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

速效疗法对难治性抑郁症连接组的干扰

• 批准号: 9109904
• 负责人: Randall Espinoza
• 金额: $ 139.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-02 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109904
• 关键词: Address; Affect; Age; Amygdaloid structure; Anhedonia; Anterior; Antidepressive Agents; Architecture; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Bipolar Depression; Blood; Brain; Cerebrovascular Circulation; Characteristics; Clinical; Clinical assessments; Combined Modality Therapy; Communities; Comorbidity; Cross-Sectional Studies; Data; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Electroconvulsive Therapy; Emotional; Emotions; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Gene Expression; Globus Pallidus; Glutamates; Goals; Health Care Costs; Heterogeneity; Hippocampus (Brain); Human; Hypersensitivity; Individual; Individual Differences; Infusion procedures; Intervention; Ketamine; Knowledge; Lead; Life; Link; Longevity; Magnetic Resonance Imaging; Maps; Measures; Medial; Mental Depression; Methods; Modality; Modeling; Molecular Profiling; Moods; National Institute of Mental Health; Neuraxis; Patients; Pattern; Perfusion; Peripheral; Pharmacotherapy; Phenotype; Physiological; Population; Prevention strategy; Protocols documentation; Proxy; Quality of life; Recording of previous events; Refractory; Research; Research Domain Criteria; Research Infrastructure; Resistance; Resources; Rest; Rewards; Severity of illness; Sleep Deprivation; Spin Labels; Suicide; Symptoms; System; Technology; Therapeutic Intervention; Treatment Efficacy; Treatment outcome; Unipolar Depression; Variant; Ventral Striatum; antidepressant effect; base; behavior test; behavioral construct; biosignature; cingulate cortex; clinical effect; cognitive control; cognitive testing; connectome; effective therapy; experience; gene function; genomic profiles; impaired productivity; interest; mood regulation; neural circuit; novel; patient stratification; peripheral blood; persistent symptom; personalized intervention; personalized medicine; predicting response; productivity loss; public health relevance; relating to nervous system; response; sex; social; standard care; transmission process; treatment group; treatment responders; treatment response; treatment strategy; treatment-resistant depression

 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.

 描述（由申请人提供）：抑郁症影响着世界上很大一部分人口，尽管可以治疗，但三分之二的患者对两种或多种标准药物疗法没有充分反应，因此被定义为治疗抵抗（TRD）。尽管进行了大量研究，但个体的神经元功能极其低下，持续的症状会导致生产力下降、社会关系受损、医疗费用高昂，在某些情况下甚至会因自杀而丧生。目前提案的总体目标是利用优化的非侵入性 MRI 技术和 NIMH/NIA 资助的人类连接组项目 (HCP, U54 MH091657) 提供的规范数据来 1) 识别连接组。 3 种治疗干预措施的成功治疗结果的特定相关性和预测因素，每种治疗干预措施均快速起效，并且 2）表征与个体临床、行为和生理差异相关的神经连接的改变TRD。在协调 HCP MRI 协议后，将收集根据 HCP 寿命协议建模的结构、功能和扩散 MRI 数据以及添加临床评估的动脉自旋标记 (ASL) 灌注 MRI，测量脑血流量和外周血流。基因功能的血液测量将补充这些方案。我们的首要目标是纵向的，并将确定大脑网络连接的变化是否与已知会引发强大抗抑郁作用的快速扰动相关并预测其反应。由于 TRD 包括不同的类别诊断，例如单相和双相抑郁症以及其他合并症，因此我们的第二个具体目标是横向的，并将确定行为和症状是否存在异质性。概况、临床病史以及性别和年龄会导致 TRD 中结构和功能连接改变模式的变化。受试者将包括 200 名有资格接受 ECT 的临床患者。 (n=60)、系列氯胺酮 (n=60) 或 TSD (n=80) 和 140 个对照，将本地收集的对照数据 (n=40) 与来自 HCP 资源的对照数据 (n=100) 结合起来。在完成其中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、消极偏见以及沉思和奖励。与抑郁症广泛相关的过敏症、由前额叶和前扣带皮层（认知控制、情绪调节）以及杏仁核、海马体、腹侧纹状体/苍白球（情绪和奖励）区域和电路控制的功能数据将发布给科学界。通过连接组协调设施，HCP 的基础设施为发现疾病和治疗反应机制提供了前所未有的机会，这可能导致更有效的治疗。基于个人连接配置文件的策略。