Katarzyna Chawarska - US grants

Autism is a complex congenitial neurodevelopmental disorder with recurrence risk in younger siblings of affected individuals reaching at least 8%. Increased rates of PDD-NOS and developmental delays have also been reported. In autism the first concerns are noted by parents prior to the child's 2nd or even 1st birthday. Despite this, the evidence regarding expression of autism in the first two years of life is very limited and depends primarily on retrospective reports and analyses of video diaries. Neither the exact timing of symptom onset, nor their developmental course in the first two years of life has been documented. This prospective study will examine development of infant siblings of children with autism contrasted with that of typically developing infants and infants at risk for developmental delays without autistic features. The infants will complete a series of conceptually linked assessment procedures targeting perceptual, social, communicative, cognitive (verbal and nonverbal), motor, and adaptive development at 3, 6, 9,12, 18, and 24 months of age, with confirmatory diagnostic assessment at 36 months. The goals are to examine: 1) perceptual precursors of specific social and communicative skills usually affected in autism, namely gaze, affect, and speech processing. 2) syndrome-specific patterns of delays, abnormalities, and strengths based on the assessment of social, cognitive, communicative, exploratory/play, adaptive, and imitation skills collected at each age level. 3) changes overtime in the syndrome expression and establish when and in which domains the developmental trajectories of infants with autism begin to diverge from pathways of typical and developmental^ delayed infants. This project will: (1) Identify behavioral markers of autism in the first year of life and provide insights in the underlying pathogenic mechanisms of autism. (2) Define sets of diagnostic criteria for autism and PDD-NOS that take under account developmental changes occurring in the first two years of life. (3) Determine the timing and sequence of skill acquisition in autism (4) Identify predictors and mediators of outcome. This research has great potential to inform clinical practice (early diagnosis), treatment (identification of pivotal target areas at various ages), and theory (e.g., elucidation of the underlying mechanisms through identification of primary symptoms and distortions in the sequence of skills acquisition).

Eye tracking has become a widespread tool throughout the cognitive sciences and has attracted particular attention as a behavioral measurement tool for children with developmental disabilities. However, there are no standardized quantitative tools for assessing broadly defined attention skills in young children, and there is a lack of analysis techniques that would allow gaze patterns to be compared across individuals, across populations, or for a single individual across time. This study will develop methods of quantitatively measuring attentional capacities by (1) designing a Visual Attention Assessment Suite (VAAS) which examines the interaction and impact of particular features of scenes on visual attention; (2) constructing novel computational analysis techniques for comparing gaze patterns across individuals, populations, and time; (3) validating these techniques against both standard behavioral assessment protocols and through an embodied modeling approach to ensure that our models capture the behaviorally important aspects of gaze.

The regulation of attention has been hypothesized as one of the fundamental factors affecting early development of children with autism. This project will develop quantitative measures that can be used as diagnostic and prognostic indicators and to evaluate the effectiveness of particular treatment approaches. This project represents the first integrated and interdisciplinary attempt to develop a much needed full-scale diagnostic instrument that operates purely through eye-tracking, computational techniques, and individual modeling. Although our primary focus is the interpretation of gaze data with respect to autism, eye tracking is used extensively in psychology, primatology, usability studies, marketing, and human-computer interaction experiments. The models and analysis tools constructed under this project will be equally applicable to these other domains. This project also has the potential to produce novel methods of assessing attentional abnormalities in other developmental disorders (e.g., mental retardation, attention deficit disorder, specific learning disabilities), novel educational assessment methods of pre-kindergarten readiness, as well as to develop training methods for teaching clinicians and educators behavioral assessment using a robot as a model illustrating various attentional patterns in children with disabilities.

