An fMRI investigation of propagated intrinsic activity in early development and autism

描述（由申请人提供）：自闭症谱系障碍（ASD）构成了一组异质性的神经发育障碍，其特征是社交功能受损、重复行为和兴趣范围受限。大约每88人中就有1人患有自闭症，而且发病率似乎还在上升。在ASD中，在适应功能、认知和语言能力以及神经合并症方面存在广泛的表型异质性，导致许多人将这些不同的疾病称为“自闭症”。因此，出现了两个关键问题：(1)尽管存在表型和遗传异质性，ASD是否具有共同的神经生物学特征？(2)这些神经生物学特征能否在人体体内进行研究？这些问题的答案将代表着我们对自闭症谱系障碍的理解，以及我们诊断和治疗这种疾病的能力向前迈出了重要的一步。我们最近开发了一种基于映射传播的内在大脑活动的静息状态fMRI数据分析新技术。当应用于高功能成人ASD的fMRI数据时，新方法在检测局灶性脑异常方面似乎比传统的功能连接分析更敏感。该项目的目标是将这项新技术应用于收集的年轻，典型发育中的儿童以及患有ASD的儿童的功能磁共振成像数据。初步结果表明，我们的方法在组水平上检测到6个月大的儿童内在活动的时间结构的变化，这些儿童随后发展为临床ASD。这一发现与最近的尸检病理学证据一致，即自闭症谱系障碍患者在生命早期，甚至可能在子宫内就出现了皮层组织紊乱。内在活动的时间结构、神经元可塑性和早期大脑发育之间的密切关系为这一研究提供了强有力的理论基础。需要研究的具体问题包括：(1)在群体水平上，ASD儿童的传播性内在活动模式与正常发育儿童不同的最早年龄是多少？(2) ASD在不同的年龄是否会影响不同的大脑区域？这些问题的答案可能阐明自闭症谱系障碍的神经生物学基础。通过调查ASD的原因和发展轨迹，我们的项目直接符合NIMH战略计划的前两个目标。我们还将探讨在典型的早期发育过程中传播的内在活动模式是如何变化的，以更好地理解正常发育里程碑的神经相关性。正常发育的特征可以为未来其他神经发育障碍的研究提供信息。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) constitute a heterogeneous group of neurodevelopmental disorders characterized by impaired social-communication function, repetitive behaviors, and a restricted range of interests. ASD affects approximately 1 in every 88 individuals and the incidence appears to be rising. Within ASD, there exists wide phenotypic heterogeneity in adaptive function, cognitive and language abilities, and neurological comorbidities, leading many to refer to these various disorders as 'the autisms'. Therefore, two key questions emerge: (1) Despite phenotypic and genetic heterogeneity, does ASD have common neurobiological signatures? (2) Can such neurobiological signatures be studied in vivo in humans? Answers to these questions would represent a significant step forward in our understanding of ASD, as well as our ability to diagnose and treat this condition. We have recently developed a new technique for the analysis of resting state fMRI data based on mapping propagated intrinsic brain activity. When applied to fMRI data obtained in high-functioning adults with ASD, the new method appears to be more sensitive than conventional functional connectivity analysis in detecting focal brain abnormalities. The objective of this project is to apply this new technique to fMRI data collected in young, typically developing children, as well as children who develop ASD. Preliminary results indicate that our method detects changes, at the group level, in the temporal structure of intrinsic activity in 6-month-old children who subsequently develop clinical ASD. This finding is consistent with recent post-mortem pathology evidence of disrupted cortical organization in individuals with ASD very early in life, perhaps even in utero. The intimate relationships between the temporal structure of intrinsic activity, neuronal plasticity, and early brain development provide a strong theoretical basis for this investigation. Specific questions to be investigated include: (1) what is the earliest age at which patterns of propagated intrinsic activity in childre with ASD differ, at the group level, from typically developing children? (2) Are different brain regions affected by ASD at different ages? Answers to these questions may illuminate the neurobiological basis of ASD. By investigating the causes and developmental trajectory of ASD, our project is directly in line with the first two objectives of the NIMH strategic plan. We will aso explore how patterns of propagated intrinsic activity change over the course of typical early development to gain a better understanding of the neural correlates of normal developmental milestones. Characterization of normal development could inform future investigations of other neurodevelopmental disorders.