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

• 批准号: 9272444
• 负责人: Natalia M Kleinhans
• 金额: $ 49.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/9272444
• 关键词: 12 year old; Address; Adenosine Monophosphate; Affect; 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; Electrophysiology (science); Emotional; Emotions; Epithelial Cells; Ethanol; Eye; Face; Face Processing; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Gender; Glutamates; Goals; Heterogeneity; Image; Impairment; Individual; Infant; Intervention; Knowledge; Life; Limbic System; Measures; Methods; Molecular; National Institute of Mental Health; Neurodevelopmental Disorder; Neurons; Nose; Odors; Periodicity; Proxy; Reporting; Research; Risk; Scalp structure; Second Messenger Systems; Sensory; Severities; Signal Pathway; Signal Transduction; Smell Perception; Social Development; Specificity; Strategic Planning; Structure; Symptoms; System; Techniques; Testing; Time; aged; attenuation; autism spectrum disorder; base; behavioral study; biosignature; clinically significant; comparison group; design; developmental disease; disorder risk; face perception; gamma-Aminobutyric Acid; habituation; high risk population; imaging biomarker; imaging study; infancy; neural circuit; neurobiological mechanism; novel; olfactory sensory neurons; olfactory stimulus; public health relevance; relating to nervous system; response; social; specific biomarkers; vanillin

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）：该项目旨在评估用于检测自闭症谱系障碍（ASD）的新型成像，生化和行为方法的功效，并发现与ASD症状相关的机制。尽管已经获得了广泛的知识，但是在生命的第一年，缺乏可靠的预测因素仍然是对ASD处于ASD的儿童进行有效的早期干预措施的主要障碍。 ASD的异质性使一个特定的生物标志物不太可能提供ASD的病理迹象。但是，在本应用中测试的生物标志物和行为指标的组合具有揭示ASD的生物签名，可以在婴儿期鉴定出来。我们专注于应用程序中的杏仁核和边缘系统功能障碍。已提出杏仁核功能障碍是ASD社会障碍的关键组成部分，这是ASD与其他神经发育障碍区分开的核心症状。但是，杏仁核功能障碍的功能成像生物标志物尚未发现和验证。当前的项目结合了ASD中杏仁核功能障碍的两种灵敏的功能磁共振成像（fMRI）测量：快速的面部检测和降低杏仁核的习惯，使面部陷入新的，稳健的fMRI fMRI习惯范式中。此外，我们使用嗅觉刺激开发了一种新型的杏仁核习惯措施。首先，我们将确认我们的杏仁核习惯措施的敏感性（使用情感面孔和气味进行测定），以区分ASD的儿童与典型的控制控制。其次，我们通过测试ASD的fMRI习惯降低是由谷氨酸（兴奋性）和/或γ-氨基丁酸（GABA，GABA，抑制性）驱动的，解决了非典型习惯的机制。最后，我们正在测试我们的嗅觉测量电池是否包括气味检测，环状腺苷（CAMP）水平（嗅觉感觉神经元使用的主要信号通路）以及fMRI改变是敏感的ASD ASD生物标志物。我们建议，鉴于嗅觉感知的至关重要，嗅觉措施可能是社会情感加工的有效替代方案，其共同的神经解剖学基板具有ASD影响的边缘结构。为了进一步研究嗅觉措施的特异性，我们将测试措施的能力 区分患有ASD的人，通常是发育中的（TD）儿童和具有临床意义的感觉处理症状（SPD）的儿童。拟议的研究通过整合行为和生物学标志物，研究神经生物学机制（特别是GABA和谷氨酸水平）如何有助于ASD中的非典型大脑习惯，从而解决了NIMH战略计划的目标1。 50名儿童（8-12岁）具有高功能ASD（全尺度智商> 70），50名具有临床意义的感觉处理症状（SPD）的儿童和50个通常开发控制措施（TD）的儿童将参与研究。根据年龄，性别和全尺度智商，TD和SPD组将与ASD组匹配。