0-11 years old; 21+ years old; ANOVA; Address; Adult; Affect; Affective; Age; Analysis of Variance; Area; Attention; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Behavior; Behavioral; Biological Neural Networks; Birth; Brain imaging; Categories; Characteristics; Child; Child Development Disorders; Child Development Disorders, Specific; Child Youth; Childhood; Children (0-21); Clinical; Clinical assessments; Cognition; Cognitive; Cognitive Discrimination; Collaborations; Color; Complex; Condition; Control Groups; Cues; Detection; Development; Developmental Delay; Developmental Delay Disorders; Developmental Disabilities; Diagnosis; Diagnostic; Discrimination; Discrimination (Psychology); Disruption; Early Intervention; Early Intervention (Education); Event; Exhibits; Eye; Eye Movements; Eyeball; Face; Feeling; Fixation; Fixation, Ocular; Focusing, Ocular; Foundations; Goals; Grouping; Heterogeneity; Human, Adult; Human, Child; Image; Impairment; Infant; Intervention; Intervention Strategies; Kanner's Syndrome; Knowledge; Lead; Learning; Life; Link; Location; Measures; Mechanics; Methods; Methods and Techniques; Methods, Other; Modeling; Monitor; Motion; NOVA2; NOVA3; Neuro-Oncological Ventral Antigen 2; Neuro-Oncological Ventral Antigen 3; Neurobiology; Nursery Schools; Ocular Fixation; Outcome Measure; Participant; Parturition; Pattern; Pb element; Perception; Performance; Predictive Value; Procedures; Process; Pursuit, Saccadic; Rate; Reaction; Reaction Time; Research; Response RT; Response Time; Risk; SUBGP; Saccades; Saccadic Eye Movements; Sampling; Scanning; Schools; Schools, Nursery; Score; Screening procedure; Series; Side; Social Conditions; Social Development; Social Perception; Socialization; Socializations; Societal Conditions; Sound; Sound - physical agent; Source; Specific qualifier value; Specified; Stimulus; Subgroup; System; System, LOINC Axis 4; Techniques; Testing; Thinking; Thinking, function; Time; Toddler; Toy; Training; Variance Analyses; Visual; Visual attention; Work; adult human (21+); autism spectrum disorder; base; behavior test; behavioral test; brain visualization; children; cognitive system; concept; data management; design; designing; directed attention; directs attention; expectation; experiment; experimental research; experimental study; facial; feelings; gaze; groupings; heavy metal Pb; heavy metal lead; imaging; impression; indexing; infancy; infantile; innovate; innovation; innovative; instrument; interventional strategy; joint attention; movie; neural circuit; neural circuitry; neural mechanism; neural network; neurobiological; neuromechanism; pediatric; preference; psychomotor reaction time; research study; sample fixation; screening; screenings; skills; social; social cognition; social communication; sound; visual fixation; vocalization; youngster

0-11 years old; Accounting; Address; Affect; Age; Age-Months; Area; Attentional deficit; Autism; Autism, Early Infantile; Autism, Infantile; Autistic Disorder; Behavior; Behavioral; Characteristics; Child; Child Development; Child Development Disorders, Specific; Child Youth; Children (0-21); Clinical; Cognition; Cognitive; Complex; Congenital Disorders; Development; Development, Infant; Developmental Delay; Developmental Delay Disorders; Diagnosis; Diagnosis, clinical; Diagnostic; Diaries; Diaries (PT); Diaries [Publication Type]; Disorders, Congenital; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Early Intervention; Early Intervention (Education); Early identification; Face; Family; Goals; Human, Child; Individual; Infant; Infant Development; Infant and Child Development; Investigators; Kanner's Syndrome; Language; Language Development; Life; Link; M.D.; Mediator; Mediator of Activation; Mediator of activation protein; Motor; Motor Skills; Neurodevelopmental Disorder; Neurological Development Disorder; Nursery Schools; Outcome; Parents; Pathway interactions; Pattern; Perception; Performance; Ph.D.; PhD; Play; Principal Investigator; Procedures; Process; Prospective Studies; Rate; Recurrence; Recurrent; Reporting; Research; Research Personnel; Researchers; Rhea; Risk; Schools, Nursery; Series; Siblings; Speech; Symptoms; Syndrome; Time; acquiring language skills; autistic psychopathology; autistic psychopathy; base; children; clinical Diagnosis; diaries; disability; early detection; facial; gaze; insight; language acquisition; language learning; pathway; skill acquisition; skills; social; social cognition; social communication; speech processing; theories; youngster

