Neural mechanisms of sensory reactivity and regulation in autism across development

项目总结/摘要 感觉过度反应（SOR）是一种对刺激极度敏感的损害性疾病 比如大声的噪音或者被触摸。SOR存在于神经发育障碍中，但特别是 在患有自闭症谱系障碍（ASD）的年轻人中普遍存在，比率至少为56- 70%。SOR是一个基础 限制个人参与社区、在学校取得成功、完成日常生活任务的能力， 社交互动。尽管如此，对于SOR几乎没有基于药物的治疗，部分原因是缺乏 了解其潜在的生物学机制。此外，虽然SOR在整个过程中趋于下降， 从青少年到成年，人们对为什么以及为谁而改善的理解很少。因此，主要 本研究的目的是明确SOR的发育过程和神经生物学机制 通过这些手段可以削弱这种影响，这两者对制定干预措施都至关重要。我们的团队进行了一些 第一批确定ASD青年中SOR关键神经机制的研究，包括1）过度反应 初级感觉皮层和杏仁核中的脑反应/降低的习惯化，2）降低的丘脑GABA，和 3)减少前额叶皮层（PFC）-杏仁核功能连接在厌恶的感觉刺激。我们 先前的研究也表明，患有ASD但低SOR的年轻人的亚组表现出杏仁核-前额叶 连接在感官刺激，这表明对SOR的弹性机制。我们的初步 数据还表明，杏仁核对厌恶性感觉刺激的反应性随着年龄的增长而下降， 增大这项建议试图在此基础上，通过研究生物机制， SOR可以通过自然发展或直接干预来减弱，目的是 翻译为治疗。使用组合的横截面和纵向设计，我们将检查： 1)与典型发育（TD）儿童相比，ASD儿童感觉反应的发育变化; 2） 在感觉调节的两个候选神经机制（丘脑GABA和PFC- 杏仁核连接），以及3）两种不同情绪调节策略（注意线索）的相对能力 vs.重新评价）参与感官调节。根据我们先前的研究和初步数据，我们预计 我们看到，行为和神经标记的SOR随着年龄的增长而下降，但这种下降发生在晚于 这是ASD青少年的典型症状，表明感觉调节发育迟缓。我们还希望， 两个候选的自上而下的感觉调节机制，前额叶-杏仁核连接，但没有 丘脑GABA将随着发育而改善，这将使我们了解为什么SOR随着发育而下降。 年龄和如何最好地对待它在不同的发展阶段。最后，我们将比较 注意力提示与重新评估，以使不同年龄和SOR严重程度的青少年参与PFC。结果将直接 为SOR的行为和精神药理学个性化干预提供信息。

PROJECT SUMMARY/ABSTRACT Sensory over-responsivity (SOR) is an impairing condition manifested as extreme sensitivity to stimuli such as loud noises or being touched. SOR is present across neurodevelopmental disorders, but is particularly prevalent in youth with autism spectrum disorders (ASD) with rates of at least 56-70%. SOR is a fundamental limitation to individuals’ ability to participate in the community, succeed in school, complete daily living tasks, and interact socially. Despite this, there are almost no empirically-based treatments for SOR, in part due to the lack of understanding of its underlying biological mechanisms. Furthermore, while SOR tends to decline across adolescence into adulthood, there is little understanding as to why and for whom it improves. Thus, the primary goals of this study are to identify the developmental course of SOR as well as neurobiological mechanisms through which it can be attenuated, both essential to developing interventions. Our team has conducted some of the first studies identifying key neural mechanisms of SOR across youth with ASD, including 1) over-reactive brain responses/reduced habituation in primary sensory cortices and amygdala, 2) reduced thalamic GABA, and 3) reduced prefrontal cortex (PFC)-amygdala functional connectivity during aversive sensory stimulation. Our prior studies also indicate that the subset of youth with ASD but low SOR show heightened amygdala-prefrontal connectivity during sensory stimulation, suggesting a mechanism for resilience against SOR. Our preliminary data also suggest that amygdala reactivity to aversive sensory stimulation declines with age while PFC activation increases. This proposal seeks to build on this foundation by examining biological mechanisms through which SOR may be attenuated either through natural development or through direct intervention, with the goal of proximate translation to treatment. Using a combined cross-sectional and longitudinal design, we will examine: 1) developmental changes in sensory reactivity in ASD compared to typically developing (TD) children; 2) developmental changes in two candidate neural mechanisms of sensory regulation (thalamic GABA and PFC- amygdala connectivity), and 3) the relative ability of two different emotion regulation strategies (attention cuing vs. reappraisal) in engaging sensory regulation. Based on our prior studies and preliminary data, we expect to see that behavioral and neural markers of SOR decrease with age, but that this decline happens later than is typical for youth with ASD, indicating a developmental delay in sensory regulation. We further expect that of our two candidate top-down mechanisms of sensory regulation that prefrontal-amygdala connectivity but not thalamic GABA will improve with development, which will inform our understanding of why SOR decreases with age and how best to treat it at different stages of development. Finally, we will compare the relative ability of attention cuing vs. reappraisal to engage PFC for youth of different ages and SOR severity. Results will directly inform both behavioral and psychopharmacological personalized interventions for SOR.