Developmental social neuroscience meets public health challenge: The next generations of children with autism spectrum disorder th Annual Autism Spectrum Disorder Update: Autism Through the Life Span Palo Alto, California, March 7 8 Ami Klin, PhD Director,, Children s Healthcare of Atlanta Georgia Research Alliance Eminent Scholar Professor & Chief, Division of Autism, Department of Pediatrics, Emory University School of Medicine Emory Center for Translational Social Neuroscience Thank You: The children and families for their participation in our research. Co-everything in eye-tracking research: Warren Jones. Autism Navigator research: Amy Wetherby & Jennifer Stapel-Wax My wonderful clinical science colleagues, Cheryl Klaiman, Kasia Chawarska, Celine Saulnier and others over the years My wonderful colleague investigators, Gordon Ramsay, Sarah Shultz, Longchuan Li, and our wonderful students and trainees over the years NIHMH, NICHD, The Marcus Foundation, JB Whitehead Foundation, The Simons Foundation, Georgia Research Alliance, Autism Science Foundation, Children s Healthcare of Atlanta Foundation, Cox Foundation Warren Jones, PhD : Addressing the needs of children and families today; building a better future for the next generations Reciprocal Social Interaction & Early Brain Development Universal Principle: the Platform for Development of Social Brain Born to Socially Orient Reciprocal Social Interaction Neuroplasticity WHITE MATTER DEVELOPMENT
Autism: Unlike in normative development, predispositions to orient to, and engage with people are significantly reduced. Developmental Trajectories Developing expertise about the Social World Developing expertise about the Physical World ASD symptoms RESULT from deviations from normative socialization Attention to Biological Motion GENETIC MECHANISMS OF SOCIALIZATION BEHAVIORAL LIABILITY SYMPTOMS not significantly different from chance, p Jones et al. (8). Arch Gen Psy, 6(8), 96-; Klin et al. (9). Nature, 9, 7-6; Jones & Klin (9). J Am Acad of Child Psy, 8(): 7-; Jones & Klin (). Nature,, 7-; Klin et al. (). Neurosci Biobehav Rev,, 89-; Constantino et al. (7). Nature, 7, -. Non-verbal mental-age Verbal mental-age match Klin A & Jones matched W. (8). control Dev Science, : -6.
Attention to Biological Motion Preference in Autism Only When Clapping Happens Typically- Developing Children Developmentally- Delayed Children Children with Autism Klin A & Jones W. (8). Dev Science, : -6. Klin, Lin, Gorrindo, Ramsay, & Jones, Nature, 9. Cumulative Audiovisual Synchrony Relative Audio-Visual Synchrony = Normalized Peak Difference Clap Location Max Synchrony Pat-a-cake Inverted Upright Feeding No Synchrony Inverted Upright
How do -year-olds with autism watch the face of a caregiver? Eye: F,6 =.87, p<. d =.6 Mouth: F,6 =.99, p<.6 d =. Jones, Carr, Klin (8). Arch Gen Psychiatry. 6(8):96-. Eye-tracking measures of Social Visual Engagement Typically-Developing -Month-Old Jones & Klin (). Nature.