DESCRIPTION (provided by applicant): Considering the early role of human faces as compelling stimuli for typically developing newborns and considering the emergence of sophisticated face recognition skills by six months in typical development, it is very likely that face processing in Autism Spectrum Disorder (ASD) is affected from the first months of life. This project aims to characterize the emergence of face processing abnormalities in infants with ASD by prospectively following, from 3 months to 36 months of life, 160 infants at high risk for developing ASD due to a genetic liability (i.e. by having an older sibling with ASD). At 36 months, clinical diagnosis of the high-risk population will afford the division of the population into three groups: 1) siblings with ASD; 2) Non-Affected siblings (NAF); and 3) siblings with various developmental delays but without ASD features (DD). Developmental changes in face processing skills will be compared against 40 low-risk, typically developing infants (TYP). The set of interrelated face processing skills to be examined include: 1) localization of faces and focused attention to faces; 2) attentional disengagement from faces; and 3) face scanning and recognition. Localization of faces and focused attention towards faces tests the hypothesis that, when presented with faces in naturalistic environments, children who later develop ASD will take longer to localize a face, and, when they do, will spend less time focused on the face. Disengagement from faces task tests the hypothesis that DD, TYP and NAF attend to faces in an obligatory manner and process them on a deeper level as compared to children who develop ASD. This hypothesis will be reflected by a longer latency in shifting attention away from the face to a remote target that appears suddenly. Face scanning and recognition will test the hypothesis that infants with ASD will, with age, exhibit a progressively atypical pattern of face scanning and that the degree of abnormality will correlate with recognition skills as well as social and cognitive deficits. The process of encoding facial features and recognition skills will be gauged via an infant-controlled habituation paradigm. It is expected that the patterns in localization of faces, focused attention towards faces, attention capture by faces, and face scanning and recognition, will, in combination, highlight the developmental divergence in high-risk and low-risk children and correlate with worsening autistic symptoms. Our goals are to identify the type of primary impairments in face processing and to understand the developmental trajectories of face processing abnormalities in the earliest stages of ASD. This will inform early diagnosis (through identification of potential early indicators of risk for ASD), treatment (though identification of pivotal target skills), and theory (through enhancing understanding of mechanisms underlying abnormalities in face perception in ASD). This project addresses several key action items of the NIH Interagency Autism Coordinating Committee, with emphasis on understanding of underlying mechanisms of social impairment and identifying behavioral markers for ASD in infancy.

DESCRIPTION (provided by applicant): Children with autism spectrum disorder (ASD) exhibit deficits in multiple domains including joint attention, imitation, and emulation. In typical development, these key social skills hinge on monitoring the activities and actions of others. Our recent study demonstrated that 20-month old toddlers with ASD attend less to activities than both age-matched typically developing (TD) toddlers and age- and cognitively-matched developmentally delayed (DD) toddlers, focusing instead more on non-social background elements such as toys. Given the cascading deficits that may arise when children are deprived of a vital route by which to learn from others, there exists a pressing need to better understand the developmental mechanisms leading to both typical and atypical activity monitoring. This proposal seeks to understand why toddlers with ASD monitor the activities of others less frequently by examining the social, perceptual, and developmental factors which may influence this ability in 20-month old toddlers with ASD and 14- and 20-month old TD toddlers. In regards to typical development, this proposal aims to chart the normative developmental changes in activity monitoring and to understand the bases for these changes, thus providing a context by which to understand limited activity monitoring in ASD. In regards to ASD, this proposal seeks to quantify to what extent limited activity monitoring in ASD is due to (1) orienting less towards the locus of the shared attention of others; (2) being less sensitive to motion cues; and (3) being more easily distracted from social activities by perceptual distractors. To answer these questions we present subjects with scenes depicting play interactions between two actors and modulate the following factors: (1) whether the actors are focused on the centrally shared area or mutually upon each other; (2) whether the scene is shown as a static image or a dynamic movie; and (3) the extent to which the background is cluttered with distractors such as toys. To clarify the impact of these factors, we also examine the relationships between patterns of attention in experimental conditions and socio-cognitive functioning in ASD. Finally, we augment traditional analysis of variance analytic approach with computational modeling and dynamic analyses in order to better understand the microstructure of activity monitoring in ASD and TD toddlers. Disruptions in activity monitoring at an age where rapid development and skill acquisition is occurring in TD children may critically impact the social experience of children with ASD. By understanding the factors contributing to limited activity monitoring in ASD, and by charting the changes in activity monitoring occurring in typical development, we hope to gain insight into those specific processes which may be altered in ASD. This work thus has the potential to lead to novel measures of outcome, to aid in the development of new tools for parsing the heterogeneity of ASD, and to inform the design of targeted treatment for ASD in early development.

