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: 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
• 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

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.

项目总结