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)，通过根据个人的大脑网络量身定做目标。我们确实是在 对这些影响近50%美国人的心理健康障碍的个性化治疗的迫切需求 在我们的有生之年，脑刺激治疗，包括rTMS，代表了这些方面的创新方法 病人。为了缓解抑郁，rTMS试图定位前额叶皮质的一个区域，该区域通常位于 驱动决策和认知控制的中央执行网络(CEN)严重受损 抑郁症。然而，rTMS的交付不以个人的CEN为目标，因此可能会无意中 在CEN之外提供刺激。这一应用程序是由该领域的最新发展推动的，包括 基于有创记录的大规模全脑连通性数据库及rTMS的应用 抑郁症患者的大脑会发生变化，预测临床症状的改善。在这项建议中，我们结合了非 对健康受试者和抑郁症患者进行有创直接刺激研究的有创TMS研究 外科病人。我们验证了这样的假设，即抑郁症时CEN连接性减弱，并且可以 通过个性化本地化最大限度地调整。该项目由三个目标组成：(1)调查 用手术患者的直接脑记录研究CEN内的兴奋性、连接性和神经元特性 (2)获得准确的经颅多普勒超声工具，无创地测量健康和抑郁症患者的CEN连接性 (3)在萧条的人口中，CEN和CEN内的个体间变异特征 前瞻性地测试TMS在个体层面的定位是否能更有效地调节这一大脑网络。这 这种方法可以推广到任何大脑区域和障碍，利用了一个大型的直接大脑数据库 记录以无与伦比的细节水平绘制大脑网络图，开发了与直接大脑记录的链接 以产生经过验证的非侵入性大脑测量，并应用这些见解来单独定位网络 并提高针对性的脑刺激。科学成果包括：(1)第一张因果功能图 来自直接脑记录的人类CEN；(2)新的非侵入性脑连接测量方法 电生理学；(3)CEN中抑郁症的原因脑信号；(4)针对个体的 CEN在临床上的应用；以及(5)使用这种方法改进了CEN的调节。总而言之，一个成功的 拟议工作的结果将产生个性化TMS目标的算法和指南 抑郁症患者的大脑信号得到充分验证。 相关性(请参阅说明)： 脑刺激治疗抑郁症的目标是中央执行网络(CEN)，参与决策和 认知控制，在抑郁症中处于核心地位，在临床上很难靶向。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)调查CEN 从直接脑记录中获得连通性，2)获得准确和因果的工具来测量CEN非连通性 在健康和抑郁人群中侵袭性，以及3)测试CEN在个体水平上的本地化是否可以更多 有效地调制这个网络。拟议工作的成功结果将产生一种算法和 基于抑郁症患者完全有效的脑信号的个性化经颅磁刺激定位指南。

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.