Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine

项目摘要 本研究的目的是针对神经生物学基础的限制和重复行为（RRB）， 自闭症谱系障碍（ASD）儿童使用N-乙酰半胱氨酸（NAC），一种耐受性良好的营养 补充剂和代谢能调节剂，其最近已显示出降低RRB严重性功效 初步审判。这个职业发展奖的目标是学习理论原则， 质子波谱（1H MRS）和脑电图（EEG）的实际应用技术 神经发育障碍儿童的方法，学习临床试验方法并培养技能 在对照试验中检查治疗效果，并学习先进的统计建模技术， 评估儿科人群中复杂的治疗相关结局。最终的总体目标是 支持一个有前途的早期职业调查员过渡到一个独立的研究职位。实现 为了实现这些目标，我们将（目标1）从表现出严重RRB的ASD儿童中获取1H MRS和EEG数据， 检查NAC在单次给药中调节皮质-纹状体回路（CSC）中兴奋性信号传导的能力 激发研究（NAC和安慰剂）。我们还将（目的2）在一项研究中检查NAC改善RRB的疗效。 12-周随机对照试验和（目的3）评估神经生物学措施的能力，兴奋性 信号（1H MRS和EEG）来预测治疗反应。CSC是一个突出的治疗目标，因为CSC 在ASD小鼠模型中，RRB与ASD儿童的RRB严重程度有关。 在患有ASD的儿童/成人中也报告了CSC区域中的兴奋性信号传导改变，并且大多数 重要的是，NAC可以调节CSC区域中的谷氨酸能信号传导。因此，兴奋性（即兴奋性） ASD患者CSC中的信号传导可能导致RRB的严重程度，至少对某些个体而言， NAC可能会带来一些临床益处，特别是对于基线水平升高的儿童。我们预计 接受NAC治疗的ASD儿童在1H MRS和EEG测量中表现出更大的降低， 与接受安慰剂的儿童相比，这将与更大的 与安慰剂相比，NAC治疗12周后RRB严重程度降低。我们预计 基线测量也将能够准确预测哪些儿童对NAC有反应，并将探索 NAC对不同亚型RRB的作用可能与不同的神经生物学改变有关。的 这项研究的结果将支持NAC治疗RRB的疗效，并阐明 NAC介导的改善的作用机制。这一点特别重要，因为 目前没有针对ASD核心症状（包括RRB）的药物治疗，严重RRB与 适应性学习的管理挑战和障碍。通过这次培训，我计划开发一个程序化的 一系列研究旨在确定ASD儿童特定症状的神经生物学并制定目标 生物标记物，可用于改善治疗相关的研究，并帮助推进精准医学。

PROJECT SUMMARY The goals of this study are to target the neurobiology underlying restricted and repetitive behaviors (RRB) in children with autism spectrum disorder (ASD) using N-acetylcysteine (NAC), a well-tolerated nutritional supplement and glutamatergic modulator that has exhibited efficacy for reducing RRB severity in recent preliminary trials. The goals of this career developmental award are to learn the theoretical principles and develop practical application techniques for proton spectroscopy (1H MRS) and electroencephalography (EEG) approaches in children with neurodevelopmental disorders, learn clinical trial methodologies and develop skills for examining treatment efficacy in controlled trials, and learn advanced statistical modeling techniques for assessing complex treatment-related outcomes in pediatric populations. The ultimate overarching goal is to support a promising early career investigator in transitioning to an independent research position. To achieve these goals, we will (Aim 1) acquire 1H MRS and EEG data from children with ASD who exhibit severe RRB and examine the ability of NAC to modulate excitatory signaling in cortico-striatal circuits (CSC) in a single dose challenge study (NAC and placebo). We will also (Aim 2) examine the efficacy of NAC for improving RRB in a 12-week randomized controlled trial and (Aim 3) assess the ability of neurobiological measures of excitatory signaling (1H MRS and EEG) to predict treatment response. CSC are a salient treatment target because CSC contribute to RRB in mouse models of ASD and exhibit relationships with RRB severity in children with ASD. Altered excitatory signaling in CSC regions have also been reported in children/adults with ASD, and most importantly, NAC can modulate glutamatergic signaling in CSC regions. Thus, excitatory (i.e. glutamatergic) signaling in CSC in ASD may contribute to the severity of RRB, at least for some individuals, and modulation with NAC may confer some clinical benefits, especially for children with elevated levels at baseline. We expect that children with ASD who receive NAC will exhibit a larger reduction in 1H MRS and EEG measures of glutamatergic signaling compared to children who receive placebo, which will be associated with a larger reduction in RRB severity following 12 weeks of treatment with NAC compared to placebo. We expect that baseline measures will also be able to accurately predict which children respond to NAC and will explore the effects of NAC on different subtypes of RRB, which may be due to different neurobiological alterations. The findings from this research will support the efficacy of NAC for the treatment of RRB and shed light on the mechanisms of action underlying NAC-mediated improvements. This is particularly important because there are currently no drug treatments for the core symptoms of ASD, including RRB, and severe RRB are associated with management challenges and barriers to adaptive learning. With this training, I plan to develop a programmatic line of research to identify the neurobiology of specific symptoms in children with ASD and develop objective biological markers that can be used to improve treatment-related research and help advance precision medicine.