Brainstem Contributions to Sensorimotor and Core Symptoms in Children with Autism Spectrum Disorder

项目概要/摘要 脑干是一个复杂且早期发育的大脑区域，负责感觉、运动、自主神经， 和生命攸关的功能。自闭症谱系障碍（ASD）的第一个基于生物学的假设表明， 脑干的网状结构可能是ASD症状的根本原因。然而，技术 这些障碍阻碍了该领域能够可靠地表征活体脑干的亚结构 小儿令人兴奋的是，新的技术进步现在使我们能够检查的微观结构特性的 脑干核团和单个白色物质束。这一提议的总体科学前提是， 脑干亚结构可能对整个大脑发育和ASD的基础有着关键的见解。 拟议工作的总体目标是确定特定的白色物质束和核内的 有助于ASD的共病感觉运动和核心症状挑战的脑干， 脑干特性与ASD中涉及的其他大脑区域有关。鉴于脑干的功能， 我们假设脑干亚结构的微结构特性与共病相关， 感觉运动症状和核心社交和重复行为症状与ASD有关。 我们进一步假设，脑干与ASD中的其他脑区明显相关，这是由于脑干的 在大脑早期发育中的作用在强有力的初步数据的指导下，这些假设将通过三个方面进行检验。 具体目标：1）确定脑干亚结构的显微结构与 共病感觉运动症状的个体差异; 2）确定 脑干亚结构与核心社会交流和重复性的个体差异有关， 行为症状;和3）识别脑干亚结构之间的不同对应关系， 大脑周围一个关键的创新是，我们将通过应用扩散加权 磁共振弥散成像（DWI）技术，解决了脑干成像以前的挑战，以提供清晰， 脑干及其亚结构的解剖学精确图像。通过这项技术，我们将量化 对80例6-9岁ASD患儿脑干亚结构（及周围脑）的显微结构进行了观察， 80名年龄匹配的儿童，具有典型的发育。标准化评估将表征感觉运动 和核心症状这项研究的成功完成将提供一个定量表征 脑干亚结构与ASD共病感觉运动特征和核心症状的关系， 将提供ASD中脑干亚结构相对于整体脑指标的定量表征。 这些贡献将是重要的，因为它们将促进对神经生物学基础的理解。 对于ASD，阐明共病感觉运动挑战和核心症状的神经基础 在ASD中，并提供定量生物标志物用作临床试验中的结果测量。

PROJECT SUMMARY/ABSTRACT The brainstem is a complex and early-developing brain region that is responsible for sensory, motor, autonomic, and critical-for-life functions. The first biology-based hypothesis of autism spectrum disorder (ASD) suggested that the reticular formation of the brainstem may be a root cause of ASD symptoms. However, technological barriers have prevented the field from being able to reliably characterize substructures of the brainstem in vivo in children. Excitingly, new technological advances now allow us to examine the microstructural properties of the brainstem's nuclei and individual white matter tracts. The overall scientific premise of this proposal is that brainstem substructures may hold key insights into overall brain development and into the underpinnings of ASD. The overall objective of the proposed work is to identify specific white matter tracts and nuclei within the brainstem that subserve the comorbid sensorimotor and core symptom challenges of ASD and to contextualize brainstem properties in reference to other brain regions implicated in ASD. Given the functions of the brainstem, we hypothesize that the microstructural properties of the brainstem substructures are associated with comorbid sensorimotor symptoms and core social-communication and repetitive-behavior symptoms implicated in ASD. We further hypothesize that the brainstem relates distinctly to other brain regions in ASD, due to the brainstem's role in early brain development. Guided by strong preliminary data, these hypotheses will be tested through three specific aims: 1) Determine extent to which the microstructure of brainstem substructures is associated with individual differences in comorbid sensorimotor symptoms; 2) Determine extent to which microstructure of brainstem substructures is associated with individual differences in core social-communication and repetitive- behavior symptoms; and 3) Identify the distinct correspondence among brainstem substructures and the surrounding brain. A key innovation is that we will accomplish these aims by applying a diffusion-weighted imaging (DWI) technique that addresses the previous challenges of brainstem imaging to provide a clear and anatomically precise image of the brainstem and its substructures. With this technique, we will quantify the microstructure of brainstem substructures (and surrounding brain) in 80 children with ASD (6-9 years old) and 80 age-matched children with typical development. Standardized assessments will characterize sensorimotor and core symptom profiles. The successful completion of this research will provide a quantitative characterization of brainstem substructures in relation to the comorbid sensorimotor features and core symptoms in ASD, and it will provide a quantitative characterization of brainstem substructures in ASD in relation to overall brain metrics. These contributions will be significant because they will advance the understanding of the neurobiological basis for ASD, elucidate the neurological underpinnings of the comorbid sensorimotor challenges and core symptoms in ASD, and provide quantitative biomarkers to be used as outcome measures in clinical trials.