Molecular Mechanisms of Atypical Habituation in Autism Spectrum Disorders

描述（由申请人提供）：本项目旨在评估一种新的影像学、生化和行为方法检测自闭症谱系障碍（ASD）的疗效，并发现与ASD症状相关的机制。尽管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指标仍然是对有自闭症风险的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定的生物标志物不太可能提供ASD的病理标志。然而，结合生物标记物和行为指标在该应用中进行测试，有可能揭示可以在婴儿期识别的ASD的生物特征。在我们的应用中，我们主要关注杏仁核和边缘系统的功能障碍。杏仁核功能障碍被认为是ASD中社交障碍的一个重要组成部分，这是区分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种敏感的功能性磁共振成像（fMRI）测量ASD杏仁核功能障碍的方法：快速面部检测和减少杏仁核对面部的习惯化，形成了一种新的、稳健的fMRI习惯化范式。此外，我们开发了一种新的杏仁核习惯化测量使用嗅觉刺激。首先，我们将确认我们的杏仁核习惯测量（使用情绪面孔和气味进行分析）在区分ASD儿童和正常发育对照方面的敏感性。其次，我们通过测试ASD中fMRI习惯化的减少是否由谷氨酸（兴奋性）和/或γ -氨基丁酸（抑制性）水平的改变驱动，来解决非典型习惯化的机制。最后，我们正在测试我们的嗅觉测量包括气味检测、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改变是否敏感和特异性的ASD生物标志物。鉴于情感在嗅觉感知中的首要地位及其在ASD中与边缘结构受影响的共同神经解剖学基础，我们提出嗅觉测量可能是社会情绪加工的有效代理。为了进一步研究嗅觉测量的特异性，我们将测试我们测量的能力

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.