Perturbation of the treatment resistant depression connectome by fast-acting therapies

 描述（由申请人提供）：抑郁症影响着世界上很大一部分人口。虽然可以治疗，但三分之二的患者对两种或更多种标准药物治疗没有充分反应，并将被定义为治疗抵抗（TRD）。这些人的生活质量极低，持续的症状导致生产力下降，社会关系受损，医疗保健费用高昂，在某些情况下，自杀导致生命损失。尽管涉及到几个不同的大脑网络，尽管有很多研究，但导致抑郁症及其成功治疗的机制仍然不清楚。当前提案的总体目标是利用NIMH/NIA资助的人类连接组项目提供的优化的非侵入性MRI技术和规范数据（HCP，U 54 MH 091657），以1）鉴定连接体特异性相关性和3种治疗干预的成功治疗结果的预测因子，每一种都具有快速起效的作用，2）表征与TRD中个体临床、行为和生理差异相关的神经连接的改变。在HCP MRI方案协调后，将收集结构、功能和弥散MRI数据以及根据HCP寿命方案建模的行为测试组合，并增加临床评估。动脉自旋标记（ASL）灌注MRI，测量脑血流量和外周血基因功能的措施将补充这些协议。我们的第一个目标是纵向的，并将确定大脑网络连接的变化是否与已知引起强大的抗抑郁作用的快速作用的扰动有关，并预测对这种扰动的反应。这些干扰包括电休克治疗（ECT），连续氯胺酮输注和完全睡眠剥夺（TSD）。由于TRD包括不同的分类诊断，如单相和双相抑郁症和其他合并症，我们的第二个具体目标是横截面，并将确定是否异质性的行为和症状特征，临床病史和性别和年龄有助于改变TRD的结构和功能连接的模式的变化。受试者将包括200名临床上有资格接受ECT（n=60）、连续氯胺酮（n=60）或TSD（n=80）治疗的患者和140名对照患者，将当地收集的对照数据（n=40）与HCP来源的对照数据（n=100）相结合。每位患者将在完成一项干预措施之前和之后接受MRI、行为/认知测试和抽血。感兴趣的行为结构和子结构将包括认知控制、消极偏见和反刍以及奖励超敏性，广泛涉及抑郁症、由前额叶和前扣带皮层（认知控制、情绪调节）和杏仁核、海马体、腹侧纹状体/苍白球（情感和奖励）区域和电路控制的功能。数据将通过Connectome协调设施向科学界发布。HCP的基础设施为发现疾病和治疗反应的机制提供了前所未有的机会，这可能导致基于个体连接特征的更有效的治疗策略。

 DESCRIPTION (provided by applicant): Depression affects a large portion of the world's population. Though treatable, two thirds of patients will not respond sufficiently to two or more standard pharmacotherapies and will be defined as treatment resistant (TRD). Quality of life for these individuals is extremely low and unremitting symptoms lead to loss of productivity, impaired social relationships, high health care costs, and in some cases, loss of life by suicide. Though several different brain networks are implicated, despite much research, the mechanisms causal to depression and its successful treatment remain unclear. The overarching goal of the current proposal is to leverage optimized non-invasive MRI technologies and normative data available through the NIMH/NIA-funded Human Connectome Project (HCP, U54 MH091657) to 1) identify connectome-specific correlates and predictors of successful treatment outcome to 3 therapeutic interventions, each with a rapid onset of action and to 2) characterize alterations in neural connectivity associated with individual clinical, behavioral and physiologica differences across TRD. Following harmonization of HCP MRI protocols, structural, functional and diffusion MRI data and behavioral testing batteries modeled from the HCP Lifespan protocol with added clinical assessments will be collected. Arterial spin labeling (ASL) perfusion MRI, measuring cerebral blood flow, and peripheral blood measures of gene function will supplement these protocols. Our first aim is longitudinal and will determine whether changes in brain network connectivity relate to and predict response to fast-acting perturbations known to elicit robust antidepressant effects. These perturbations include electroconvulsive therapy (ECT), serial ketamine infusion and total sleep deprivation (TSD). Since TRD includes different categorical diagnoses such as unipolar and bipolar depression and other comorbidities, our second specific aim is cross-sectional and will determine if heterogeneity in behavioral and symptom profiles, clinical histories and sex and age contribute to variations in the patterns of altered structural and functional connectivity in TRD. Subjects will include 200 patients clinicall eligible to receive ECT (n=60), serial ketamine (n=60) or TSD (n=80) and 140 controls, combining control data collected locally (n=40) with control data from the HCP resource (n=100). Each patient will receive MRI, behavioral/cognitive testing and a blood draw before and after completing one of the interventions. Behavioral constructs and sub-constructs of interest will include cognitive control, negativity bias and rumination and reward hypersensitivity, widely implicated in depression, functions that are governed by prefrontal and anterior cingulate cortex (cognitive control, mood regulation) and amygdala, hippocampus, ventral striatum/pallidum (emotion and reward) regions and circuitry. Data will be released to the scientific community through the Connectome Coordination Facility. The infrastructure of the HCP provides an unprecedented opportunity for to discover the mechanisms of disease and treatment response, which could lead to more effective treatment strategies based on individual connectivity profiles.