CRCNS US-France Research Proposal: Probing the Dorsolateral Prefrontal Cortex and Central Executive Network for Improving Neuromodulation in Depression

这项工作的总体目标是改善耐药神经精神疾病的治疗， 重复经颅刺激（rTMS）通过定制目标到个人的大脑网络。我们确实在 这些个性化的心理健康障碍治疗的迫切需要，影响了近50%的美国人 在我们的有生之年，脑刺激治疗，包括rTMS代表了这些创新的方法， 患者为了缓解抑郁，rTMS试图瞄准前额叶皮层的一个区域，该区域通常位于 中央执行网络（CEN），它驱动决策，认知控制，并严重受损， 萧条然而，rTMS是在不针对个体的CEN的情况下递送的，因此可能无意中 在CEN外提供刺激。本申请的动机是该领域的最新发展，包括 从侵入性记录中获得的大规模全脑连接数据库以及rTMS 在抑郁症患者中诱导大脑变化，预测临床改善。在本提案中，我们将联合收割机非 在健康受试者和抑郁症患者中进行的侵入性TMS研究， 手术病人我们检验了CEN连接在抑郁症中减弱的假设， 最大限度地通过个性化定位进行调节。该项目包括三个目标：（1）调查 在手术患者中使用直接脑记录的CEN内的兴奋性、连接性和神经元特性 （2）获得准确的TMS工具，以非侵入性方式测量健康和抑郁患者的CEN连接 （3）在抑郁人群中，表征CEN内的个体间变异性， 前瞻性地测试在个体水平上使用TMS的定位是否更有效地调节该大脑网络。这 一种可以推广到任何大脑区域和疾病的方法，利用了直接大脑的大型数据库， 记录，以无与伦比的细节水平绘制大脑网络，开发了一个链接到直接的大脑记录， 以产生有效的非侵入性大脑测量，并应用这些见解来单独定位网络 并改善有针对性的脑刺激。科学成果包括：（1）第一个因果，功能地图的 人类CEN从直接的大脑记录;（2）新的非侵入性的大脑连接措施接地， 电生理学;（3）CEN中抑郁症的因果脑特征;（4）针对个体的方法学 临床中的CEN;和（5）使用该方法改善CEN的调节。总之，一个成功的 所提出的工作成果将产生一种算法和指导方针，用于个性化TMS目标定位， 完全验证了抑郁症的大脑特征 相关性（参见说明）： 抑郁症的脑刺激针对中央执行网络（CEN），参与决策和 认知控制，抑郁症的核心，在临床上难以瞄准。在这里，我们建议研究连通性 使用侵入性和非侵入性脑记录相结合的CEN;我们将1）研究CEN 直接脑记录的连接，2）获得准确和因果的工具来测量CEN连接非 在健康和抑郁人群中的侵袭性，以及3）测试CEN在个体水平上的定位是否可以更多地 有效地调节这个网络。所提出的工作的成功结果将产生一个算法， 基于充分验证的抑郁症大脑特征的个性化TMS靶向指南。

The overarching goal of this work is to improve treatments of medication-resistant neuropsychiatric diseases with repetitive transcranial stimulation (rTMS) by tailoring the target to an individual's brain networks. We are indeed in critical need of these individualized treatments for mental health disorders, which affect nearly 50% of Americans during our lifetimes, and brain stimulation treatments, including rTMS represent innovative approaches for these patients. To alleviate depression, rTMS attempts to target a region of the prefrontal cortex generally located within the central executive network (CEN), which drives decision making, cognitive control, and is critically impaired in depression. However, rTMS is delivered without targeting an individual's CEN, and as such may inadvertently deliver stimulation outside the CEN. This application is motivated by recent developments in the field, including a large-scale whole-brain connectivity database derived from invasive recordings and the demonstration that rTMS in depressed patients induces brain changes that predict clinical improvement. In this proposal, we combine non- invasive TMS studies in healthy subjects and depressed patients with invasive direct stimulation studies from surgical patients. We test the hypothesis that the CEN connectivity is weakened in depression and can be maximally modulated by individualizing localization. The project consists of three aims: (1) investigate the excitability, connectivity, and neuronal properties within the CEN using direct brain recordings in surgical patients with epilepsy; (2) derive accurate TMS tools to measure CEN connectivity non-invasively in healthy and depressed populations; and (3) in a depressed population characterize inter-individual variability within the CEN and prospectively test if localization with TMS at the individual level more effectively modulates this brain network. This approach, which can be generalized to any brain region and disorder, utilizes a large database of direct brain recordings to map a brain network at an unparalleled level of detail, develops a link to direct brain recordings in order to yield validated non-invasive brain measures, and applies these insights to individually localize the network and improve targeted brain stimulation. Scientific outcomes include: (1) the first causal, functional map of the human CEN from direct brain recordings; (2) novel non-invasive brain measures of connectivity grounded in electrophysiology; (3) causal brain signatures of depression in the CEN; (4) a methodology to target an individual's CEN in the clinic; and (5) improved modulation of the CEN using this methodology. In summary, a successful outcome of the proposed work would yield an algorithm and guidelines for personalized TMS targeting based on fully validated brain signatures in depression. RELEVANCE (See instructions): Brain stimulation for depression targets the central executive network (CEN), involved in decision making and cognitive control, core in depression, and difficult to target in the clinic. Here we propose to study the connectivity of the CEN using a combination of invasive and non-invasive brain recordings; we will 1) investigate CEN connectivity from direct brain recordings, 2) derive accurate and causal tools to measure CEN connectivity non- invasively in healthy and depressed populations, and 3) test if CEN localization at the individual level can more effectively modulate this network. A successful outcome of the proposed work would yield an algorithm and guidelines for personalized TMS targeting based on fully validated brain signatures in depression.