Warren R. Jones, Ph.D. - US grants

The present application builds on recent research in our laboratory in which we collected data, beginning in the first 2 months of life, from infants at high-risk for autism spectrum disorder (ASD). Following confirmatory diagnosis at 36 months, analyses of ASD-positive infants revealed that when looking at an approaching caregiver, from at least 2 months of age, infants with ASD follow a significantly different developmental trajectory from typical peers, with decline in fixation on others' eyes and increased fixation on body and object areas. Longitudinal change in measures of their visual fixation to caregivers was highly correlated with severity of clinical outcome at 24 months. In addition, based only on data collected in the first 6 months of life, measures of their developmental rate of change in looking at others' eyes and bodies predicted diagnostic classification with high sensitivity and specificity. To our knowledge, these are the eariiest known indicators of ASD in the extant literature and mark crucial first steps in advancing our understanding of the developmental pathogenesis of ASD. They also advance our efforts to enable the eariiest possible diagnostic identification of ASD-a critical factor in promoting optimal long-term outcome. The present application will build on these findings to study developmental profiles of social visual engagement as risk indices (Aim 1); as profiles for positive outcome (Aim 2); and as predictors of treatment response in eariy intervention (Aim 3). A cohort of 330 infants will be enrolled in this project, consisting of infant siblings of children with autism who are at High Risk for developing an ASD (HR-ASD, N=230); infants at High Risk for Developmental Delays without familial history of ASD (HR-DD, N=50); and children at Low Risk of developmental delays, with Typical Development expected (LR-TDx, N=50). Data will be collected longitudinally and prospectively, beginning in the first month of life, with confirmatory diagnostic assessment at 36 months. This project directly addresses several of the aspirational goals for autism set forth by the NIH Interagency Autism Coordinating Committee, with emphasis on identification of eariy risk; measures of developmental pathogenesis; and prognostic indicators for treatment and outcome. RELEVANCE (See instructions): Project I of this Emory/Marcus ACE application will identify and refine quantitative, performance-based indices of risk and resilience for social disability, beginning in the first months of life, to test the extent to which these measures of social engagement (in tandem with Project II) predict treatment response and outcome (Project lil). These same constructs and measures are then shared with Projects IV & V to interrogate the genetic and neurobiological underpinnings of species-typical social development.

6. Project Summary / Abstract The goal of this project is to study prospectively the development of social visual engagement in infants with autism spectrum disorders (ASD) by means of eye-tracking technology and innovative quantification of visual attention during viewing of naturalistic social situations. We will measure (1) visual fixation time during viewing of adults engaged in infant-directed approaches, and (2) temporally-sensitive visual scanning patterns during viewing of infants engaged in play. Experimental data will be collected at 2, 4, 6, 9, 12, 18, and 24 months. A cohort of 235 infants will be enrolled in this project, consisting of infant siblings of children with autism who are at High Risk for developing an ASD (HR-ASD, N=135); infants at High Risk for Developmental Delays without familial history of ASD (HR-DD, N=50); and children at Low Risk of developmental problems with Typical Development expected (LR-TDexpected, N=50). Confirmatory diagnostic assessment will take place at 36 months. The primary analyses will focus on comparisons between children who develop an ASD in comparison with DD and TD children. Given the familial nature of ASD and the potential for advancing research on mediating phenotypes, comparisons will also be made between all siblings of children with ASD (entire HR-ASD sample) in relation to the HR-DD and LR-TDexpected groups. This work builds on our findings of anomalous visual fixation patterns to dynamic social stimuli in adolescents (R01 HD04217) and in 24- to 36-month-olds (U54 MH66494, Yale STAART) with ASD. In both cases, summaries of visual fixation on regions of interest (eyes, mouth, body, & object) were strong predictors of concurrent, standardized measures of social disability. Here we extend this work in two ways: (1) we will employ novel group measures of moment-by-moment visual scanning behavior developed by our lab which are particularly sensitive to time-delimited social and physical cues occurring naturally in infants' surrounding environment; and (2) we will quantify the ontogeny of a key mechanism of socialization and its hypothesized derailment in the early pathogenesis of ASD by studying longitudinally a group of infants at greater risk for developing the disorder. We capitalize on a project focused on the detailed clinical characterization of the same cohort (Project 1, PO1 HD003008), and on the conceptual and technological advancements resulting from our continuing studies of young children with ASD (Project 1, P50 HD055726). Our programmatic goals are to (1) study early mechanisms of socialization and the role of these mechanisms in the heterogeneity of syndrome expression in ASD; and (2) to develop performance-based measures capable of predicting developmental and diagnostic outcome and able to serve as screening protocols for infants at risk for ASD. This project addresses several key action items of the NIH Interagency Autism Coordinating Committee, with emphasis on developmental markers and screening in infants, and neurodevelopmental processes. 7. Project Narrative In this project we will map and quantify the unfolding of social visual engagement from 2 to 24 months of age, using measures of visual fixation and visual scanning to study how infants with autism interact with the social world. Through a prospective study of the infant siblings of older children with autism, this project will measure the developmental course of altered social engagement in infants subsequently diagnosed with an autism spectrum disorder. The three goals of this project quantitative diagnostic markers, predictors of outcome, and endophenotypes capable of parsing the heterogeneity of the broader autism spectrum are also key objectives of the NIH Interagency Autism Committee. Like the Committee's action items, this project emphasizes developmental markers and screening in infants, as well as neurodevelopmental processes, and is, therefore, highly relevant to public health.

