Cortical Plasticity in Autism Spectrum Disorders

描述（由申请人提供）：自闭症谱系障碍（ASD）的临床、社会和经济负担是惊人的。它们是最普遍的发育障碍，其发病率正在上升。然而，ASD的表型变异性很大，ASD症状可以在不同年龄和不同程度上表现出来。部分由于这些原因，自闭症谱系障碍的临床诊断是具有挑战性的，通常要到3-5岁才能做出诊断。因此，对有效可靠的内表型的需求仍未得到满足，这将有助于ASD的早期诊断，能够有效地研究ASD的危险因素，并最终作为有用的生物标志物，为未来临床试验开发有效的治疗方法和评估治疗反应提供信息。本研究的总体目标是探索经颅磁刺激（TMS）测量脑可塑性作为一种新的神经生理内表型在高功能和低功能成人和ASD儿童中的应用。迄今为止，我们的工作证明了这些措施在高功能ASD成人患者中的潜在效用，试点数据支持将相同措施应用于儿童和低功能个体的可行性和安全性，其中这种内表型的价值尤其高。因此，我们建议应用单脉冲TMS来评估特定的重复TMS方案（称为θ脉冲刺激（TBS））诱导的皮质脊髓反应性的调制。比较单脉冲TMS在TBS前后引起的运动反应是一种独特的非侵入性测量人类大脑可塑性的方法，我们发现它在高功能成年ASD患者中显示了可靠的异常。我们的假设是，tbs诱导的经颅磁刺激反应调节的改变是一种常见的神经病理生理特征，与ASD表型可靠地联系在一起，而且这种特征不仅限于高功能成人，也适用于儿童和低功能个体。因此，我们预计，拟议研究的数据将满足对跨年龄和功能水平的ASD患者可获得的快速、无创、可靠和安全的内表型的重要需求。

DESCRIPTION (provided by applicant): The clinical, social and financial burden of Autism Spectrum Disorders (ASD) is staggering. They are the most prevalent of the developmental disorders and their incidence is rising. However, the ASD phenotype variability is large, and ASD symptoms can manifest over a range of ages and to different degrees. In part for these reasons, the ASD clinical diagnosis is challenging and often is not made until 3-5 years of age. Thus, there remains an unmet need for a valid and reliable endophenotype which would facilitate ASD diagnosis early in life, enable efficient study of ASD risk factors, and eventually serve as a useful biomarker to inform the development of effective therapies and assess treatment response in future clinical trials. The overarching goal of this proposal is to explore te utility of transcranial magnetic stimulation (TMS) measures of brain plasticity as a novel neurophysiologic endophenotype in high- and low-functioning adults and children with ASD. Our work to date demonstrates the potential utility of these measures in higher-functioning adults with ASD, and pilot data support the feasibility and safety of applying the same measures to children and lower functioning individuals in whom the value of such an endophenotype would be particularly high. We thus propose to apply single-pulse TMS to evaluate the modulation in corticospinal reactivity induced by a specific repetitive TMS protocol known as theta burst stimulation (TBS). The comparison of the motor responses induced by single-pulse TMS before and following TBS is a unique noninvasive measure of brain plasticity in humans, and we have found that it shows a reliable abnormality in high-functioning adult individuals with ASD. Our hypothesis is that the alteration of TBS-induced modulation of TMS responses is a common neuropathophysiologic trait that is reliably linked to the ASD phenotype, and that will not be limited to high functioning adults but be also valid in children and low-functioning individuals. W thus anticipate that data from the proposed studies will address an important need for a rapid, noninvasive, reliable and safe endophenotype available to patients with ASD across ages and level of function.