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

基本信息

批准号：
10619173
负责人：
John Patrick Hegarty
金额：
$ 6.6万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619173
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 Effectiveness Electroencephalography Etiology Evoked Potentials Exhibits Fostering Foundations Functional disorder Glutamates Goals Heterogeneity Individual Intervention Intervention Studies Investigation K-Series Research Career Programs Learning Light Measures Mediating Membrane Potentials Mentors Methodology Neurobiology Neurodevelopmental Disorder Obsessive compulsive behavior Outcome Pathway interactions Pharmacology 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 base biomarker discovery career career development cingulate cortex clinical investigation dietary supplements effective intervention efficacy evaluation glutamatergic signaling improved interest motor behavior mouse model neuroimaging neuropsychiatric disorder novel practical application precision medicine programs randomized placebo controlled trial recruit reduce symptoms relating to nervous system repetitive behavior research and development response skill acquisition skills targeted agent theories treatment response

项目摘要

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.

项目概要本研究的目标是针对限制性和重复性行为（RRB）背后的神经生物学患有自闭症谱系障碍 (ASD) 的儿童使用 N-乙酰半胱氨酸 (NAC)，这是一种耐受性良好的营养品补充剂和谷氨酸调节剂，近年来表现出降低 RRB 严重程度的功效初步试验。该职业发展奖的目标是学习理论原理并发展质子光谱（1H MRS）和脑电图（EEG）的实际应用技术治疗患有神经发育障碍的儿童的方法，学习临床试验方法并培养技能用于检查对照试验中的治疗效果，并学习先进的统计建模技术评估儿科人群复杂的治疗相关结果。最终的总体目标是支持有前途的早期职业研究者过渡到独立研究职位。达到为了实现这些目标，我们将（目标 1）从表现出严重 RRB 的 ASD 儿童那里获取 1H MRS 和 EEG 数据检查单剂量 NAC 调节皮质纹状体回路 (CSC) 兴奋性信号传导的能力挑战研究（NAC 和安慰剂）。我们还将（目标 2）检查 NAC 在改善 RRB 方面的功效 12 周随机对照试验和（目标 3）评估神经生物学测量兴奋性的能力信号（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 有助于 ASD 小鼠模型中的 RRB，并与 ASD 儿童的 RRB 严重程度相关。据报道，患有 ASD 的儿童/成人 CSC 区域的兴奋性信号发生改变，并且大多数重要的是，NAC 可以调节 CSC 区域的谷氨酸信号传导。因此，兴奋性（即谷氨酸能）自闭症谱系障碍 (ASD) 中的 CSC 信号传导可能会导致 RRB 的严重程度（至少对于某些个体而言），并且调节使用 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。我们期望接受 NAC 的 ASD 儿童的 1H MRS 和 EEG 测量值将出现更大程度的降低与接受安慰剂的儿童相比，谷氨酸信号传导增强，这与更大的与安慰剂相比，NAC 治疗 12 周后 RRB 严重程度降低。我们期望基线测量还将能够准确预测哪些儿童对 NAC 做出反应，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所致。这这项研究的结果将支持 NAC 治疗 RRB 的功效，并阐明 NAC 介导的改善的作用机制。这一点尤其重要，因为有目前还没有针对 ASD 核心症状（包括 RRB）的药物治疗，并且严重的 RRB 与 ASD 相关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确定自闭症儿童特定症状的神经生物学并制定目标的研究路线可用于改善治疗相关研究并帮助推进精准医学的生物标记。