Molecular Mechanisms of Atypical Habituation in Autism Spectrum Disorders

自闭症谱系障碍非典型习惯的分子机制

基本信息

批准号：
8755424
负责人：
Natalia M Kleinhans
金额：
$ 47.49万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8755424
关键词：
12 year old Address Affect Afferent Neurons Age Amygdaloid structure Autistic Disorder Behavioral Behavioral Assay Behavioral Symptoms Biochemical Biochemical Markers Biological Biological Assay Biological Markers Brain Brain imaging Brain region Butyric Acids Child Complement Cyclic AMP Detection Development Disease Early Diagnosis Early Intervention Emotional Emotions Epithelial Cells Ethanol Eye Face Face Processing Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Gender Glutamates Goals Heterogeneity Housing Image Impairment Individual Infant Intervention Knowledge Life Limbic System Measures Methods Molecular National Institute of Mental Health Neurodevelopmental Disorder Neurons Nose Odors Perception Process Process Measure Proxy Reporting Research Risk Scalp structure Second Messenger Systems Sensory Process Severities Signal Pathway Signal Transduction Social Development Specificity Strategic Planning Structure Symptoms System Techniques Testing aged attenuation autism spectrum disorder base biosignature clinically significant comparison group design developmental disease disorder risk gamma-Aminobutyric Acid high risk infancy neural circuit neurobiological mechanism novel olfactory stimulus public health relevance relating to nervous system response second messenger social vanillin

项目摘要

DESCRIPTION (provided by applicant): This project is designed to evaluate the efficacy of a novel imaging, biochemical, and behavioral approach for detecting autism spectrum disorder (ASD) and discovering mechanisms associated with ASD symptomology. Although considerable knowledge has been gained, the lack of reliable predictors during the first year of life remains a major impediment to implementing effective early interventions in children at-risk for ASD. The heterogeneity in ASD renders it unlikely that one specific biomarker will provide a pathognomonic sign of ASD. However, the combination of biomarkers and behavioral indicators being tested in this application has the potential to reveal a biosignature of ASD that can be identified in infancy. We are focusing on the amygdala and limbic system dysfunction in our application. Amygdala dysfunction has been proposed as a critical component of social impairment in ASD, the core symptom that differentiates ASD from other neurodevelopmental disorders. However, functional imaging biomarkers of amygdala dysfunction are yet to be discovered and validated. The current project combines two sensitive functional magnetic resonance imaging (fMRI) measures of amygdala dysfunction in ASD: rapid face detection and reduced amygdala habituation to faces into a new, robust, fMRI habituation paradigm. In addition, we developed a novel amygdala habituation measure using olfactory stimuli. First, we will confirm the sensitivity of our amygdala habituation measures (assayed using emotional faces and odors) for distinguishing children with ASD from typically developing controls. Second we address the mechanisms for atypical habituation, by testing whether reduced fMRI habituation in ASD is driven by alterations in levels of glutamate (excitatory) and/or gamma-amino butyric acid (GABA, inhibitory). Lastly, we are testing whether our battery of olfactory measures including odor detection, cyclic adenosine monophosphate (cAMP) levels (the primary signaling pathway used by olfactory sensory neurons), and fMRI alterations are sensitive and specific biomarkers of ASD. We propose that olfactory measures may be an effective proxy for socioemotional processing given the primacy of emotion in olfactory perception and its shared neuroanatomical substrates with limbic structures affected in ASD. To further investigate the specificity of olfactory measures, we will test the ability of our measures to discriminate between individuals with ASD, typically developing (TD) children and children with clinically significant sensory processing symptoms (SPD). The proposed research addresses Objective 1 of the NIMH Strategic Plan by integrating behavioral and biological markers and examining how neurobiological mechanisms - specifically GABA and glutamate levels - contribute to atypical brain habituation in ASD. Fifty children (8-12 years of age) with high functioning ASD (Full-scale IQ > 70), 50 children with clinically significant sensory processing symptoms (SPD) and 50 typically developing controls (TD) will participate in the study. The TD and SPD groups will be matched to the ASD group according to age, gender, and Full-scale IQ.

描述（由申请人提供）：该项目旨在评估一种新颖的成像、生化和行为方法在检测自闭症谱系障碍 (ASD) 和发现与 ASD 症状学相关的机制方面的功效。尽管已经获得了大量知识，但在生命第一年缺乏可靠的预测因素仍然是对有自闭症谱系障碍风险的儿童实施有效早期干预的主要障碍。自闭症谱系障碍的异质性使得一种特定的生物标志物不太可能提供自闭症谱系障碍的病理征兆。然而，本申请中测试的生物标志物和行为指标的组合有可能揭示可在婴儿期识别的自闭症谱系障碍的生物特征。我们在应用中关注杏仁核和边缘系统功能障碍。杏仁核功能障碍被认为是自闭症谱系障碍社交障碍的一个关键组成部分，而自闭症谱系障碍是区分自闭症谱系障碍和其他神经发育障碍的核心症状。然而，杏仁核功能障碍的功能成像生物标志物尚未被发现和验证。当前的项目结合了自闭症谱系障碍中杏仁核功能障碍的两种灵敏功能磁共振成像（fMRI）测量：快速面部检测和减少杏仁核对面部的习惯，形成一种新的、强大的功能磁共振成像习惯范式。此外，我们还开发了一种利用嗅觉刺激的新型杏仁核习惯测量方法。首先，我们将确认杏仁核习惯测量（使用情绪面孔和气味进行测定）的敏感性，以区分患有自闭症谱系障碍（ASD）的儿童与正常发育的对照组。其次，我们通过测试自闭症谱系障碍 (ASD) 中功能磁共振成像 (fMRI) 习惯化的减少是否是由谷氨酸（兴奋性）和/或 γ-氨基丁酸（GABA，抑制性）水平的变化驱动的，来解决非典型习惯化的机制。最后，我们正在测试一系列嗅觉测量指标，包括气味检测、环磷酸腺苷 (cAMP) 水平（嗅觉感觉神经元使用的主要信号通路）和功能磁共振成像改变，是否是 ASD 的敏感和特异性生物标志物。鉴于嗅觉感知中情绪的首要地位及其与自闭症谱系障碍患者边缘系统共享的神经解剖学基础，我们认为嗅觉测量可能是社会情绪处理的有效代理。为了进一步研究嗅觉测量的特异性，我们将测试我们的测量的能力区分 ASD 患者、典型发育中 (TD) 儿童和具有临床显着感觉处理症状 (SPD) 的儿童。拟议的研究通过整合行为和生物标记并研究神经生物学机制（特别是 GABA 和谷氨酸水平）如何导致 ASD 患者的非典型大脑习惯，来解决 NIMH 战略计划的目标 1。 50 名患有高功能自闭症谱系障碍（全面智商 > 70）的儿童（8-12 岁）、50 名具有临床显着感觉处理症状（SPD）的儿童和 50 名典型发育对照（TD）儿童将参与该研究。 TD 和 SPD 组将根据年龄、性别和全面智商与 ASD 组进行匹配。