age when the brain is developing and before core autism symptoms have emerged, it might be possible to alter the developmental trajectory of children at risk for the disorder and have a significant impact on long-term outcome. Both clinical progress and basic science will profit from the identification of endophenotypes [unreadable] intermediate, quantifiable traits that predict an individual's risk of having a disorder, which can be linked to underlying cause. The goals of Project II are two-fold: First, in a sample of infant sibs, we aim to investigate whether neurophysiological risk indices (endophenotypes) measured at 6-7 mos of age will improve our ability to identify infants who will develop autism or autism-related symptoms by age 2. Second, we will assess whether it is possible to alter risk processes via early intervention with high-risk infants, thereby reducing severity of autism symptoms. Specifically, we plan to investigate the efficacy of early intervention that is designed to enhance early social responsiveness and communication in infants who are at risk for autism (infant siblings of children with autism). Despite the fact that our ability to identify infants at risk for autism is rapidly improving, early interventions for infants at risk for autism have not yet been tested. This project represents a first step toward developing effective interventions for at-risk infants. The proposed work on early autism risk factors will have impact on several key areas: (1) Identification of the biological and/or behavioral risk indices in infancy, for the development of autism and autism- related symptoms, such as language and social impairments; (2) development of intervention methods for infants and toddlers to lower the age for which there are efficacious interventions; (3) identification of individual characteristics that predict response to behavioral treatment; and (4) provision of evidence that cases of autism might be secondarily prevented through early identification and early treatment.

ABSTRACT ? Project 2: Neural signatures, developmental precursors, and outcomes in young children with ASD and ADHD Although recognized as distinct diagnostic conditions, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly comorbid. The overlap in clinical presentation, risk factors, and co- heritability of ASD and ADHD has led some authors to propose that these disorders share underlying biological mechanisms and that ADHD is a milder, less severe subtype within the ASD syndrome. Moreover, the presence of co-occurring ADHD has significant clinical implications, where individuals with comorbid ASD and ADHD have substantially poorer outcomes. To date, very little research has focused on the overlap of ASD and ADHD during early childhood. Thus, we know relatively little about the extent to which ASD and ADHD represent distinct conditions or the impact of co-occurring ADHD symptoms on early behavioral patterns and brain mechanisms in ASD. In Project 2, we will study the neural signatures, biomarkers, developmental trajectories, and clinical outcomes associated with comorbid ASD and ADHD with the overarching goal of generating knowledge that will allow earlier detection of these overlapping conditions and more individualized treatment approaches that take into account the additive and interactive effects of both conditions. The primary goals of Project 2 are to (1) elucidate shared and distinct neural signatures and biomarkers related to ASD vs. ADHD, (2) examine the functional and clinical impact of co-occurring ADHD symptoms in young children with ASD, and (3) identify early characteristics of infants and toddlers later diagnosed with ASD with and without elevated ADHD symptoms. To this end, in Project 2, we will recruit four groups of children between 36-72 months of age with the following clinical features: ASD only, ASD+ADHD, ADHD only, and typically-developing (TD) children. The specific aims to achieve our overall study goals are to (1) identify differences and commonalities in neural signatures and biomarkers based on neurophysiology and eye-gaze tracking across the four groups; (2) examine how these biomarkers are correlated with specific symptom profiles based on shared and distinct phenotypic characteristics of ASD and ADHD; (3) determine the clinical impact of ADHD in young children with ASD; and (4) explore the extent to which developmental precursors linked to diagnostic outcome can be detected during the infant-toddler period. The latter aim will be accomplished by analyzing home video recordings taken in the first and second year of life of children later diagnosed with ASD only, ADHD only, ASD+ADHD, vs. TD, based on observations made via automated computer vision analysis of movement and affect, as well as human coding of vocalizations/verbalizations, joint attention, gaze and orienting behavior, affect, and repetitive behaviors. Project 2 will provide a detailed, comprehensive understanding of unique developmental trajectories and impacts of co-occurring ADHD in children with ASD.