Growth Charts: of Social Visual Engagement Attention to eyes is present but in decline in 6-month-old infants later diagnosed with autism First Replication Cohort Warren Jones,, & Ami Klin,, TD, N=6 ASD, N= Fixation Time (%) Change in Fixation (% per month) 7 6 - - Jones & Klin, Nature,. mean 9% CI 6 9 8 Age (in months) 6 9 8 Age (in months) TD eyes ASD eyes Dt TD eyes Dt ASD eyes First Replication Cohort Eye Fixation in the first 6 months of life TD, N=6 ASD, N= ASD, N= Fixation Time (%) Change in Fixation (% per month) 7 6 - - mean 9% CI 6 9 8 Age (in months) 6 9 8 Age (in months) TD eyes ASD eyes ASD eyes Dt TD eyes Dt ASD eyes Dt ASD eyes Markers of ASD in the first 6 months of life Predictive of individual child s diagnostic classification at outcome (-6 months) Internal and external validation of results
Predicts level of disability at outcome How to link these quantifications of behavior to the genetic bases of autism? Measuring the genetic structure of social visual engagement John Constantino, MD toddlers: 8 monozygotic twins ( pairs) 8 dizygotic twins ( pairs) 8 non-sibling comparison children ( non-sib control pairs) age.(.) months non-sibs matched < day Decline in eye fixation (- through - months) predictive of outcome levels of ASD severity at 6 months Constantino et al. Nature, 7; 7(766):- The genetic basis of Social Visual Engagement Concordance in social visual engagement as a function of zygosity. Nature, 7; 7(766):-
Individual variation in eye-looking is strongly influenced by genetics. Chance Age and sex Partially shared genotype Fully shared genotype a b c d e Non Siblings Randomly Paired N = pairs Non Siblings Age, Sex Matched Twin Pairs Twin Pairs N = pairs N = pairs N = pairs ICC Values Child, Child, Twin, Twin, Child, Child, Twin, Twin, f g h i j...6.8 ICC Nature, 7; 7(766):- Strong genetic influence persists across development. a b c d Child, 7 Randomly Matched Child, (N=, N=) 8 Child, Fixation Time (%) 7 8 Child, Fixation Time (%) Twin, Twin, Twin, Fixation Time (%) 8 7 Twin Pairs Twin, Twin, 7 8 Twin, Fixation Time (%) Twin, Twin, Twin, Fixation Time (%) Twin Pairs Twin, e f g h 8 7 Twin, Twins tested i again months j later, at 6 months. k l 7 8 Twin, Fixation Time (%) ICC Values...6.8 ICC...6.8 ICC...6.8 ICC Genetic influence persists whether twins watch the same or different videos. Twin, Twin, Child, All Videos Twin, Twin, Child, Twin, Twin, Child, Same Videos Twin, Twin, Child, Twin, Twin, Child, Different Videos Twin, f g h i Twin, k Age-, Sex-Matched l m n Child, Twin, Eyes (Normalized) Twin, Eyes (Normalized) Child, Eyes (Normalized) Twin, Dyadic Twin, Triadic Different Mutual Gaze Peer Content Interaction Twin Twin Twin & Twin Twin OR Twin Different Same Videos Videos Categories All Videos a b c d Different Content Categories Twin, Eyes (Normalized) Twin, Eyes (Normalized) Child, Eyes (Normalized) e j o ICC Values...6.8 ICC...6.8 ICC...6.8 ICC Presentation order Figure of video Monozygotic stimuli () was twins randomized, exhibit high twin-twin so each concordance twin saw in eye-looking, separate whether watching the same or different video stimuli, videos, the majority evidence of of which active were niche-picking the same in the goal-directed (M(SD)=86.(9.)%) seeking of social information. but some a-d, of Paired measures of eye-looking in twins for (a) all video stimuli presenting dyadic interaction, (b) measures collected when both twins watched the same dyadic interaction videos, (c) measures collected when each which were different twin watched (.6(9.)%), different dyadic seen interaction by videos, only or one (d) measures among collected the pair. when each twin watched different content categories, showing either dyadic caregiver interaction (twin ) or triadic peer interaction (twin ). See Extended Data Figure 6 for examples of video stimuli. e, Intraclass correlation coefficients and 9% confidence intervals for a-d. f-j, Measures in twins for the same comparisons as in (a-e). k-o, Measures in age- and sex-matched non-siblings for the same comparisons as in (a-e). Dyadic Mutual Gaze Stimuli Dyadic Mutual Gaze Stimuli Triadic Peer Interaction Stimuli P e- e- e- e- e- Lightness a b c d P e- e- e- e- e- Color Opp Red-G Color Opp Red-G Triadic Peer Interaction Stimuli Lightness k Twin : l m n k l m n - - i j - Lightness a b c d Twin : P i j s t Lightness Color Opp Red-G Color Opp Red-G
