A Transdiagnostic Assessment of Electroconvulsive Therapy Modulation of Anhedonia and Reward circuitry: Targets, Biomarkers and Predictors of Response

电休克治疗(ECT)是精神病学中最有效的治疗方法之一，也是最有效的治疗方法之一 在医学上很有效。尽管其明显的非局部性效应会导致全身癫痫发作，但其治疗作用 益处仅限于少数临床症状，包括严重抑郁障碍(MDD)和躁郁症 抑郁(BD)。这两种症状都存在奖赏处理的核心缺陷(即快感缺失)。电休克疗法 改善情绪障碍和症状的快感缺乏，暗示对功能性的选择性影响 奖励网络的动力学和结构特性。 奖赏相关功能代表了病理相关性的关键行为维度 神经精神障碍，并在RDoC矩阵中作为正价结构占据中心位置。那里 越来越多的人认识到，“快感缺乏症”并不代表单一的维度；在其 子类别，出现了与行为和疾病明显相关的三个概念：完善(喜欢)， 动力(想要)和强化(学习)。其中的每一个都有量化的行为衡量标准 第三，将临床效度作为反应的生物标志物和预测因子。 奖赏网络的解剖是众所周知的，其核心位于腹侧被盖区(VTA)和 伏隔核(NAC)和经中皮质边缘向皮质和皮质下结节的投射 路径及其分支。人类连接组计划(HCP)显著推动了 人类脑连接成像技术，加速新兴领域的创新 连接学。来自我们小组的初步数据描述了获得多模式磁共振测量的可行性 接受ECT治疗的患者的奖赏回路生物学(形态测量、纤维束成像、功能连通性)，以及 提取临床有意义的信息，以确定治疗目标并开发生物标记物和预测因子。 在治疗研究因缺乏明确的目标和有用的药物而停滞不前的时候 生物标志物，了解我们最有效的治疗机制是我们领域的优先事项。在这 研究中，我们提出了一种新的翻译策略，该策略利用了 ECT，并使用它在电路水平上探测目标接合。有了系统神经科学框架，在 根据NIMH的战略优先事项和RDoC计划，我们将专注于奖励电路及其临床 ECT通常治疗的两种临床症状的维度：MDD和BD。我们将使用 HCP多模式MRI方案结合有效的奖赏结构的行为测量来评估 患者在ECT前、中和之后，以及一组匹配的健康对照组将被成像 两次。本研究的创新之处在于提出了将ECT和多模式MRI相结合作为研究框架的建议 跨诊断的快感缺乏症，翻译的目标是(1)发现治疗靶点，(2)发展 生物标志物和(3)确定反应的预测因素。

Electroconvulsive Therapy (ECT) is the most effective treatment in psychiatry, and among the most effective in medicine. Despite its apparent non-focal effects leading to a generalized seizure, its therapeutic benefits are specific to a few clinical syndromes, including major depressive disorder (MDD) and bipolar depression (BD). These two syndromes share core deficits in reward processing (i.e. anhedonia). ECT improves anhedonia across mood disorders and syndromes, implying selective effects on the functional dynamics and structural properties of reward networks. Reward-related functions represent key behavioral dimensions of pathological relevance across neuropsychiatric disorders, and have a central place as positive valence constructs in the RDoC matrix. There has been a growing recognition that “anhedonia” does not represent a unitary dimension; among its subcategories, three constructs emerge with clear relevance to behavior and disease: consummation (liking), motivation (wanting) and reinforcement (learning). Quantitative behavioral measures exist for each of these three, with clinical validity as biomarkers and predictors of response. The anatomy of the reward network is well known, with a core in the ventral tegmental area (VTA) and the Nucleus Accumbens (NAc), and projections to cortical and subcortical nodes via the mesocorticolimbic pathway and its ramifications. The Human Connectome Project (HCP) has significantly advanced the technologies for imaging brain connections in humans, accelerating innovation in the emerging field of Connectomics. Preliminary data from our group describes the feasibility of obtaining multimodal MRI measures of reward circuit biology (morphometry, tractography, functional connectivity) in patients undergoing ECT, and extracting clinically meaningful information to identify treatment targets and develop biomarkers and predictors. At a time when therapeutic research is stalled due to the absence of clear targets and useful biomarkers, understanding the mechanisms of our most effective treatments is a priority for our field. In this study, we propose a novel translational strategy that takes advantage of the high efficacy and fast response of ECT, and uses it to probe target engagement at the circuit level. With a systems neuroscience framework, in line with NIMH strategic priorities and the RDoC Initiative, we will focus on reward circuitry and its clinical dimensions across two clinical syndromes that are commonly treated with ECT: MDD and BD. We will use HCP multimodal MRI protocols combined with validated behavioral measures of reward constructs to assess patients before, during and after ECT, in addition to a cohort of matched healthy controls that will be imaged twice. This study is innovative in its proposal to combine ECT with multimodal MRI as a framework to study anhedonia transdiagnostically, with the translational aims to (1) discover treatment targets, (2) develop biomarkers and (3) identify predictors of response.