ABSTRACT ? Administrative Core The overall goal of the Duke Autism Center of Excellence is to characterize how co-occurring symptoms of attention deficit hyperactivity disorder (ADHD) influence the early detection, clinical presentation, neural signatures, developmental trajectories, and treatment outcomes of young children with autism spectrum disorder (ASD). The Administrative (?Admin?) Core will serve as the hub for the Center, coordinating and overseeing all research projects and cores so that they function effectively and efficiently as a whole in an integrated and synergistic fashion. The goals of the Admin Core are to promote communication and collaboration among team investigators, reduce the administrative burden on Center investigators, monitor regulatory compliance, and ensure scientific rigor, progress, and productivity. The Admin Core will be responsible for achieving the following specific aims: (1) coordinate, promote, and streamline communication across all components of the Center to ensure close collaboration and scientific progress through all phases of the research program. To accomplish this aim, the Admin Core will coordinate monthly Executive Committee and Center-wide meetings at which project and core Leads and other key personnel and staff members will review target recruitment goals, expenditure summaries, resources, timelines, and deliverables; identify any barriers to achieving the Center's goals; and develop and implement strategies for addressing barriers; (2) provide overall management and oversight of the Center. The Core will oversee and support the Center's scientific efforts by setting goals, defining deliverables, and closely monitoring and evaluating progress and productivity, thereby ensuring timely progress toward milestones and deliverables. Evaluation of each project and core, as well as the overall Center, will be based on scientific progress relative to these agreed-upon milestones and in relation to expected expenditures; and (3) provide timely financial accounting and ensure compliance with all institutional, state, and federal research and ethical guidelines. The Core will provide expertise and infrastructure to ensure financial management and compliance with relevant university, state, DHHS, NIH, and federal research regulations, including those related to human subjects research. The Admin Core will be closely connected to and will integrate all projects and cores. In this way, the Admin Core will ensure a unified, compliant research effort and will support the Center's overall goals to shed light on the early detection, developmental trajectories, neural signatures, and treatment of co-occurring ADHD symptoms in young children with ASD.  

SCALABLE COMPUTATIONAL PLATFORM FOR ACTIVE CLOSED-LOOP BEHAVIORAL CODING IN AUTISM SPECTRUM DISORDER ABSTRACT Despite significant recent advances in molecular genetics and neuroscience, behavioral ratings based on clinical observations are still the gold standard for screening, diagnosing, and assessing outcomes in neurodevelopmental disorders, including autism spectrum disorder (ASD). Such behavioral ratings are subjective, require significant clinician expertise and training, typically do not capture data from the children in their natural environments, and are not scalable for large population screening, low-income communities, or longitudinal monitoring. The development of scalable digital approaches to standardized objective behavioral assessment is thus a significant unmet need in ASD, here addressed via machine learning and computer vision with the goal of providing scalable methods for assessing existing biomarkers, from eye tracking to movement and posture patterns, and tools for novel discovery. Our long-term goal is to develop validated scalable tools for the automatic behavioral analysis of neurodevelopmental disorders. The proposed computational project leverages results and big data derived from our previous studies (N=1,864 participants) and our recently funded NIH Autism Center of Excellence (ACE) award (N=7,436 participants). The ACE project will allow us to develop and validate our tools on several thousand toddlers recruited in Duke pediatric primary care and followed longitudinally for whom gold-standard diagnoses of ASD, attention deficit hyperactivity disorder (ADHD), developmental and language delay and extensive electronic health record (EHR) data will be available; and in a case control study of 224 age-matched groups of young children with ASD, ADHD, and typical development from whom gold-standard diagnostic, extensive phenotypic, Tobii eye- tracking, and EEG will be collected. This project aims to develop novel computational methods using these datasets, from sensing in scalable fashion behaviors such as attention and gaze (Aim 1) and motor/posture (Aim 2), to their multimodal integration (Aim 3). A unique aspect of our computational approach is the closed- loop integration of stimuli design for actively eliciting behavioral symptoms, use of consumer-grade sensors, and automatic behavioral analysis. This contrasts with the current approach of independently selecting stimuli and using expensive lab-based professional grade sensors with off-the-shelf algorithms to capture behavioral biomarkers expected from the stimuli. Our approach involves active elicitation of behavior which is also different from commonly used digital approaches that involve gathering large datasets from passive sensing, such as actigraphy monitoring of spontaneous behavior at home. Our framework results in active closed-loop sensing, where participants are engaged in short and developmentally appropriate activities on ubiquitous devices, while the sensors in the same device capture information for the automatic and quantitative analysis of behavioral biomarkers. This scalable, objective, and standardized way of stimulating, sensing, and analyzing allows the collection of large behavioral datasets for machine learning.