A Multimodal Investigation of Inhibitory Dysfunction in Autism Spectrum Disorder

自闭症谱系障碍抑制功能障碍的多模式研究

• 批准号: 9306203
• 负责人: Nicolaas Puts
• 金额: $ 8.27万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306203
• 关键词: Autistic Disorder; Behavior; Behavioral; Brain; Child; Clinical; Communication impairment; Complement; DSM-V; Data; Detection; Development; Discrimination; Emotional; Foundations; Functional disorder; Future; Goals; Grant; Impairment; Intervention; Investigation; Knowledge; Lead; Link; Magnetic Resonance Spectroscopy; Measures; Methodology; Methods; Motor; Motor Evoked Potentials; Movement; Neurotransmitters; Outcome; Perception; Performance; Peripheral; Pharmacology; Pharmacology Study; Phase; Physiologic pulse; Play; Process; Protocols documentation; Psychophysics; Publishing; Quality of life; Regulation; Reporting; Research; Role; Sensorimotor functions; Sensory; Severities; Social Development; Social Interaction; Somatosensory Evoked Potentials; Suggestion; Symptoms; Tactile; Techniques; Testing; Touch sensation; Training; Transcranial magnetic stimulation; Work; autism spectrum disorder; base; behavioral impairment; cohort; communication behavior; gamma-Aminobutyric Acid; improved; in vivo magnetic resonance spectroscopy; innovation; insight; macromolecule; motor control; multimodality; neurochemistry; neurophysiology; neurotransmission; public health relevance; reduce symptoms; repetitive behavior; response; skills; symptomatology; therapy development; training opportunity

 DESCRIPTION (provided by applicant): It is thought that impairments in the main inhibitory neurotransmitter GABA underlie Autism, at least to some degree. Children with Autism often show abnormal touch processing as well as abnormal motor control, which have a large impact on social interactions and quality of life. GABA plays an important role in the regulation of both tactile and motor processing and it is possible that such symptoms are driven by impaired GABAergic function. However, it remains unclear how cortical dysfunction leads to behavioral dysfunction and how different GABAergic processes contribute to behavioral abnormalities. It has become possible to measure tactile sensitivity objectively using psychophysics, and we developed tasks that are based on invasive studies of sensory function, and can be linked to GABAA and GABABergic mechanisms. Recently we have shown impaired tactile sensitivity in children with Autism, showing poor amplitude discrimination (GABAA) and detection threshold (GABAB), and we showed reduced GABA levels using Magnetic Resonance Spectroscopy. However, a direct connection between specific GABAergic mechanisms and behavior has not yet been shown. It is possible to directly test GABAA and GABAB-ergic mechanisms using peripheral and transcranial magnetic stimulation (TMS) methods as has been shown by pharmacological studies. Applying these non-invasive stimulation methods will form the training portion of this application. The overall goal of this grant is to investigate specific inhibitory mechanisms in SM1 in children with ASD and their relation to sensory behavior. Using a multimodal non-invasive approach, we aim to test whether different GABAergic mechanisms are indeed impaired in children with Autism, whether these are linked to sensorimotor behavior and symptom severity, and how these relate to cortical GABA levels. We hypothesize that behavioral tasks and brain stimulation protocols that utilize inhibition will be impaired in childrn with ASD, and that performance that performances between conditions that probe the same GABAergic mechanisms (GABAA (e.g. amplitude discrimination and TMS measuring short-interval cortical inhibition) or GABAB (e.g. detection thresholds and TMS measuring long-interval cortical inhibition) are associated. A better understanding of the role of GABAergic dysfunction in autism may allow for the development of specific therapies that can alleviate the symptoms and improve quality of life.

 描述（由申请人提供）：据认为，主要抑制性神经递质GABA的损伤是自闭症的基础，至少在某种程度上是如此。自闭症儿童通常表现出异常的触摸处理以及异常的运动控制，这对社会交往和生活质量有很大的影响。GABA在触觉和运动处理的调节中起重要作用，并且这些症状可能是由受损的GABA能功能驱动的。然而，皮质功能障碍如何导致行为功能障碍以及不同的GABA能过程如何导致行为异常仍不清楚。它已经成为可能，以客观地测量触觉敏感性使用心理物理学，我们开发的任务是基于侵入性研究的感觉功能，并可以链接到GABAA和GABA能机制。最近，我们发现自闭症儿童的触觉敏感性受损，表现出振幅辨别力（GABAA）和检测阈值（GABAB）较差，并且我们使用磁共振光谱法显示GABA水平降低。然而，具体的GABA能机制和行为之间的直接联系尚未显示。如药理学研究所示，可以使用外周和经颅磁刺激（TMS）方法直接测试GABAA和GABAB能机制。应用这些非侵入性刺激方法将构成本申请的培训部分。这项资助的总体目标是研究ASD儿童SM1的特定抑制机制及其与感觉行为的关系。使用多模式非侵入性方法，我们的目标是测试是否不同的GABA能机制确实受损自闭症儿童，这些是否与感觉运动行为和症状严重程度，以及这些如何与皮质GABA水平。我们假设ASD儿童的行为任务和利用抑制的脑刺激方案将受损，并且在探测相同GABA能机制（GABAA（例如幅度辨别和TMS测量短间隔皮层抑制）或GABAB（例如检测阈值和TMS测量长间隔皮层抑制））的条件之间的表现是相关的。更好地了解GABA能功能障碍在自闭症中的作用可能有助于开发可以缓解症状和改善生活质量的特定疗法。

项目成果

GABA Levels in Left and Right Sensorimotor Cortex Correlate across Individuals.

左右感觉运动皮层的 GABA 水平在个体之间存在相关性。

• DOI: 10.3390/biomedicines6030080
• 发表时间: 2018
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Puts,NicolaasAJ;Heba,Stefanie;Harris,AshleyD;Evans,ChristopherJohn;McGonigle,DavidJ;Tegenthoff,Martin;Schmidt-Wilcke,Tobias;Edden,RichardAE
• 通讯作者: Edden,RichardAE