Pathogenic insight into ASD from the study of neonatal brain-behavior transitions

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Project Summary/Abstract The goal of this Mentored Research Scientist Development Award (K01) is to promote an independent research career by bridging the candidate's training in infant development and pediatric neuroimaging with innovations in biomedical imaging, advances in statistical methods for longitudinal data analysis, and cutting- edge clinical science.  The candidate's short-term goal is to identify changes in the brain that accompany transitions in social behavior in typical infancy and disruptions thereof in ASD. This work is motivated by a recent finding that preferential attention to the eyes of others—a basic mechanism of social adaptive action in typical infants—was not immediately diminished in infants later diagnosed with ASD. Instead, infants later diagnosed with ASD 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 coincides with a developmental transition, around month 2, in which typical infants are thought to move from experience-expectant mechanisms of social adaptive action (that is: subcortically- mediated, `reflex-like' behaviors) to experience-dependent ones (i.e., cortically-mediated voluntary actions that build iteratively on new experiences). This theoretical account suggests a specific hypothesis in ASD: reflex- like adaptive action may initially be present, while the emergence of experience-dependent voluntary social adaptive action subsequently fails. This study will test this hypothesis by measuring, from birth to 6 months in infants at low and high-risk for ASD,: 1) the decline of reflex-like predispositions and the emergence of voluntary behaviors (eye-looking and social smiling, measured by eye-tracking and parent-infant interaction); and 2) developmental change in subcortical and cortical networks (measured by fMRI and DTI) and their relationship to unfolding behavior. To achieve these aims, the candidate will receive training in 5 areas: 1) phenotypic assessment of infants at low and high-risk for ASD; 2) advances in eye-tracking technology that optimize data acquisition in neonates; 3) innovations in biomedical imaging for improving acquisition and pre- processing of infant neuroimaging data; 4) analysis of infant resting-state fMRI and DTI data; and 5) breakthroughs in statistical methods for the analysis of infant longitudinal data. The training plan is supported by a multidisciplinary team of mentors—including Drs. Ami Klin, Warren Jones, John Pruett, Gordon Ramsay, and Xiaoping Hu—and the strengths of two centers within Emory: the Marcus Autism Center, one of only three NIH Autism Centers of Excellence, providing groundbreaking research and clinical care for individuals with ASD, and the Biomedical Imaging Technology Center, a center for cutting-edge biomedical imaging research. The intersection of these strengths provides an ideal training environment for promoting the candidate's long- term goal of understanding the pathogenesis of ASD and informing intervention.