Genetic influence exerts effects on a moment-by-moment basis. 9 twins are more likely to vs. Change in Twin s Probability of Making Saccade (%) Time (sec) c d e 6 6 Time Before/After Twin s Saccade (msec) 6 6 6 6 Time Before/After Twin s Saccade (msec) f g h 9% CI 9% CI vs. Change in Twin s Probability of Initiating Saccade (%) Time Before/After Start of Twin s Saccade (msec) 9% CI 9% CI 6 6 Time Before/After Start of Twin s Saccade (msec) a X Position Y Position b X Position Y Position c d e vs. Change in Twin s Probability of Making Saccade (%) twins are more likely to Change in Twin s Probability of Initiating Saccade (%) 6 6 Time Before/After Twin s Saccade (msec) f g h vs. - 6 6 Time Before/After Start of Twin s Saccade (msec) i j k l % Within +/- twin twin - 6 7 8 9-6 7 8 9 twin twin - 6 7 8 9-6 7 8 9 Time (sec) vs. chance.7. Distance at Saccade Initiation 9 6 6 - -6-9 Difference in Saccade Direction 6 6 Time Before/After Twin s Saccade (msec) 6 6 Time Before/After Start of Twin s Saccade (msec) chance chance +/-8 +/-8 m n o eyes 9% CI 9% CI 9% CI 9% CI - - 9 6 6 - - -6-9 Difference in Saccade Direction eyes move their eyes at the same moments in time. p Z Score vs. eyes mouth eyes mouth move their in the same directions. Z Score (Colocated Fixations Relative to Chance) mouth Z Score mouth
twins are more likely to The markers of social visual engagement that are most highly heritable m n o p Z Score Eyes vs. Mouth Z Score (Count of Colocated Fixations Relative to Chance) eyes mouth eyes mouth eyes mouth eyes mouth fixate on the same semantic content at the same moments in time. Z Score eyes mouth eyes mouth eyes mouth eyes mouth 9 The markers of social visual engagement that th are most highly heritable Classification of ASD Comparison Cohort.8 are also those that most clearly distinguish.6 typically-developing children from those with autism. TD Cohort:,, non-siblings (N =, ) ASD Comparison Cohort (N =, ) ASD Replication Cohort (N =, ) True Positive Rate True Positive Rate.8.6.. AUC =.88 (.8-.9)...6.8 False Positive Rate.. TD Cohort: Density Distribution Percentiles th th th th Empirical Fitted 9% CI ASD Replication Cohort AUC =.86 (.8-.9)...6.8 False Positive Rate Empirical Fitted 9% CI TD Cohort:,, non-siblings (N =, ).8 are also those that most clearly distinguish.6 typically-developing children from those with autism.. Empirical Fitted 9% CI. AUC =.88 (.8-.9)...6.8 ASD False Comparison Positive Rate Cohort ASD Comparison Cohort (N =, ) ASD Replication Cohort ASD Replication Cohort.8 (N =, ) The markers of social visual.8.6 engagement that.6. Empirical Fitted are most highly heritable 9% CI.. Empirical Fitted AUC =.88 (.8-.9) 9% CI....6.8 False Positive Rate AUC =.86 (.8-.9) Classification of...6.8 ASD False Replication Positive Cohort ASD Replication Cohort Rate (N =, ) TD Cohort:,, non-siblings (N =, ) ASD Comparison Cohort (N =, ) True Positive Rate True Positive True Positive Rate Rate TD Cohort: Density Distribution Percentiles are also those that most clearly distinguish typically-developing children from those with autism. True Positive Rate.8.6.. th th th th 9 th TD Cohort: Density Distribution Percentiles ASD Comparison Cohort th th th th 9 th Empirical Fitted 9% CI AUC =.86 (.8-.9)...6.8 False Positive Rate
Hundreds of natural experiments within a -minute free viewing video experiment high Heritability (eye- & mouth-looking) + high Probability (shifting eyes at same moments, in same directions, towards same content) = profound influence on human biological niche construction In ASD: ~7 divergences in minutes of video ~,68 divergences in a -hour period of real-life social experience 6 hour social exposure/day results in ~,, divergences over the course of one year of real-life exposure to social environments Scarr & McCartney, 98. TD normative funnels = ASD comparison scanpaths = Translational Opportunities Public Health Opportunities High-throughput, low-cost, deployment of universal screening in the community Early detection, early intervention, optimal outcome Prevention or attenuation of intellectual disability in ASD Support a system that does not have sufficient expert clinicians A new, promising view of autism, with universal design implications Genetic influence informs modality of early treatment Reduce the child, family, health, education, and societal costs of autism
