Neural Connectivity Affecting the Antidepressant Response: Testing a Lesion Model

描述（由申请人提供）：患有晚期抑郁症（LLD）的个体很难获得缓解，他们通常需要积极的治疗。这一挑战部分是由于与年龄相关的血管变化，这在LLD中很常见。成功的抗抑郁治疗涉及情感、认知和默认模式网络的改变。我们假设，在LLD中，血管疾病通过破坏这些网络的连通性，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。基于以往的工作和试点数据，我们先验地关注于扣带束和钩扣束。这些关键的纤维束连接着与认知和情感反应有关的额叶区、颞叶区和扣带区。我们的中心假设是，对扣带束和钩扣束的缺血性损伤导致了这些束的结构和功能连接缺陷。这导致断开效应，改变连接区域的功能。反过来，这增加了抗抑郁药反应不良的风险。我们的方法是招募130名60岁以上诊断为重度抑郁症的成年人。受试者将完成临床评估、认知测试和MRI/fMRI会话，包括fMRI情感古怪任务，包括注意力和情感成分。参与者将按

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.