IMAGING AND MODELING THERAPEUTIC MECHANISMS OF ACTION

描述（由申请人提供）：建议的长期愿景

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.