Investigation of cortico-limbic networks and their dynamics in depression

描述（由申请人提供）：重复经颅磁刺激（rTMS），当传递到背外侧前额叶皮层（DLPFC）时，是临床有效的治疗重度抑郁症（MDD）的方法。MDD的网络模型越来越被人们所接受，功能连接MRI （fcMRI）揭示了MDD中功能网络结构的地形特异性畸变。然而，尽管有迹象表明rTMS的治疗效果是通过对皮层和皮层下边缘中心的分布式影响来驱动的，但rTMS的网络效应仍然是一个谜。本研究旨在研究rTMS对DLPFC的调节刺激部位与关键边缘区域，亚属扣带（sgACC）之间以及sgACC与其他边缘区域之间网络功能连接的方式。我的策略是使用高频rTMS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。这将在一组重度抑郁症患者和一组精心匹配的对照组中完成。这些受试者将在rTMS治疗前后接受扫描，作为评估效果的一种方法。我们的小组（Eldaief et al）最近证明了这种设计的可行性。PNAS 2011)。刺激引起的变化将用一种新型的联合MRI-PET（正电子发射断层扫描）扫描仪绘制，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中两个网络的差异效应，以及(2)通过跟踪rTMS诱导的DLPFC和sgACC局部葡萄糖代谢变化与这些区域之间分布连接变化之间的动态相互作用来动态表征皮质边缘网络。在一个探索性的目的中，重度抑郁症患者将在三个月后（在他们接受了精神科医生的非特异性治疗干预之后）再次接受相同的rTMS/fcMRI/FDG-PET程序。这一目标将确立，作为原则的证明，重度抑郁症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，希望这项工作将导致异常皮质动力学作为重度抑郁症的生物标志物的出现。此外，这项工作可能会为未来的研究提供参考，这些研究将异常皮质动力学作为神经调节干预可能干预的新治疗靶点。

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.