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

项目总结 本研究的目标是研究限制和重复行为(RRB)的神经生物学基础。 应用耐受性良好的N-乙酰半胱氨酸治疗儿童自闭症谱系障碍(ASD) 近年来显示出减轻RRB严重程度的补充剂和谷氨酸能调节剂 初审。这个职业发展奖的目的是学习理论原理和发展 质子谱(1H MRS)和脑电(EEG)的实用技术 神经发育障碍儿童的方法，学习临床试验方法和发展技能 在对照试验中检查治疗效果，并学习高级统计建模技术 评估儿科人群中与治疗相关的复杂结果。最终的首要目标是 支持有前途的早期职业研究人员过渡到独立的研究职位。要实现 这些目标，我们将(目标1)从表现出严重RRB和RRB的ASD儿童获取1H MRS和EEG数据 单次给药检测NAC对皮质纹状体回路(CSC)兴奋信号的调制能力 挑战研究(NAC和安慰剂)。我们还将(目标2)检查NAC在改善RRB方面的效果。 12周的随机对照试验和(目的3)评估兴奋性神经生物学措施的能力 发出信号(1H MRS和EEG)以预测治疗反应。CSC是一个显著的治疗靶点，因为CSC 在ASD小鼠模型中促进RRB，并显示与ASD儿童RRB严重程度的关系。 CSC区域兴奋信号的改变在ASD的儿童/成人中也有报道，大多数 重要的是，NAC可以调节CSC区的谷氨酸能信号。因此，兴奋性(即谷氨酸能) ASD患者CSC中的信号可能有助于RRB的严重程度，至少对某些人来说是如此，并可能导致调制 使用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治疗的自闭症儿童在1H MRS和EEG测量中显示出更大的减少 谷氨酸能信号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的严重程度降低。我们期待着 基线测量还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的影响可能与不同的神经生物学改变有关。这个 这项研究的发现将支持NAC治疗RRB的疗效，并为 NAC介导的改进背后的作用机制。这一点特别重要，因为有 目前还没有针对ASD核心症状的药物治疗，包括RRB和严重的RRB与 适应性学习的管理挑战和障碍。通过这次培训，我计划制定一项计划 确定ASD儿童特定症状的神经生物学研究路线并制定目标 可用于改进与治疗相关的研究和帮助推进精准医学的生物标记。

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.