? DESCRIPTION (provided by applicant): The current project will identify maturational changes in the infant brain that accompany important transitions in social behavior in the first 6 months o life. This work is motivated by a surprising feature of a recent study in which we identified the earliest known indicators of social disability in autism (Jones & Klin, Nature, 2013). The data falsified a prior hypothesis by revealing that eye-looking-a basic mechanism of social adaptive action in typical infants-was not immediately diminished in infants with autism; instead, infants with autism exhibited a slight but significant increase in eye-looking at 2 months, which then declined; in contrast, typical infants exhibited a relative low point in eye-looking at 2 months, which then increased. The timing of this difference highlights a narrow developmental window, around month-2, that spans an important period of dynamic transition in typical infants. At approximately 4-6 weeks, reflex-like neonatal predispositions-including among others: non-social, endogenous smiling1, 2; reflexive imitation3-5; and reflexive attention to faces6-decline. This decline is followed by major changes in infant behavior: after month 2, infants begin to engage in contingent social interaction: they increase time spent looking at others' eyes10,11 and produce socially-elicited smiles during interaction with caregivers2,12,13. The neural mechanisms supporting these critical transitions are thought to be a shift from subcortical to cortical control1,6,8,14-16, with initial reflex- like predispositions (subserved by subcortical structures) declining as cortical control matures. This account appears well-fitted by our eye-tracking data11, and suggests a very specific hypothesis in autism: in infants with autism, reflex-like (subcortically-mediated) orientation to the eyes of others may initially be intact, while the emergence of experience-dependent (cortically-mediated) voluntary eye-looking subsequently fails. Despite the appeal of this proposed model, no studies have prospectively tracked the development of these neural systems and their relationship to unfolding behavior in typical development, a critical step before examining disruptions thereof in autism. In N=50 typical infants we will examine developmental changes in brain connectivity associated with 2 critical transitional behaviors, eye-looking and social-smiling, to identify: (1) brain networks differentialy associated with either decline in reflexive eye-looking or with the emergence of voluntary eye-looking, (2) brain networks differentially associated with either the decline of endogenous, reflexive smiling or with the emergence of socially-elicited smiling, and (3) brain networks common to social adaptive action. Behavioral and neuroimaging measures will be collected longitudinally at 7 and 3 time points, respectively, between birth and 6 months. Brain connectivity will be measured both structurally (as tract- specific diffusion parameters, including fractional anisotropy (FA) and mean diffusivity (MD), via diffusion tensor imaging (DTI) and tractography) and functionally (via measures of resting-state functional connectivity).

