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; 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（适用提供）：抑郁会影响世界上大部分人口。尽管治疗，但三分之二的患者对两个或多个标准药物疗法的反应不足，并且将被定义为耐药性（TRD）。这些人的生活质量极低，症状极为不足，导致生产力降低，社会关系受损，高昂的医疗保健成本以及在某些情况下是自杀丧生。尽管实施了几种不同的大脑网络，但目的地进行了大量研究，但抑郁症的机制及其成功治疗仍不清楚。当前建议的总体目标是通过NIMH/NIA资助的人类连接项目（HCP，U54 MH091657）利用优化优化的非侵入性MRI技术和正常数据，以1）确定连接符的相关性和预测因素与3个治疗良好相关性的连接，并与NER的相关性相关性，并在2个治疗方面进行纽约的连接，并与2）相关效果，并与2）相关效果，并以2的相关性和2）的作用，以2）的作用和预测2） TRD的临床，行为和生理差异。在协调HCP MRI方案之后，将收集从HCP寿命方案模拟的MRI数据和行为测试电池，并收集临床评估。动脉自旋标记（ASL）灌注MRI，测量脑血流和基因功能的外周血测量值将补充这些方案。我们的第一个目标是纵向，将确定大脑网络连通性的变化是否与已知的快速作用扰动的反应，并预测已知的快速作用扰动的反应。这些扰动包括电击疗法（ECT），连续氯胺酮输注和总睡眠剥夺（TSD）。由于TRD包括不同的分类诊断，例如单极和躁郁症抑郁症以及其他合并症，因此我们的第二个特定目的是横截面，并将确定行为和症状特征，临床历史以及性别和年龄的异质性是否有助于改变TRD的结构和功能连接性的模式变化。受试者将包括200名在临床上有资格接受ECT（n = 60）的患者，串行氯胺酮（n = 60）或TSD（n = 80）和140个对照组，结合了本地收集的控制数据（n = 40）与HCP资源的控制数据（n = 100）。每个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。行为结构和感兴趣的子构建将包括认知控制，消极情绪偏见，反省和奖励超敏反应，广泛涉及抑郁症，由前额叶和前扣带回皮层（认知控制，情绪调节，情绪调节）和amygdala和amygdala，amygdala，Hippocampus，Hipperiatiatum/teriatiatum/pallidum and Crowdion（情感和奖励）（情感和奖励）（情感和奖励）。数据将通过Connectome协调设施发布给科学界。 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，这可能会导致基于个体连通性概况的更有效的治疗策略。