FMRI STUDIES OF EMOTIONAL CIRCUITRY IN DEPRESSION

描述（由申请人提供）：这项竞争性拨款更新申请提出了新的实验，以测试抑郁症引起的情绪失调模型和药物治疗与认知行为疗法（CBT）治疗的差异变化。本项目提出：1)抑郁相关的负性情绪内隐和外显调节功能障碍与边缘结构的过度激活有关，而边缘结构的过度激活又导致前额叶皮层的激活受损。杏仁核和DLPFC的异常激活以及边缘和控制结构之间正常的反相关性的丧失证明了这一点；2)负性情绪调节过程中，扣带背回和额叶中回表现为过度活跃，可能是由于激活效率低下所致。3)边缘结构间活动相关性降低；4)这种相关性的丧失可以通过在CBT过程中反复练习重构负面情绪材料来改善。在基线和随后的CBT （n=30）或抗抑郁药（n=30）治疗中，我们将在两项任务和静息状态fMRI采集中评估抑郁症受试者（n=60）与对照组（n=30）的脑区域功能。抑郁受试者将随机接受艾司西酞普兰抗抑郁治疗或12期CBT治疗，并进行第二次功能磁共振成像治疗。将比较CBT和抗抑郁治疗在脑区域激活的变化和脑区域活动之间的相关性。1)我们假设CBT和抗抑郁药在冲突和调节任务中都会降低杏仁核活动，增加DLPFC活动。我们将把这两个任务中的区域激活联系起来。2)我们假设与抗抑郁药类似，CBT将恢复DLPFC和杏仁核在任务状态和静息状态之间的正常反相关关系。我们假设，与抗抑郁药不同，CBT也会恢复大脑边缘结构之间的正常关联。我们将把关键基线变量（包括HAMD分数、MASQ分数和BIS/BAS分数）的个人分数与杏仁核活动联系起来。3)我们假设这些变量的高分将与杏仁核活动呈正相关。我们进一步假设这些变量将与治疗后的杏仁核活动相关。意义：了解情绪的调节对抑郁症研究至关重要，无论是了解日常情绪调节，还是了解CBT可能运作的机制。我们的总体目标是了解无法调节抑郁症中的内隐和外显负面情绪的区域贡献以及理解治疗的含义。抗抑郁药物与CBT的比较将为这些治疗如何影响情绪回路提供重要的比较信息，并将测试情绪回路功能障碍的明确模型。在这个项目中，我们将对60名抑郁症患者和30名匹配的对照受试者进行功能磁共振成像研究。我们将在三种不同的情况下检查认知行为疗法（CBT）或抗抑郁药物治疗后大脑区域的变化。一个是情绪消极冲突任务。第二个任务是让人们调节自己对负面图片的情绪反应。第三个是在休息状态。大脑活动将在CBT和抗抑郁药物治疗前和治疗后进行比较。这将增加我们对重度抑郁症治疗机制的理解。

DESCRIPTION (provided by applicant): This competitive grant renewal application proposes novel experiments to test a model of depression induced emotional dysregulation and differential changes with medication versus cognitive behavioral therapy (CBT) treatment. This project proposes: 1) Depression-related dysfunction in both implicit and explicit regulation of negative affect is associated with hyperactivations in limbic structures that in turn produce impairment in prefrontal cortex activation. This is evidenced in abnormalities in activations in amygdala and DLPFC and a loss of the normal anticorrelation between limbic and control structures; 2) During regulation of negative affect regions in dorsal cingulate and middle frontal gyrus show hyperactivity, perhaps resulting from inefficient activation. 3) Correlation in activity among limbic structures decreases; and 4) This loss of correlation can be ameliorated by the repeated practice of reframing negative emotional material during CBT. At baseline and following treatment with CBT (n=30) or antidepressants (n=30) we will evaluate regional brain function in depressed subjects (n=60) compared with controls (n=30) in two tasks and a resting state fMRI acquisition. Depressed subjects will be randomized to treatment with either a course of antidepressant treatment with escitalopram or a 12-session course of CBT, and a second fMRI session will be conducted. CBT and antidepressant treatment will be compared with respect to changes in regional activations and correlations among activity in brain regions. 1) We hypothesize that both CBT and antidepressants will decrease amygdala activity and increase DLPFC activity following treatment in both the Conflict and Regulate tasks. We will correlate regional activations during both tasks. 2) We hypothesize that similar to antidepressants, CBT will reinstate the normal anticorrelation between DLPFC and amygdala in both task-based and resting state correlations. We hypothesize that unlike antidepressants, CBT will also restore normal correlations among limbic structures. We will correlate individual scores on key baseline variables (including HAMD scores, MASQ scores and BIS/BAS scores) with amygdala activity. 3) We hypothesize that high scores on these variables will be positively correlated with amygdala activity. We further hypothesize that these variables will correlate with amygdala activity following treatment. Significance: Understanding regulation of emotion is crucial to depression research, both for understanding day to day mood regulation and also as the mechanism through which CBT may operate. Our overall goal is to understand the regional contributions to inability to modulate implicit and explicit negative emotions in depression and what the implications are for understanding treatment. The comparison of antidepressant medication with CBT will add important comparative information about how these treatments affect emotional circuitry and will test an explicit model of emotional circuit dysfunction. PUBLIC HEALTH RELEVANCE In this project we will conduct functional magnetic resonance imaging studies in 60 depressed patients and 30 matched comparison subjects. We will examine changes in brain regions following cognitive behavioral therapy (CBT) or antidepressant treatment during three different conditions. One is an emotionally negative conflict task. The second is a task in which people regulate their emotional reaction to negative pictures. The third is during the resting state. Brain activity will be compared before and after treatment for these tasks in both CBT and antidepressant medication. This will add to our understanding of treatment mechanisms for major depression.