Neural Connectivity Affecting the Antidepressant Response: Testing a Lesion Model

影响抗抑郁药反应的神经连接：测试病变模型

• 批准号: 8995688
• 负责人: Warren D Taylor
• 金额: $ 6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995688
• 关键词: Accounting; Adult; Affect; Affective; Affective Symptoms; Age; Anterior; Antidepressive Agents; Attention; Blinded; Blood Vessels; Brain; Brain region; Bupropion; Cerebrum; Characteristics; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Depressed mood; Diagnosis; Diffuse; Disease remission; Double-Blind Method; Elderly; Emotional; Enrollment; Escitalopram; Failure; Fiber; Figs - dietary; Functional Magnetic Resonance Imaging; Goals; Health; Impairment; Individual; Knowledge; Lesion; Link; Magnetic Resonance Imaging; Major Depressive Disorder; Measures; Medial; Mental Depression; Modeling; Multimodal Imaging; Neurotransmitters; Outcome; Participant; Pathology; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Placebo Effect; Placebos; Randomized; Refractory; Rest; Risk; Serotonin; Severities; Stimulus; Structure; Symptoms; System; Testing; Translating; Translations; Vascular Diseases; White Matter Disease; Work; age related; base; cognitive task; cognitive testing; cohort; design; disability; experience; geriatric depression; individualized medicine; innovation; memory process; monoamine; mortality; neural circuit; neuroimaging; novel; open label; personalized medicine; predicting response; processing speed; relating to nervous system; research clinical testing; response; vascular depression; vascular factor; week trial; white matter

DESCRIPTION (provided by applicant): It can be difficult to achieve remission in individuals with late-life depression (LLD) and they often require aggressive treatment. This challenge is in part due to age-related vascular changes that are common in LLD. Successful antidepressant treatment involve changes across affective, cognitive, and default mode networks. We hypothesize that in LLD, vascular disease adversely affects response to antidepressants by disrupting connectivity of these networks. The primary goal of this project is to characterize how focal vascular damage affects regional connectivity and response to antidepressants. Based on past work and pilot data, we a priori focus on the cingulum bundle and uncinate fasciculus. These key fiber bundles connect frontal, temporal, and cingulate regions involved in cognition and affective responses. Our central hypothesis is that ischemic damage to the cingulum bundle and uncinate fasciculus contributes to structural and functional connectivity deficits of those tracts. This results in a disconnection effect that alters the function of connected regions. In tun, this increases the risk of a poor response to antidepressants. Our approach is to enroll 130 adults over age 60 years with a diagnosis of Major Depressive Disorder. Subjects will complete clinical evaluation, cognitive testing, and MRI/fMRI sessions, including an fMRI emotional oddball task that includes attentional and affective components. Participants will be stratified by cerebral lesion severity and randomized in a 2:1 ratio to a double-blinded 8-week trial of escitalopram or matching placebo. Those who do not remit will transition to an 8-week trial of open-label bupropion, an antidepressant with a different mechanism of action. This will allow us to determine if different and distinct circuit deficits affect response to antidepressants with different mechanisms of action while also accounting for the placebo response. Exploratory aims include a) examination of cognitive tasks that could serve as markers of fiber tract damage and b) whole-brain approaches examining neural contributions to poor antidepressant response. This application is significant and innovative as it uses tract-specific measures of white matter lesions to examine how focal vascular damage is associated with functional connectivity measures and brain activity. We will then examine how these measures predict response to antidepressants. This project will have broad significance for understanding how vascular disease affects brain function and contributes to LLD. Importantly, the identification of relationships between circuit deficits and antidepressant response may have clinical implications, particularly if we can identify cognitive test markers that serve as a surrogate for tract damage.

描述（由申请人提供）：在患有晚期抑郁症（LLD）的个体中可能很难缓解，他们通常需要积极的治疗。这一挑战部分是由于年龄相关的血管变化在LLD中常​​见。成功的抗抑郁药涉及情感，认知和默认模式网络之间的变化。我们假设在LLD中，血管疾病通过破坏这些网络的连通性来不利影响对抗抑郁药的反应。该项目的主要目标是表征局灶性血管损伤如何影响区域连通性和对抗抑郁药的反应。根据过去的工作和试点数据，我们先验地关注扣带束和束缚。这些关键的纤维束连接了与认知和情感反应有关的额叶，时间和扣带回区域。我们的中心假设是，缺血性损坏对扣带的束缚和筋膜不造成筋膜有助于这些区域的结构和功能连通性缺陷。这会导致断开效应，从而改变了连接区域的功能。在TUN中，这增加了对抗抑郁药反应不佳的风险。我们的方法是招募60岁以上的130名成年人，并诊断为重度抑郁症。受试者将完成临床评估，认知测试和MRI/fMRI会议，包括fMRI的情感奇怪任务，其中包括注意力和情感成分。参与者将由 脑病变严重程度，并以2：1的比例与依他张兰氏症或匹配安慰剂的双盲试验为2：1。那些不屈服的人将过渡到为期8周的开放标签安非他酮试验，这是一种具有不同作用机理的抗抑郁药。这将使我们能够确定不同和不同的电路缺陷是否影响对抗抑郁药具有不同作用机理的反应，同时还会考虑安慰剂反应。探索性目的包括a）检查可以用作纤维道损害标志的认知任务，b）b）检查对抗抑郁反应不良的神经贡献的全脑方法。该应用具有重要的和创新性，因为它使用了白质病变的区域特异性测量方法来检查局灶性血管损伤如何与功能连通性测量和大脑活动相关。然后，我们将研究这些措施如何预测对抗抑郁药的反应。该项目对于理解血管疾病如何影响大脑功能并有助于LLD具有广泛的意义。重要的是，鉴定电路缺陷与抗抑郁反应之间的关系可能具有临床意义，特别是如果我们可以识别成为道路损伤的替代物的认知测试标记。