DESCRIPTION (provided by applicant): The proposed project aims to evaluate the feasibility and acceptability of a novel behavioral intervention, Infant-Toddler Years Pivotal Response Treatment (ITY-PRT), designed to enhance the frequency of communication and social engagement in infant siblings of children with Autism Spectrum Disorders (ASD; SIBSASD). Genetic studies reveal that SIBSASD are at risk for a variety of developmental challenges, with a significantly increased risk for ASD (Bailey, Phillips, & Rutter, 1996) and other social, cognitive, and language difficulties (Bailey et al., 1995; Bolton et al., 1994). Given the high genetic risk, prospective studies of infant SIBSASD have beeninitiated in order to elucidate the developmental processes in ASD and enhance early identification. Emerging research indicates that symptoms of ASD may be present as early as 12 months of age (Rogers, 2009). While we are not yet able to differentiate children at 12 months of age who will ultimately develop ASD from those with other developmental delays or transient issues, these children warrant intervention based on their risk status and clinical presentation. Thus, prospective studies at the Yale Child Study and other major research centers around the country are documenting the early emergence of the symptoms of ASD and identifying infants who are likely to face developmental challenges and warrant referrals for clinical services as early as 12 months of age. However, there is currently a paucity of empirically-supported interventions available for infant SIBSASD, urging the need to design developmentally appropriate interventions for at-risk infants. In synergy with the ongoing prospective studies for infant SIBSASD at the Yale Child Study Center (PI: Katarzyna Chawarska), we will pilot ITY-PRT, a downward extension of Pivotal Response Treatment (PRT). PRT is an empirically supported intervention for children with ASD and is documented by the National Research Council (NRC) as one of 10 comprehensive intervention models for ASD (NRC, 2001). Utilizing a randomized-controlled group design, 30 infant SIBSASD who demonstrate significant delays in communication and/or social interaction at 12-15 months of age will be randomly assigned to receive either ITY-PRT in addition to a standard referral to community treatment, Treatment As Usual (TAU), or assigned to receive TAU only. ITY-PRT will consist of five hours/week of parent education (including two hours of group parent education, and three hours of individual sessions) over the course of six months. Outcomes will be focused on the feasibility and acceptability of this program, including measures of attendance, utilization of intervention procedures outside of intervention sessions, and overall parent satisfaction. We will also evaluate the preliminary efficacy of ITY-PRT by analyzing the frequency of child communication, child social interaction behaviors, and parental bids for communication during parent-child interaction probes, as well as changes in standardized measures of development and social behavior both from pre to post and across treatment and control groups. PUBLIC HEALTH RELEVANCE: This project will pilot a downward extension of Pivotal Response Treatment for infant siblings of children with Autism Spectrum Disorders who demonstrate developmental delays at 12-15 months of age. This project will (a) assess the feasibility and acceptability of this novel intervention for children at 12-15 months of age; (b) explore the preliminary efficacy of this approach in preparation for larger clinical trials of efficacy, and (c) promote new models of early intervention for autism. These are amongst key objectives of the NIH Interagency Autism Committee and therefore highly relevant to public health.

DESCRIPTION (provided by applicant): Older individuals with ASD show deficits in the pragmatic and spontaneous use of emotional information, but little is known about emotional processing in the early stages of ASD. Our preliminary work suggests that deficits in emotion processing are present as early as at 12 months in the affected infants. In typical development, infants detect and orient towards affective cues in the first months of life. These attentional biases for affectively valenced information play a critical role in the development of attachment, communication, empathy, and non-social cognition. Considering that later-emerging and more complex emotion processing and regulation skills are affected in toddlers with ASD, this project examines early- emerging emotional attention skills such as capture by, hold by, and preference for affective cues. Key questions are: Are deficits in emotional attention general, affecting multiple modalities (e.g. faces, biomotion, and prosodic cues) and attentional mechanisms (e.g., capture, bias, and preference)? Is orienting to specific emotions preserved (e.g. fear, anger, and joy)? Is there an association between the child's attentional biases for perceiving the emotional cues of others and their own emotional functioning? What is the relationship between early emotional dysfunction and later core and comorbid symptoms? We propose to examine these questions in 12-24-month-old toddlers with ASD, developmental delay (DD) and typical development (TD) (T1) followed prospectively at 36-42 months (T2). At T1 we will evaluate aspects of emotional attention in response to facial expressions, body movements, and prosodic cues using eye-tracking. We will also examine in vivo aspects of emotional functioning and regulation skills. Combining eye-tracking and behavioral tasks will allow us to both quantify emotional functioning at the early stage of syndrome emergence in an unprecedented fashion and to evaluate their unique contribution to outcomes 1-2 years later. This project will allow us to identify preserved domains of affective processing (upon which therapies can be scaffolded), identify deficient domains (which may be targeted directly for treatment), advance our understanding of the unique contribution of emotional disturbance to core and comorbid symptoms of ASD (helping to identify novel predictors of outcome and homogenous subgroups within ASD), and suggest mechanisms that may illuminate the role of emotional attention difficulties in the etiology of autism.

