A Multimodal Investigation of Inhibitory Dysfunction in Autism Spectrum Disorder

 描述(由申请人提供)：人们认为主要抑制性神经递质GABA的损害是自闭症的基础，至少在某种程度上是这样。自闭症儿童经常表现出触摸加工异常以及运动控制异常，这对社会交往和生活质量有很大影响。GABA在调节触觉和运动过程中起着重要作用，这些症状可能是由GABA能功能受损引起的。然而，目前尚不清楚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。使用心理物理学客观地测量触觉敏感性已经成为可能，我们开发了基于对感觉功能的侵入性研究的任务，并可以与GABAA和GABA能机制联系起来。最近，我们发现自闭症儿童的触觉敏感性受损，表现出较差的幅度辨别能力(GABAA)和检测阈值(GABAB)，磁共振波谱显示GABA水平降低。然而，具体的GABA能机制和行为之间的直接联系还没有被证明。药理学研究表明，使用外周和经颅磁刺激(TMS)方法可以直接测试GABAA和GABAB能机制。应用这些非侵入性刺激方法将构成本应用程序的培训部分。这项拨款的总体目标是研究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，我们的目标是测试自闭症儿童是否确实存在不同的GABA能机制受损，这些机制是否与感觉运动行为和症状严重程度有关，以及这些机制与皮质GABA水平如何相关。我们假设在患有自闭症的儿童中，利用抑制的行为任务和脑刺激方案将受到损害，并且探测相同GABA能机制(例如，GABAA(例如，测量短间隔皮质抑制的幅度辨别和TMS)或GABAB(例如，检测阈值和TMS测量长间隔皮质抑制))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特定的治疗方法，从而缓解症状并提高生活质量。

 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.