Massive Challenge - Massive Opportunity 6, children born every year will have autism (:68); societal cost of autism is $6B/year in US alone; early detection and intervention is a game changer (NIH) A cohort of children with autism followed from birth reaching years of age without developmental delays: diversity, not disability 7, children with autism in schools; annual cost $7B/year; median age of diagnosis of autism in the US:. -. years 6,6, special education children (% of all students); 9% with autism; % language impairment; % with developmental delays or intellectual disability These are all conditions originating in disrupted early brain development due to genetic, medical or environmental vulnerabilities Maybe ~% are inevitable ; in ~9%, burdens can be significantly attenuated if not prevented altogether Neurodevelopmental Medicine of the st century: optimizing outcomes Developmental Social Neuroscience meets Public Health Opportunities We are genetically programmed to be social beings This programming is altered in autism But social experiences are co-created by environment We can engineer these experiences via parent-delivered treatment Augmenting Access to Early Treatment Family Primary Care Physician Amy Wetherby, PhD Early Intervention Provider Jennifer Stapel- Wax, PsyD www.autismnavigator.com www.firstwordsproject.com
the Community: Families, Pediatricians, Early Intervention Providers Treating deviations from normative social engagement: Parent- Delivered Social Interaction Parent-Delivered Early Social Interaction Amy Wetherby, PhD Wetherby et al., 6 Universal design because there is only one platform for early brain development Pediatric Medicine of the st century: The criticality of Public Health considerations For children with complex genetic burden: Autism, Williams syndrome For children with compromising medical conditions: Extremely Preterm, Congenital Heat Disease For children from disadvantaged backgrounds Not necessarily curing diseases BUT OPTIMIZING OUTCOMES Universal screening, accessing identification, increasing access to early intervention Cost-effective, community-viable Value Proposition!
Dr. Jack Shonkoff Dr. David Willis Dr. Brenda Fitzgerald Take Away Messages - Autism is a massive public health challenge and an enormous public health opportunity Children s lifetime outcomes can be optimized with Early Detection, Access to Diagnostic Services, Access to Early Intervention The greatest burdens of autism are not inevitable and be significantly ameliorated Intellectual Disability, Language Disability, Severe Behavior Challenges What moves early brain development is reciprocal social engagement, and early experiences shape the trajectories of social and communication skills and social-communicative brain Infants & toddlers create their own social environment: these behaviors are under stringent genetic control and disrupted (and diagnostic) in the case of young children with autism Take Away Messages - But we can engineer social learning experiences via manipulation of children s environment - via parent-delivered treatments We need cost-effective and community-viable solutions for Universal Screening, Diagnosis, and Early Treatment Solutions for screening and diagnosis are not far off Solutions for early treatment are being studied at a grand scale right now Solutions for optimizing the development of children with autism are relevant to a much broader group of children The future of neurodevelopmental medicine is likely to be focused on optimizing the outcome of children born with genetic, medical or environmental challenges rather than on the cure of these complex conditions
Our ultimate goal: To change the narrative of autism To make autism an issue of diversity, not of disability