Molecular Mechanisms of Atypical Habituation in Autism Spectrum Disorders

描述（由申请人提供）：该项目旨在评估一种新的成像，生物化学和行为方法检测自闭症谱系障碍（ASD）和发现与ASD神经病学相关的机制的有效性。虽然已经获得了相当多的知识，但在生命的第一年缺乏可靠的预测因素仍然是对ASD风险儿童实施有效早期干预的主要障碍。ASD的异质性使得一种特异性生物标志物不太可能提供ASD的特异性体征。然而，在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以在婴儿期识别的ASD的生物特征。在我们的申请中，我们关注杏仁核和边缘系统功能障碍。杏仁核功能障碍已被认为是ASD中社交障碍的关键组成部分，ASD是区分ASD与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。目前的项目结合了两个敏感的功能磁共振成像（fMRI）措施杏仁核功能障碍的ASD：快速人脸检测和减少杏仁核习惯到一个新的，强大的，fMRI习惯化范式。此外，我们开发了一种新的杏仁核习惯性措施，使用嗅觉刺激。首先，我们将确认我们的杏仁核习惯化措施的敏感性（使用情绪化的面孔和气味进行分析），以区分自闭症儿童与典型的发展控制。第二，我们解决的机制，非典型的习惯，通过测试是否减少功能磁共振成像习惯在ASD是由谷氨酸（兴奋性）和/或γ-氨基丁酸（GABA，抑制性）水平的改变。最后，我们正在测试我们的嗅觉测量方法，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fMRI改变是否是ASD的敏感和特异性生物标志物。我们建议，嗅觉措施可能是一个有效的代理socioemotional处理的首要地位的情绪在嗅觉感知和其共享的神经解剖学基板与边缘系统结构的影响，在ASD。为了进一步研究嗅觉测量的特异性，我们将测试我们测量的能力 以区分ASD个体，通常是发育中（TD）儿童和具有临床显著感觉处理症状（SPD）的儿童。拟议的研究通过整合行为和生物标志物并研究神经生物学机制-特别是GABA和谷氨酸水平-如何促进ASD的非典型大脑习惯化来解决NIMH战略计划的目标1。50名患有高功能ASD（全量表IQ > 70）的儿童（8-12岁）、50名具有临床显著感觉处理症状（SPD）的儿童和50名典型发育对照（TD）将参与该研究。TD和SPD组将根据年龄、性别和全量表IQ与ASD组匹配。

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.