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

使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学

• 批准号: 10758985
• 负责人: John Patrick Hegarty
• 金额: $ 24.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758985
• 关键词: Acetylcysteine; Affect; Aftercare; Animals; Anterior; Award; Behavior; Behavior assessment; Biological; Biological Markers; Child; Childhood; Clinical; Clinical Trials; Complex; Corpus striatum structure; Cross-Over Studies; Data; Development; Disease; Dose; Double-Blind Method; Electroencephalography; Etiology; Evoked Potentials; Exhibits; Fostering; Foundations; Functional disorder; Glutamates; Goals; Heterogeneity; Individual; Intervention; Intervention Studies; Investigation; K-Series Research Career Programs; Learning; Measures; Mediating; Membrane Potentials; Mentors; Methodology; Neurobiology; Neurodevelopmental Disorder; Obsessive compulsive behavior; Outcome; Pathway interactions; Pharmacotherapy; Placebos; Population; Positioning Attribute; Prediction of Response to Therapy; Protons; Randomized, Controlled Trials; Reporting; Research; Research Personnel; Role; Scientist; Sensory; Severities; Signal Transduction; Specificity; Spectrum Analysis; Statistical Models; Subgroup; Symptoms; Techniques; Training; Training Support; Treatment Efficacy; adaptive learning; adult with autism spectrum disorder; aged; autism spectrum disorder; autistic children; biomarker discovery; career; career development; cingulate cortex; clinical investigation; dietary supplements; effective intervention; effectiveness evaluation; efficacy evaluation; glutamatergic signaling; improved; interest; motor behavior; mouse model; neural; neuroimaging; neuropsychiatric disorder; novel; pharmacologic; practical application; precision medicine; programs; randomized placebo controlled trial; recruit; reduce symptoms; repetitive behavior; research and development; response; skill acquisition; skills; targeted agent; theories; treatment response

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.

项目摘要 这项研究的目标是针对神经生物学的基本限制和重复行为（RRB） 使用N-乙酰半胱氨酸（NAC）的自闭症谱系障碍儿童（ASD），一种耐受性的营养 在近期降低RRB严重程度的功效的补充和谷氨酸能调节剂 初步试验。这个职业发展奖的目标是学习理论原则并发展 质子光谱法（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发展技能 检查对照试验中的治疗功效，并学习高级统计建模技术 评估儿科人群中与复杂治疗相关的结果。最终的总体目标是 支持有前途的早期职业调查员过渡到独立的研究职位。实现 这些目标，我们将（AIM 1）从ASD儿童中获取1H MRS和EEG数据，这些儿童表现出严重的RRB和 检查NAC在单剂量中调节皮质 - 纹状体电路（CSC）中兴奋性信号传导的能力 挑战研究（NAC和安慰剂）。我们还将（AIM 2）检查NAC在A中提高RRB的功效 12周的随机对照试验和（目标3）评估兴奋性神经生物学测量的能力 信号传导（1H MRS和EEG）预测治疗反应。 CSC是一个显着的治疗目标 在ASD的小鼠模型中有助于RRB，并在ASD儿童中与RRB严重程度显示出关系。 在患有ASD的儿童/成人中，CSC区域的兴奋信号传导发生了改变，大多数 重要的是，NAC可以调节CSC区域的谷氨酸能信号传导。因此，兴奋（即谷氨酸能） 至少对于某些人而言，ASD中CSC的信号可能导致RRB的严重程度，并调制 使用NAC可以赋予一些临床益处，特别是对于基线水平升高的儿童。我们期望 接受NAC的ASD儿童将显示1H MRS和EEG的量度较大 与接受安慰剂的儿童相比，谷氨酸能信号传导将与较大的 与安慰剂相比，使用NAC治疗12周后，RRB严重程度降低。我们期望这一点 基线措施也将能够准确预测哪些孩子对NAC的反应，并将探索 NAC对RRB不同亚型的影响，这可能是由于不同的神经生物学改变。这 这项研究的发现将支持NAC对RRB治疗的功效，并阐明 NAC介导的改进的作用机制。这尤其重要，因为有 目前，包括RRB在内的ASD核心症状和严重RRB的核心症状没有药物治疗 管理挑战和自适应学习的障碍。通过这项培训，我计划开发一个程序化 研究线以识别ASD儿童的特定症状的神经生物学并发展目标 可用于改善治疗相关的研究并有助于提高精确医学的生物标记。