IMAGING AND MODELING THERAPEUTIC MECHANISMS OF ACTION

描述（由申请人提供）：拟议的长期愿景 研究计划是开发成像策略来研究作用机制 大脑疾病的治疗干预。这件事的直接目标是 建议是研究治疗特发性 帕金森病（IPD）。作用机制是一个至关重要的 研究目标，作为新的治疗方法的合理发展需要， 了解行动机制。行动机制是及时的 成像研究的方向，因为方法正在出现， 证明与作用机制直接相关的变量的变化， 即：1）任务绩效策略（测量为脑功能的集合 （2）信息交换（测量为 区域间功能协方差）;以及3）连通性 &突触加权和其中的塑性变化（作为区域间测量） 休息时的功能协方差）。结构方程模型（SEM） 提供了一个建模结构，用于将这三种类型的测量合并为 功能系统模型因此，我们建议研究 Lee Silverman Voice Treatment（LSVT）治疗IPD患者的发音减退。图像数据 采集将包括：静息和言语期间的功能性MRI， 休息期间、讲话期间和图像引导TMS至SMA期间。任务绩效 策略将通过在公开演讲期间的功能活动来评估（第 阅读）用H2O PET和fMRI两者成像。信息交流 （任务期间的区域间协方差）将根据每个函数计算 数据集解剖连接性（休息期间的区域间协方差）将 用TMS/PET和静息态MRI测量。结构方程 建模将应用于PET和fMR 1衍生的策略测量， 信息交换和连接，以模拟语音运动系统前， 以及LSVT后所有测量将在LSVT 4周前后进行 10例低音IPD患者选择LSVT。一旦建立，这些 方法有潜力为探索作用机制提供工具 从而为开发新的治疗方法提供了理论基础 在IPD中，以及在许多神经学、精神病学和发育学中， 紊乱

DESCRIPTION (provided by applicant): The long-range vision of the proposed research program is to develop imaging strategies to study mechanisms of action of therapeutic interventions in brain disorders. The immediate goal of this proposal is to study mechanisms of action of treatment in Idiopathic Parkinson's Disease (IPD). Mechanism of action is a fundamentally important research objective, as the rational development of new treatments demands an understanding of mechanisms of action. Mechanism of action is a timely direction for imaging research, because methods are emerging which can demonstrate changes in variables directly related to mechanism of action, namely: 1) task-performance strategy (measured as the set of brain functional areas recruited by the task); 2) information exchange (measured as inter-regional functional co-variance during performance); and 3) connectivity & synaptic weighting and plastic changes therein (measured as inter-regional functional covariance during rest). Further, Structural Equation Modeling (SEM) offers a modeling construct for merging these three types of measurement into a functional system model. Herein, we propose to study the mechanism of action of the Lee Silverman Voice Treatment (LSVT) for hypophonia in IPD. Image-data acquired will include: functional MRI at rest and during speech, H21 0 PET at rest, during speech and during image guided TMS to the SMA. Task-performance strategy will be assessed by functional activity during overt speech (paragraph reading) imaged with both H2O PET and with fMRI. Information exchange (inter-regional covariance during task) will be computed from each functional data set. Anatomical connectivity (interregional covariance during rest) will be measured with TMS/PET and with resting-state MRI. Structural Equation Modeling will be applied to PET- and fMR1-derived measures of strategy, information exchange and connectivity, to model the speech-motor system pre- and post-LSVT. All measures will be performed before and after 4 weeks of LSVT in 10 hypophonic IPD patients selected for LSVT. Once established, these methods have the potential to provide tools for exploring mechanism of action and thereby providing a rationale basis for the development of new treatments in IPD, as well as in many neurological, psychiatric and developmental disorders.