DESCRIPTION (provided by applicant): Recent eye-tracking studies have shown that 20-month old toddlers with autism spectrum disorders (ASD), as compared to typically developing (TD) and developmentally-delayed (DD) toddlers, attend less to the shared activities of others1 as well as to faces trying to engage them using direct eye-contact and child-directed speech2 (i.e. bids for dyadic engagement). Since attending to others, and especially their actions, is critically linked to both social skill development and observational learning, teaching toddlers and children with ASD normative strategies for viewing others and their activities may provide new opportunities for them to learn about their social world. This proposal initiates a highly nove line of research which uses adaptive eye-tracking technology and non-adaptive perceptually augmented cues in order to help 20-month-old toddlers allocate their attention to people and their actions in a more typical fashion. The project will be conducted in two phases. In the first phase, normative gaze patterns will be collected from 18-24 month old typically developing (TD) toddlers (N=50) watching videos of actresses engaged in everyday activities, with an emphasis on scenarios incorporating bids for dyadic engagement and shared activities. In the second phase, 20-month-old toddlers with a preliminary diagnosis of ASD will be shown videos in the following 3 conditions: (1) a non-adaptive cue condition (N=16), where perceptual enhancement will be employed at selected scene locations (e.g. increasing contrast or emphasizing motion) in order to maintain the viewers' attention towards normative locations of scanning; (2) an adaptive cue condition (N=16), where, as viewers deviate from the normative gaze pattern, the scene automatically redirects attention back towards the normative pattern by darkening or deemphasizing atypical locations on the scene; and (3) a control condition (N=16), where toddlers will view the scenes without manipulation, as is shown to TD participants in the first phase. Manipulated blocks will be preceded and followed by dyadic bid scenes and activity scenes which will establish both baseline scanning patterns and the effects of gaze manipulation. Behavioral assessments will be employed before and after the eye-tracking sessions in order to gauge the generalizability of any changes to visual scanning strategies. If successful, this study may point towards new methods for training attention towards social information in toddlers with ASD, and may also lead to new eye-tracking paradigms that may be more sensitive to atypical patterns of attention.

? DESCRIPTION (provided by applicant): Although we now have the tools and expertise to diagnose autism spectrum disorders (ASD) reliably in the 2nd year of life, most children are still diagnosed after their 4th birthday and, in under-resourced, ethnically diverse communities, as late as 8 years of age. These gaps highlight our failure to translate state-of-the art screening and diagnostic practices into practical solutions for identifying the most vulnerable children across socioeconomic strata. This disconnect is highly concerning given that early implementation of treatment leads to more positive outcomes. Factors contributing to the gaps include the limited awareness of early signs of ASD amongst parents and professionals, limited feasibility of deploying traditional paper-and-pencil screeners in primary care centers, and difficulties accessing appropriate services. In low-resource communities, these problems are further compounded by lack of supportive environments and language and literacy issues. This study aims to pilot a solution to surmount some of these challenges through the development of a new generation, tablet-based screening system comprised of two parts: (1) A novel video-based screener (Yale Adaptive Multimedia Screener, YAMS) based on early syndrome expression data collected over a decade at the Yale Toddler Developmental Disabilities Clinic (YTDDC) (Aim 1). By using simple spoken language, this screener will circumvent literacy-related issues. By providing visual examples, it will add clarity to concepts that may be complex for new parents. The screener will be adaptive, with questions contingent on prior responses, thus maintaining diagnostic precision within a time-efficient system highly acceptable by parents and staff; (2) Digital implementation of the M-CHAT-R/F, with automatic scoring for increased efficiency and with high-level interpretations and recommendations to increase physician utility. This adaptation will provide an established measure to augment our research goals and to serve as a comparison system for the YAMS (Aim 3). To gauge the utility and feasibility of our approach (Aim 2), we will test YAMS through collaborations with community primary care centers serving low-resource and ethnically diverse populations. 200 parents will be recruited to participate at their child's 18- or 24-month well-care visit. All who screen positive on the M-CHAT- R/F and/or our YAMS (N~20) will be invited for expert follow-up assessment at the YTDDC. Data from this community screening sample will be augmented by a clinic-based sample of 18-24 month-old toddlers with diagnoses of ASD (N=70), developmental delay (DD, N=20), or typical development (N=70). The combination of these two samples will provide preliminary validation of the usability, utility, and potential of our screener. Our study represens a cohesive, unified approach that leverages the full capabilities of modern, low-cost, hand-held technologies to move us towards the goal of early universal screening for ASD. Our unique focus combines attention to not just the development of the screening system itself, but also the usability of the system in diverse settings and the integration of the screener as a facilitating agent of the clinical care process.

