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表型变异性很大，ASD症状可以在一系列年龄和不同程度上表现出来。部分由于这些原因，ASD临床诊断具有挑战性，并且通常直到3-5岁才进行。因此，仍然存在对有效且可靠的内表型的未满足的需求，所述内表型将促进生命早期的ASD诊断，使得能够有效地研究ASD风险因素，并且最终用作有用的生物标志物以告知有效疗法的开发并在未来的临床试验中评估治疗反应。本提案的总体目标是探索经颅磁刺激（TMS）作为高功能和低功能ASD成人和儿童的新型神经生理内表型的脑可塑性测量的效用。迄今为止，我们的工作证明了这些措施在患有ASD的高功能成人中的潜在效用，并且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，其中这种内在表型的价值特别高。因此，我们建议应用单脉冲TMS来评估由特定的重复TMS协议（称为θ爆发刺激（TBS））引起的皮质脊髓反应性的调制。比较TBS前后单脉冲TMS诱导的运动反应是人类大脑可塑性的一种独特的非侵入性测量方法，我们发现它在患有ASD的高功能成人个体中显示出可靠的异常。我们的假设是，TBS诱导的TMS反应调制的改变是一种常见的神经病理生理特征，与ASD表型可靠相关，并且不仅限于高功能成人，而且在儿童和低功能个体中也有效。因此，我们预计，从拟议的研究数据将解决一个重要的需求，快速，非侵入性，可靠和安全的内表型可用于不同年龄和功能水平的ASD患者。

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.