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、生化和行为方法在检测自闭症谱系障碍(ASD)和发现与ASD症状相关的机制方面的有效性。虽然已经获得了大量的知识，但在生命的第一年缺乏可靠的预测因素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的异质性使得一个特定的生物标志物不太可能提供ASD的病因学标志。然而，在这项应用中测试的生物标记物和行为指标的组合有可能揭示ASD的生物特征，可以在婴儿时期识别。我们的应用重点是杏仁核和边缘系统功能障碍。杏仁核功能障碍被认为是ASD社会功能障碍的关键组成部分，ASD是区别于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ASD患者杏仁核功能障碍的两个敏感功能磁共振成像(FMRI)指标：快速人脸检测和减少杏仁核对人脸的习惯性，形成了一个新的、稳健的fMRI习惯化范例。此外，我们利用嗅觉刺激开发了一种新的杏仁核习惯性测量方法。首先，我们将确认我们的杏仁核习惯化测量(使用情绪面孔和气味进行分析)的敏感性，以区分ASD儿童和典型的发育中的对照组。其次，我们通过测试ASD患者fMRI习惯性降低是否由谷氨酸(兴奋性)和/或伽马氨基丁酸(GABA，抑制性)水平的变化驱动，来探讨非典型习惯性的机制。最后，我们正在测试包括气味检测、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改变在内的一系列嗅觉指标是否是ASD的敏感和特异的生物标志物。我们认为，鉴于情绪在嗅觉知觉中的首要地位及其与ASD边缘结构共同的神经解剖学基础，嗅觉测量可能是社会情绪处理的有效替代。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能力 区分ASD患者，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。这项拟议的研究通过整合行为和生物标记物，并检查神经生物学机制--特别是GABA和谷氨酸水平--如何有助于ASD患者非典型的大脑习惯性，从而解决了NIMH战略计划的目标1。50名高功能自闭症儿童(8-12岁)、50名临床上有显著感觉加工症状(SPD)的儿童和50名典型发育正常儿童(TD)将参与这项研究。TD组和SPD组将根据年龄、性别和全面智商与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.