SUMMARY The Administrative Core supports the work of the five Projects and three Cores in terms of administrative planning, oversight, and management of the Yale ACE. It will also monitor utilization of the other Core resources and integration of the projects within the Center as well as coordinate, as appropriate, activities with other grants within the Yale Autism Program, as well as with NIH and central data repositories such as the National Database for Autism Research (NDAR) and the OpenfMRI database. Allocation of resources and general oversight of the entire program project are central functions of this Core. The overall concerns of the Administrative Core are to maintain efficiency, to ensure compliance with university and HIC regulations, and to maintain smooth and efficient functioning of the research program as well as optimal utilization of Core resources. The work outlined in the five Project areas is thematically connected through links in scientific constructs, subject cohorts, methods, and data sharing, thus, this multidisciplinary Center requires a highly integrated system of communication and coordination from the Administrative Core. An internal Executive Committee (EC) will be convened, comprising all Project Directors (Dr. Chawarska, Dr. Constable, Dr. Ment, and Dr. Vaccarino) and Core Leads (Dr. Powell, Dr. McPartland, Dr. Volkmar, Dr. Macari, and Dr. Chang). The EC will oversee the entire Center, meeting on a monthly basis to set policies, engage in fiscal planning, review progress in the specific project areas and budgets, foster integration and communication across projects and Cores, manage data sharing across the Center, and supervise the publication plan. We will also establish an Internal Advisory Committee, who will receive quarterly updates and meet annually with the EC to discuss progress and provide quality control. In addition, a Center Advisory Committee will be established, including external scientific members as well as lay members. A key effort of the Administrative Core will be to make certain that the abundant resources of the Yale Autism Program, the Child Study Center, and the Medical School are streamlined in support of this endeavor. A web-based collaborative work-space will be created and a communications tool will be implemented, both of which will enhance collaboration and communication. Coordination of the work of the Administrative Core with that of the Clinical Characterization and Statistical Analysis Cores will be a key objective, in order to monitor use of resources, ensure compliance with NIH and IRB regulations, and engage in overall strategic planning. Similarly, efforts to ensure effective dissemination of research findings, community outreach, and recruitment enhancement by the Dissemination and Outreach Core will be supported by this Core to maximize the impact of the program project. This effort will use the expertise and experience of Drs. Chawarska and Constable in coordination of research activities involving various investigators and disciplines.

Project Summary Anxiety disorders are highly prevalent in childhood and are associated with substantial impairment and disability. Symptoms of anxiety are widespread in preschoolers with ASD, limiting their learning and social interaction opportunities above and beyond difficulties related to core autism symptoms. Our preliminary work suggests that temperamental precursors of anxiety are already elevated in the second year of life in ASD. However, knowledge about the mechanisms underlying the emergence of anxiety symptoms in ASD remains limited. This project will experimentally quantify attentional, affective, behavioral, physiological, and temperamental factors associated with anxiety in 4-year-olds with ASD (n=160), other developmental disorders and concerns (ATYP, n=80), and typical development (TYP, n=80). We will investigate the associations between affective attentional biases to threat (ABT) and emotional-regulatory functions as well as the hypothesized, but relatively unexplored, role of these features in emerging anxiety in ASD. ABT represents a rapid attentional response to threat that is evidenced by longer latencies required to decouple attention from threatening stimuli. ABT is among the best-replicated neurobehavioral markers of clinical and subclinical anxiety. Decreasing this bias lowers anxiety symptoms in school-age children, implicating ABT in maintenance of anxiety. Give that attentional system has been implicated in ASD, ABT offers an unexplored but highly innovative and generative framework for investigating mechanisms underlying the emergence of anxiety in very young children with ASD. The key questions in this proposal are: (1) Are children with ASD more biased toward or away from threat than other 4-year-olds? (2) Is ABT associated with anxiety severity in 4-year-olds with and without ASD? (3) What role do the facets of ABT play in the emergence of anxiety symptoms from 2 to 4 years? (4) Given the heterogeneity of anxiety expression in early childhood, can we identify homogeneous subgroups based on neurobehavioral and physiological measures across diagnostic categories that will inform about unique underlying mechanisms and novel treatment targets or strategies? To answer these questions, we will evaluate anxiety-related aspects of attention in response to threat using an eye-tracking attention disengagement task developed and tested in our lab. We will also examine in vivo reactivity to threat at affective, attentional, and physiological levels. Combining these multimodal indices of response to threat will allow for quantification of anxiety-related features in an unparalleled manner and evaluation of each feature's unique contributions to clinical phenotypes, at the time when anxiety symptoms first become apparent. By focusing our investigation on 4-year-olds we aim to identify, essential from a translational standpoint, the early ?developmental tethers? that bias children's development toward maladaptive pathways. Furthermore, identifying subgroups based on neurocognitive attentional and physiological responses may contribute to the development of a neuroscience-based approach to classification of anxiety disorders in preschoolers.

