Neural Connectivity Affecting the Antidepressant Response: Testing a Lesion Model

描述(由申请人提供)：老年抑郁症患者很难缓解，他们通常需要积极的治疗。这一挑战的部分原因是LLD中常见的与年龄相关的血管变化。成功的抗抑郁药物治疗涉及情感、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接而对抗抑郁药物的反应产生不利影响。该项目的主要目标是表征局部血管损伤如何影响区域连通性和对抗抑郁药物的反应。在前人工作和先导数据的基础上，我们先验地将重点放在扣带束和钩状束上。这些关键纤维束连接涉及认知和情感反应的额叶、颞叶和扣带区。我们的中心假设是扣带束和钩状束的缺血性损伤导致了这些束的结构和功能连接缺陷。这会导致断开效应，从而改变相连区域的功能。在TUN中，这增加了对抗抑郁药物反应不佳的风险。我们的方法是招募130名60岁以上的被诊断为严重抑郁症的成年人。受试者将完成临床评估、认知测试和核磁共振/功能磁共振成像课程，包括一项包含注意力和情感成分的功能磁共振情绪古怪任务。参赛者将按以下顺序进行分层 脑损伤严重程度按2：1随机与艾司西普兰或匹配安慰剂的双盲8周试验进行比较。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的试验，这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和不同的回路缺陷是否会影响对具有不同作用机制的抗抑郁药物的反应，同时也解释了安慰剂反应。探索性的目的包括a)检查可以作为纤维束损伤标志的认知任务，以及b)全脑方法检查神经对抗抑郁反应不良的影响。这一应用具有重要意义和创新意义，因为它使用脑白质病变的特定部位测量来检查局灶性血管损伤与功能连通性测量和脑活动的关系。然后，我们将研究这些指标如何预测抗抑郁药物的反应。该项目将对了解血管疾病如何影响大脑功能并导致LLD具有广泛的意义。重要的是，识别回路缺陷和抗抑郁药物反应之间的关系可能具有临床意义，特别是如果我们能够识别认知测试标记物作为肌束损伤的替代品。

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.