A longitudinal study of brain development in children with autism

 描述（由申请人提供）：我们的实验室观察到自闭症谱系障碍（ASD）儿童的静息状态（RS）和听觉神经活动异常。这些发现有一个临床组成部分，RS和听觉脑节律预测症状的严重程度。有一个发展/成熟的组成部分，与年龄的横断面研究结果表明，更大的临床功能障碍的儿童ASD与RS和听觉过程的成熟最延迟。最后，有一个结构组件，我们的分析表明丘脑参与RS和听觉神经异常。鉴于丘脑在调节和协调神经活动中的核心作用，了解丘脑结构和丘脑皮质连接对ASD皮质振荡异常的贡献具有重要意义。这一拟议的R 01将证明ASD的神经功能障碍和临床症状部分是由丘脑和丘脑皮质结构异常引起的。该提案的主要原则是，了解ASD儿童的脑功能障碍需要评估发育过程，而不是单个时间点（快照）测量。为此，提出了一项三个时间点的纵向研究，在6至8岁的典型发育对照（TDC）和ASD参与者中获得大脑和临床指标，然后在18和36个月后（入组时每组N=70）。假设患有ASD的儿童将显示出大脑节律/模式的较慢发展，变化率（即斜率）而不是单个时间点测量更好地分离TDC和ASD。还假设变化率而不是单个时间点测量将更好地预测功能能力，基线测量显示病理学（例如，听觉处理异常），但变化率指示成功的脑成熟的程度，从而提供更大的预后效用。预计R 0研究结果将通过激发开发“丘脑疗法”的需求来提供概念创新，R 01人类神经和相关的丘脑皮质白质异常将转化为动物模型，并通过动物研究确定潜在的药物治疗。动物研究可能会建立在目前的基因和神经干细胞治疗研究的基础上。髓鞘形成前疗法和图像引导的脑深部电刺激或其他基于目标的神经调节治疗也可能是未来的兴趣。

 DESCRIPTION (provided by applicant): Our laboratory has observed abnormalities in resting-state (RS) and auditory neural activity in children with autism spectrum disorder (ASD). There is a clinical component to these findings, with RS and auditory brain rhythms predicting symptom severity. There is a developmental/maturational component, with age cross-sectional findings indicating greater clinical impairment in the children with ASD with the most delayed maturation of RS and auditory processes. Finally, there is a structural component, with our analyses demonstrating thalamic involvement in RS and auditory neural abnormalities. Given the central role of the thalamus in modulating and coordinating neural activity, understanding the contribution of thalamic structure and thalamocortical connectivity to cortical oscillatory abnormalities in ASD is of high priority. This proposed R01 will demonstrate that neural dysfunction and clinical symptoms in ASD arise, in part, from abnormal thalamic and thalamocortical structure. A primary tenet of this proposal is that understanding brain dysfunction in children with ASD requires assessing developmental processes rather than a single time-point (snapshot) measure. To this end, a three time-point longitudinal study is proposed, with brain and clinical measures obtained in typically developing control (TDC) and ASD participants aged 6- to 8-years and then both 18 and 36 months later (N=70 per group at enrollment). It is hypothesized that children with ASD will show slower development of brain rhythms/patterns, with rate of change (i.e. slope) rather than single time-point measures better separating TDC and ASD. It is also hypothesized that rate of change rather than single time-point measures will better predict functional capacity, with baseline measures demonstrating pathology (e.g., auditory processing abnormalities) but with rate-of-change indicating the degree of successful brain maturation and thus offering greater prognostic utility. It is expected that R0 findings will offer conceptual innovation by motivating the need to develop 'thalamic therapies', with R01 human neural and associated thalamocortical white-matter abnormalities back-translated to animal models, and with animal research identifying potential pharmaceutical treatments. Animal work will likely build on current gene and neural stem cell therapy research. Pro-myelinating therapies and image-guided deep brain stimulation or other target-based neuro-modulation treatments may also be of future interest.