The Yale Center represents a multidisciplinary research program consisting of five inter-related research projects and four cores dedicated to advancing understanding of early neurobiology of ASD. The proposal brings together a team of experts from the fields of developmental psychopathology and neurobiology, genetics, neurology, radiology, neuroscience, and statistics to identify the molecular, cellular, and neural mechanisms related to ASD from prenatal stages to childhood. We focus our investigation on two cohorts of younger siblings of children with ASD who, due to familial factors, are at high risk (HR) for developing the disorder: a prospective cohort recruited pre- and perinatally and followed through 24 months, and a cohort of HR siblings who was well-characterized at 24 months through our past studies and will reach the age of 12 years during the life of the Yale ACE. These cohorts enable our search for neural signatures of ASD during fetal, neonatal, and school-age periods, as well as to examine the connectome across the spectrum of risk for ASD both in males and females. Although neural and behavioral markers of ASD have been reported in 6- month-old infants later diagnosed with ASD, to our best knowledge, this is the first investigation into both fetal and neonatal functional connectivity in ASD. Emerging data suggest that male, but not female, ASD subjects demonstrate significant alterations in neural networks, and ? for the first time ? the proposed studies will identify not only the changes in connectivity in ASD but also the impact of fetal/neonatal sex upon these changes. Since recent studies demonstrate neuroplasticity in the developing brain across the late second and third trimesters of gestation, it is essential to understand if the factors associated with ASD are developing in this same time frame and to understand any sex differences that may be apparent even at that early age. The iPSC derived organoid system models human fetal development, allowing us to investigate neurobiological risk and protective factors that play a unique role in this period and may enable the discovery of patient-specific neuronal or stem cell biomarkers that could be used as predictors of risk or resilience in ASD. The Yale ACE aims rely on application of cutting-edge approaches to the analysis the connectome, fetal and neonatal imaging modeling neural development using the iPSC methodology with high resolution dual photon imaging approaches, the development of early markers for ASD, studying early attention and learning, novel predictive models relating brain organization to behavior, and statistical approaches for integrating the spectrum of data types across to address these aims. Results from the combined projects have a great potential to identify novel diagnostic and prognostic markers at the time of birth, identify neural, cellular, and molecular bases of risk and protective mechanisms in ASD, and clarify neural bases of sex differences in ASD.

Limited attention to faces of conspecifics constitutes one of the markers of ASD.1-4 Limited attention to faces is associated with increased severity of autism symptoms and poor adaptive functioning,5-8 and early individual differences in attention to faces contribute to the variability in later social and cognitive outcomes.5 Attention to faces is enhanced in 6-month-old unaffected females at familial risk for ASD and predicts better social functioning 1.5 years later.9 Despite the well-documented role that monitoring faces of conspecifics plays in socio-cognitive development, the brain mechanisms underlying such deficits in ASD are unknown and treatments typically focus on ameliorating symptoms rather than addressing underlying causes. Considering that signs of atypical attention to faces are evident by 6 to 9 months in infants later diagnosed with ASD both in laboratory1-3, 10 and real-world environments, 11-13, [Preliminary Study (PS#1)], we hypothesize that the neural foundations for these impairments are already reflected in functional brain organization (the connectome) at birth. Attentional functions in the brain are subserved by the Salience Network (SN), the Executive Control Network (ECN), and the Default Mode Network (DMN), all of which have been implicated in ASD,14-16 and have been found to be atypical in newborns at risk for ASD due to non-familial factors (PS#2). Here we propose to examine whether, when compared to unaffected high-risk (HR) and low-risk (LR) newborns, HR newborns who, at 24 months, meet criteria for ASD exhibit abnormal strength of functional connectivity within the three networks. We will also examine whether the strength of functional connectivity in the three networks at birth is predictive of later performance on a selective social attention (SSA) eye-tracking task at 6 and 24 months and severity of autism symptoms at 24 months. By targeting neonates, we plan to investigate properties of attentional networks known to be affected in ASD14-16 before they are shaped extensively by extra-uterine experience. To achieve these aims, we propose to study 120 neonates who have an older sibling with ASD (HR) and 30 neonates without familial history of ASD (LR). The neonates will undergo a resting-state functional connectivity MRI (rs fcMRI) at 42-44 post-menstrual weeks and at 6 and 24 months will be administered the SSA task. Performance on this task discriminates between ASD and non-ASD groups during prodromal stages of the disorder in high-risk siblings of children with ASD,1 in clinic-referred toddlers newly diagnosed with ASD,17 and in school-age children (PS#3) and shows strong associations with autism symptom severity5 (PS#3). Diagnostic assessment will be completed at 24 months through which severity of autism symptoms and diagnostic grouping will be determined. The project advances integration of psychological and brain science in autism by investigating whether functional brain organization in ASD is altered at birth and, if so, how this disruption affects social development in infants at risk for ASD.

