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

项目概要/摘要 这个指导研究科学家发展奖（K01）的目标是促进一个独立的 研究事业的桥梁候选人的培训，婴儿发育和儿科神经影像学与 生物医学成像的创新，纵向数据分析统计方法的进步，以及切割- 边缘临床科学 候选人的短期目标是确定大脑的变化，伴随着 典型婴儿期的社会行为转变及其在ASD中的中断。这项工作的动机是 最近的发现，优先注意他人的眼睛-社会适应行动的基本机制， 在后来诊断为ASD的婴儿中，相反， 诊断为ASD的患者在2个月时表现出轻微但显著的眼睛注视增加，然后下降; 与此相反，典型的婴儿在2个月时表现出眼睛注视的相对低点，然后上升。的 这种差异的时间与发育过渡相吻合，大约在2个月左右，典型的婴儿 认为从社会适应行动的经验预期机制（即：皮层下- 介导的，"反射样"行为）到经验依赖性行为（即，皮层介导的自愿行动， 迭代地构建新的体验）。这一理论解释提出了ASD的一个特定假设：反射- 类似的适应性行动可能最初是存在的，而经验依赖的自愿社会行为的出现， 自适应操作随后失败。这项研究将通过测量从出生到6个月的婴儿， ASD低风险和高风险的婴儿：1）反射样倾向的下降和 自愿行为（通过眼动追踪和亲子互动测量的眼睛注视和社交微笑）; 和2）皮层下和皮层网络的发育变化（通过fMRI和DTI测量）及其 与展开行为的关系。为了实现这些目标，候选人将接受5个方面的培训： ASD低风险和高风险婴儿的表型评估; 2）眼动追踪技术的进展， 优化新生儿数据采集; 3）生物医学成像创新，改善采集和预处理 婴儿神经影像学数据的处理; 4）婴儿静息状态fMRI和DTI数据的分析;以及5） 婴儿纵向数据分析统计方法的突破。培训计划得到支持 由一个多学科的导师团队，包括阿米·克林博士，沃伦·琼斯，约翰·普鲁特，戈登·拉姆齐， 以及埃默里大学内两个中心的优势：马库斯自闭症中心， NIH自闭症卓越中心，为患有自闭症的个人提供开创性的研究和临床护理。 ASD和生物医学成像技术中心，一个尖端的生物医学成像研究中心。 这些优势的交叉点为促进候选人的长期发展提供了理想的培训环境， 长期目标是了解ASD的发病机制并提供干预信息。

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.