Investigation of cortico-limbic networks and their dynamics in major depressive d

描述(申请人提供)：重复经颅磁刺激(RTMS)，当被送到背外侧前额叶皮质(DLPFC)时，是一种治疗严重抑郁障碍(MDD)的临床有效方法。MDD的网络模型越来越为人们所接受，功能性连通性磁共振成像(FcMRI)揭示了MDD功能网络结构的局部特异性异常。然而，尽管有迹象表明rTMS的治疗作用是通过对皮质和皮质下边缘中心的分布式影响来实现的，但rTMS的网络效应仍然是个谜。本研究旨在研究rTMS至DLPFC如何调节刺激部位与关键边缘区域亚膝扣带(SgACC)之间以及sgACC与其他边缘区域之间的网络功能连接。我的策略是使用高频rTMS来刺激左侧DLPFC(概括治疗方法)，但专门针对与sgACC功能相关和反相关的DLPFC区域。这将在一组MDD患者和一组精心匹配的对照组中完成。这些受试者将在rTMS交付之前和之后进行扫描，作为衡量其效果的一种方式。我们的小组(Eldaef等人)最近证明了这种设计的可行性。PNAS 2011)。刺激引起的变化将由一种新型的MRI-PET(正电子发射断层扫描)组合扫描仪绘制成图表，该扫描仪能够同时记录fcMRI BOLD(血氧水平依赖)和18氟脱氧葡萄糖(FDG)PET数据。这将允许通过(1)检查刺激DLPFC中的两个网络的不同效果，以及(2)通过跟踪rTMS引起的DLPFC和sgACC局部葡萄糖代谢的变化以及这些区域之间分布连接的变化，来动态地表征皮质-边缘网络。在一个探索性的目标中，MDD患者将在三个月后(在他们接受了精神科提供者的非特定治疗干预之后)返回接受相同的rTMS/fcMRI/FDG-PET程序。这一目标将确立，作为原则的证据，MDD的治疗与皮质-边缘功能网络结构和皮质-边缘动力学的变化有关。最终，人们希望这项工作将导致作为MDD生物标记物的异常皮质动力学的出现。此外，这项工作可能会为未来的研究授粉，这些研究使用异常皮质动力学作为神经调节干预可能干预的新的治疗靶点。

DESCRIPTION (provided by applicant): Repetitive transcranial magnetic stimulation (rTMS), when delivered to the dorsolateral prefrontal cortex (DLPFC) is a clinically effective treatment fo major depressive disorder (MDD). Network models of MDD are increasingly gaining acceptance, and functional connectivity MRI (fcMRI) has revealed topographically specific aberrations in functional network architecture in MDD. And yet, despite hints that the therapeutic effects of rTMS are actuated through distributed impacts upon cortical and subcortical limbic centers, the network effects of rTMS remain mysterious. This proposal seeks to investigate the way rTMS to DLPFC modulates network functional connectivity between the site of stimulation and a critical limbic region, the subgenual cingulate (sgACC), and between the sgACC and other limbic regions. My strategy is to use high frequency rTMS to stimulate the left DLPFC (recapitulating the therapeutic methodology), but to specifically target DLPFC regions that are functionally correlated and anti-correlated with the sgACC. This will be accomplished in a group of patients with MDD, and in a group of carefully matched controls. These subjects will be scanned before and after rTMS is delivered, as a way of gauging its effects. The feasibility of this design was recently demonstrated by our group (Eldaief et al. PNAS 2011). Changes induced by the stimulation will be charted with a novel combined MRI-PET (Positron Emission Tomography) scanner, which is capable of simultaneously recording fcMRI BOLD (Blood oxygenation level-dependent) and 18Flurodeoxyglucose (FDG) PET data. This will permit cortico-limbic networks to be characterized dynamically through (1) examination of the differential effects of stimulating two networks in the DLPFC, and (2) by tracking the dynamic interplay between rTMS induced changes in local glucose metabolism at DLPFC and sgACC on the one hand, and changes in distributed connectivity between these regions on the other. In an exploratory aim, MDD patients will return three months later (after they have undergone a non-specific treatment intervention with their psychiatric provider) for the identical rTMS/fcMRI/FDG-PET procedures. This aim will establish, as proof of principle, that treatment of MDD is associated with changes in cortico-limbic functional network architecture, and in cortico-limbic dynamics. Eventually, it is hoped that this work will lead to the emergence of aberrant cortical dynamics as a biomarker for MDD. In addition, this work might pollinate future studies which use aberrant cortical dynamics as a novel therapeutic target upon which neuromodulatory interventions might intervene.