Neural Connectivity Affecting the Antidepressant Response: Testing a Lesion Model

描述（由申请人提供）：老年抑郁症（LLD）患者很难缓解，通常需要积极治疗。这种挑战部分是由于LLD中常见的年龄相关的血管变化。成功的抗抑郁治疗涉及情感、认知和默认模式网络的变化。我们假设在LLD中，血管疾病通过破坏这些网络的连接对抗抑郁药的反应产生不利影响。该项目的主要目标是描述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。基于过去的工作和试点数据，我们先验地专注于扣带束和钩束。这些关键的纤维束连接额叶、颞叶和扣带区域，参与认知和情感反应。我们的中心假设是，缺血性损伤的扣带束和钩束有助于结构和功能的连接缺陷，这些束。这会导致断开效应，从而改变连接区域的功能。与此同时，这增加了对抗抑郁药反应不良的风险。我们的方法是招募130名60岁以上的成年人，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会话，包括包含注意力和情感成分的fMRI情感古怪任务。受试者将按以下因素分层： 脑损伤严重程度，并以2：1的比例随机分配至艾司西酞普兰或匹配安慰剂的双盲8周试验。那些没有缓解的人将过渡到为期8周的开放标签安非他酮试验，安非他酮是一种具有不同作用机制的抗抑郁药。这将使我们能够确定不同的和独特的回路缺陷是否影响对具有不同作用机制的抗抑郁药的反应，同时也解释安慰剂反应。探索性目的包括a）检查可作为纤维束损伤标志物的认知任务，和B）检查神经对不良抗抑郁反应的贡献的全脑方法。这种应用是重要的和创新的，因为它使用特定的白色物质病变的测量来检查局灶性血管损伤如何与功能连接测量和大脑活动相关联。然后，我们将研究这些措施如何预测抗抑郁药的反应。该项目将对了解血管疾病如何影响脑功能并导致LLD具有广泛的意义。重要的是，回路缺陷和抗抑郁反应之间的关系的识别可能具有临床意义，特别是如果我们可以确定认知测试标记物，作为一个替代道损伤。

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.