One of the markers of autism spectrum disorders (ASD) in infants and toddlers is impaired selective attention to faces1-6 (Preliminary Study, PS#1). This impairment diminishes their ability to learn from and interact adaptively with others in real-world environments.7 Attentional selection in the social domain relies, in part, on one?s ability to encode reward values of people and store these values in long-term memory as stable values.8- 10 The ?stable? values (henceforth, ?values?) are learned over the course of repeated learning opportunities, and once acquired, they are signaled rapidly, preferentially directing gaze to encoded faces of importance (high- value, HV) based on their hedonic or informative properties in the past.11 Automatic responses based on values stored in long-term memory are essential for survival when decisions have to be made rapidly (e.g., mother versus stranger). Learning about values is subserved by the reward learning system in the brain involving basal ganglia (BG) circuitry.11 This circuitry is implicated in the pathophysiology of ASD12, 13 and extant evidence suggests that individuals with ASD exhibit specific impairments in learning the reward value of social stimuli such as faces.14 (PS#2) Based on this evidence, we propose that limited attention to faces in toddlers with elevated autism symptoms (ASD+) is, in part, driven by impaired value learning in the social domain, affecting their ability to rapidly and preferentially select HV faces and ignore low-value (LV) faces in the complex real-world environment. Consequently, they exhibit diminished spontaneous attention to faces in general, and when they look at faces, they may distribute their limited attentional resources between high- (e.g., mother or therapist) and low-value (stranger) individuals in a trial-and-error fashion. We further hypothesize that reinforcing attention of children with ASD+ toward specific faces through social value training (SVT) will increase their attention to these faces in real-world environments. Here we propose to test a novel SVT in the ASD+ group at 18 months (n=48). In the proposed pilot study, ASD+ toddlers will undergo SVT using a gaze-contingent eye-tracking paradigm. SVT will be administered over a two-day period and the training effects will be assessed by changes in visual attention to HV faces as compared to LV faces between baseline, post-baseline (day 3), and a long-term follow-up (1 month) using two tasks: a laboratory selective attention (LSA) task and real-world selective attention (RWSA) task. We will also evaluate acceptability and feasibility of the value training and contribution of sex, nonverbal developmental level, and severity of autism symptoms to response to the training. Taking advantage of the overlapping cohorts between Projects 1 (neonatal imaging) and Project 5, we will examine if characteristics of resting-state functional connectivity at birth predict response to training in the ASD+ toddlers. To our best knowledge, this is the first study to directly target a marker for ASD by engaging the reward learning system and to evaluate functional integrity of neonatal connectome as a potential predictor of response to training at 18 months.

SUMMARY Autism Spectrum Disorder (ASD) is characterized by social impairments and restricted and repetitive behaviors. Those with a genetic liability for social deficits, including individuals with ASD and their unaffected relatives are also at high risk for internalizing and externalizing conditions. The presence of comorbid affective and behavioral conditions impairs adaptive functioning, increases family stress, and is associated with psychiatric hospitalizations and residential placement. Identification of risk factors for internalizing and externalizing disorders amongst young children with ASD and their siblings would improve diagnostic practices and promote implementation of preventative and early interventions. Extensive research in the general population indicates that precursors of internalizing and externalizing disorders can be identified in the first two years of life as indexed by elevated or attenuated levels of Emotional Reactivity (eReactivity), or intensity of emotional reactions in response to internal or external triggers. Extant, albeit limited, evidence suggests that toddlers with ASD and their unaffected siblings exhibit atypical eReactivity profiles both on the behavioral and physiological levels, though the evidence is incomplete and both their origins and the links with later psychopathology are largely unknown. To fill this gap, we propose to prospectively examine the development of eReactivity from 4 to 30 months in 150 younger siblings of children with ASD, who, due to familial factors, are at high risk for developing ASD (HR) and 30 low-risk (LR) siblings. We plan to examine eReactivity to real- world triggers aimed to elicit fear, anger, and joy, and to evaluate the effects of the social and nonsocial nature of the triggers on eReactivity across the three emotions using a state-of-the-art multi-method behavioral and physiological approach. Aim 1 will evaluate prospectively whether the HRASD group (siblings with ASD), HRATP (siblings with developmental challenges), and HRTD (siblings without developmental challenges) are characterized by distinct patterns of eReactivity to social vs nonsocial triggers as measured by behavioral and physiological indices between 4 and 30 months compared to the LRTD group. The aim will clarify if differential emotional reactivity to social and nonsocial triggers constitutes an emerging characteristic of the autism phenotype in ASD. Aim 2 will examine predictive relationships between development of eReactivity in infancy and severity of internalizing and externalizing symptoms at 30 months. Identification of early predictors of internalizing/externalizing problems will facilitate access to early interventions aimed at amelioration of behavioral and emotional challenges. Consistent with the Research Domain Criteria research framework recommendations, the project (1) employs multiple levels of analysis, (2) investigates negative and positive valence systems as well as arousal systems, and (3) examines a spectrum of ASD risk with long-term goals of improving diagnostic precision in ASD and enabling discovery of novel treatment targets and interventions both during prodromal and early syndromal stages of the disorder.