PROJECT SUMMARY The present application builds on recent research in our laboratory showing that social visual engagement?the way in which infants visually explore, engage, and ultimately learn from and adapt to their surrounding world? is (1) tightly coupled to genetic variation, with concordance in identical toddler twins equal to 0.91; (2) highly phylogenetically conserved, with infant rhesus monkeys exhibiting patterns of early eye-looking that are strikingly homologous to human infants; and (3) pathognomonically impaired in infants later diagnosed with ASD, with differences observed from at least month 2 onwards in initial and replication cohorts. The present application will build on these findings to study pivotal transitions in early infancy that set the stage for future attainment of social- communicative milestones. We will investigate early infant transitions from reflex-like to volitional social adaptive action in the first 2 months post-partum (Aim 1); the emergence of reciprocal and contingent infant social interaction (Aim 2); and the cascading consequences of very early infant social engagement?or the disruption thereof in ASD?on later, long-term social-communicative outcomes (Aim 3). Finally, we will connect these measures to concomitant changes in developing structural and functional brain networks (in Projects III and V), to the emergence of spoken communication (in Project II), and to response to early social interaction therapy (in Project IV). A cohort of 250 infants will be enrolled, consisting of infant siblings of children with autism who are at High Risk for developing ASD (HR-ASD, N=150) as well as infant siblings at Low Risk of developmental delays, with Typical Development expected by virtue of having no familial history of ASD (LR-TDx, N=100). Data will be collected longitudinally and prospectively, beginning in the first week after birth. This project directly addresses several of the aspirational goals for autism set forth by the NIH Interagency Autism Coordinating Committee, with emphasis on understanding the unfolding developmental trajectories, underlying mechanisms, and biological signatures of ASD.

PROJECT SUMMARY/ABSTRACT This project builds on recent research in our laboratory that showed for the first time that genes directly shape the way a child sees the world: what a child spends time looking at?as well as how, when, and where she looks?are all strongly influenced by genetic variation (Constantino et al, Nature, 2017). Identical twins, who share the same genetic variation, effectively synchronize their looking to social content. Moreover, these same measures of social looking are markedly and differentially decreased in children with autism spectrum disorder (ASD) (?2= 64.03, P < 0.0001). In the current project, we will measure genetic and environmental influence on social visual engagement and brain growth from birth through toddlerhood, quantifying effects of gene- environment transactions over time. We will use eye-tracking to measure how infants look at the social world and MRI to measure changing brain connectivity under conditions of controlled genetic variation: identical & fraternal twins followed from the first week after birth. We will enroll 240 twins (120 pairs), collecting eye- tracking data at 10 time points, neuroimaging data at 5 time points, and standardized assessments of social- communicative competency at 3 time points. This application will test the hypothesis that gene-by- environment-by-age transactions in the first years of life serve as a powerful developmental canalizing mechanism, a mechanism capable of providing the necessary shared medium for typical social development, and yet equally capable of channeling diverse initial liabilities off-course, into atypical social development resulting in the syndromic social disability called autism spectrum disorder. By quantifying the developmental timing of gene-environment transactions, together with their impact on phenotypic presentation of social behavior and brain growth, this project will provide insights into modifiable behavioral pathways that offer the greatest therapeutic potential to prevent or preempt the emergence of deleterious consequences of atypical development as found in ASD and other neurodevelopmental disabilities.

PROJECT SUMMARY This project is in response to NIMH RFA-MH-19-120 calling for the development and validation of new screening methods for autism spectrum disorder (ASD) that can be used in infancy (0-12 months of age). We will deploy a cost-effective, high-throughput methodology utilizing performance-based, objective, and highly quantitative eye- tracking assays of social visual engagement?the way in which infants visually explore, engage, and ultimately learn from and adapt to their surrounding world?collected on a standalone, mobile eye-tracking data collection device, created in our lab (the Marcus Autism Center Investigational Device, MAC-ID). We will collect eye- tracking data from a population-based sample of N=2,000 9-month-old infants recruited consecutively in primary care practices at the time of their 9-month well-child visits. These infants will be followed longitudinally from 9 until 26 months for completion of a series of sequential screening and clinical ascertainment procedures designed to maximize sensitivity and achieve clinician-best-estimate diagnostic assignments of ASD vs. non- ASD and Affected [including ASD and non-ASD developmental delays] vs. Unaffected. We will measure the accuracy of eye-tracking-based screening at the age of 9 months relative to clinician best estimate diagnosis at 24 months (primary analysis), and we will measure dimensional agreement between eye-tracking assays at 9 months relative to outcome levels of social disability, verbal ability, and nonverbal cognitive ability (secondary analyses). Our overarching goal is to develop high-quality, objective, performance-based tools that can function as an effective and community-viable means of screening for ASD and other actionable developmental delays in infancy, to ultimately facilitate improved access to and benefit from early intervention.