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

电惊厥治疗快感缺失和奖励回路调节的跨诊断评估：目标、生物标志物和反应预测因子

• 批准号: 9398707
• 负责人: Joan A Camprodon
• 金额: $ 75.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398707
• 关键词: Amygdaloid structure; Anatomy; Anhedonia; Anisotropy; Anterior; Ants; Area; Behavior; Behavioral; Bilateral; Biological Markers; Biology; Bipolar Depression; Brain; Brain imaging; Clinical; Clinical Trials; Data; Diagnosis; Diffuse; Dimensions; Disease; Dorsal; Electroconvulsive Therapy; Generalized seizures; Goals; Hippocampus (Brain); Human; Image; Imaging technology; Inferior; Inferior frontal gyrus; Insula of Reil; Lead; Learning; Lobule; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Medicine; Methodology; Mood Disorders; Motivation; National Institute of Mental Health; Neurosciences; Nucleus Accumbens; Parietal; Pathologic; Pathway interactions; Patients; Positive Valence; Property; Protocols documentation; Psychiatry; Psychological reinforcement; Radial; Research Domain Criteria; Rewards; Severities; Structure of superior frontal gyrus; Subcategory; Symptoms; Syndrome; System; Therapeutic; Therapeutic Human Experimentation; Time; Unipolar Depression; Ventral Tegmental Area; base; behavior measurement; cingulate cortex; cohort; connectome; dentate gyrus; effective therapy; experience; improved; innovation; morphometry; multimodality; neuroimaging; neuropsychiatric disorder; neuroregulation; novel; pleasure; predicting response; putamen; response; reward circuitry; reward processing; stem; targeted biomarker; therapeutic target; tool; tractography; translational approach

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.

电休克疗法（ECT）是精神病学中最有效的治疗方法，也是最有效的治疗方法之一。 尽管其明显的非局灶性作用会导致全身性癫痫发作，但其治疗作用却很有效。 益处特定于一些临床综合征，包括重度抑郁症 (MDD) 和双相情感障碍 抑郁症（BD）。这两种综合征在奖赏处理方面都有共同的核心缺陷（即快感缺失）。 改善情绪障碍和综合症的快感缺乏，这意味着对功能的选择性影响 奖励网络的动力学和结构特性。 奖励相关功能代表了病理相关性的关键行为维度 神经精神疾病，并且在 RDoC 矩阵中作为正价结构占据中心位置。 人们越来越认识到“快感缺乏”并不代表其单一维度； 在子类别中，出现了与行为和疾病明显相关的三个结构：完善（喜欢）、 每一个都存在动机（想要）和强化（学习）的定量行为测量。 三、作为生物标志物和反应预测因子的临床有效性。 奖励网络的解剖结构众所周知，其核心位于腹侧被盖区 (VTA)， 伏核 (NAc)，以及通过中皮质边缘到皮质和皮质下节点的投射 人类连接组计划（HCP）显着推进了这一过程。 人类大脑连接成像技术，加速新兴领域的创新 连接组学。我们小组的初步数据描述了获得多模态 MRI 测量的可行性。 接受 ECT 的患者的奖赏回路生物学（形态测量、纤维束成像、功能连接），以及 提取有临床意义的信息来确定治疗目标并开发生物标志物和预测因子。 由于缺乏明确的目标和有用的治疗研究陷入停滞 生物标志物，了解我们最有效的治疗机制是我们领域的首要任务。 研究中，我们提出了一种新颖的转化策略，该策略利用了高效和快速响应的优势 ECT，并使用它通过系统神经科学框架来探测电路层面的目标参与。 根据 NIMH 战略重点和 RDoC 计划，我们将重点关注奖励电路及其临床 我们将使用 ECT 常用的两种临床综合征的维度：MDD 和 BD。 HCP 多模态 MRI 协议结合经过验证的奖励结构行为测量来评估 ECT 之前、期间和之后的患者，以及一组将进行成像的匹配健康对照 这项研究的创新之处在于提出将 ECT 与多模态 MRI 相结合作为研究框架。 快感缺乏跨诊断，其转化目标是（1）发现治疗目标，（2）开发 生物标志物和（3）确定反应的预测因子。