Biological systems underlying the impact of potential threat on cognitive control in mood disorders

7.项目摘要/摘要 抑郁症使个人付出巨大的痛苦和磨难，经济代价约为102美元。 每年因工作效率下降而损失数十亿美元。抑郁情绪和功能性的关键因素 抑郁症的损害是认知功能的紊乱。认知功能障碍是一种持久的 抑郁症的特征，不容易治愈。初步工作表明，急性应激的程度- 在认知任务中经历的诱发焦虑有可能解释前额叶的异质性 大脑皮层(PFC)介导了抑郁症的认知控制缺陷。动物工作指出了 杏仁中央核和蓝斑-去甲肾上腺素(LC-NE)系统作为应激的中介- 引发焦虑。然而，导致应激诱导焦虑的特定生物学机制及其 心境障碍患者前额叶功能障碍、抑郁情绪和功能结局下降的作用 目前仍不清楚。阐明应激性焦虑的生物学机制及其对健康的影响 认知控制可能为识别特定的个人铺平道路，这些个人的干预是有选择的 抑郁症的目标认知控制缺陷将是最有效的。这项研究的目标1建议评估 LC-NE系统对应激诱导的焦虑的变异性的贡献；目标2将检查两者之间的联系 在LC中，腹侧被盖区(VTA)-中皮质多巴胺能环路与认知控制有关。要实现 这些目标是140名年龄在30-50岁之间的男性和女性，表现为抑郁症谱系障碍(即 抑郁障碍、持续性抑郁障碍或其他特定的抑郁障碍)和40名健康人 控件将完成认知任务-负担表示、维护和更新方面的负担 认知控制--在潜在威胁和非威胁条件下。神经回路的激活 将使用功能磁共振成像(FMRI)进行评估，以定位和评估活动 在LC、VTA和认知控制网络内(即，在背外侧前额叶皮质内)。此外, 并发的瞳孔测量将被收集并用作LC激活的二级指标，因为它的高 与LC神经放电的相关性。我们将使用内分泌来评估应激反应的大小(例如， 唾液α-淀粉酶)、生理(即皮肤电导)和自我报告评估(即状态焦虑)。 此外，还将使用行为表现和反应时间数据来评估压力对 认知控制。目标3将确定应激诱导的焦虑和认知控制的神经生物标志物 在实验室环境中观察，前瞻性地预测抑郁和焦虑情绪和功能结果 日常生活中的压力环境。参与者将被跟踪两周，并被要求完成 对他们的工作效率、社会/家庭功能和情绪进行随机和回应的评估 应激的生理检测。因此，这一建议将阐明LC-NE系统在认知方面的作用 控制障碍及其对功能损害的影响。

7. Project Summary/Abstract Depression exacts a great personal cost in pain and suffering and an economic cost of approximately $102 billion a year due to lost work productivity. A key factor underlying depressive mood and functional impairment in depression is disrupted cognitive functioning. Disrupted cognitive functioning is an enduring feature of depression that is not readily treated. Preliminary work indicates that the degree of acute stress- induced anxiety experienced during a cognitive task has the potential to explain heterogeneity in prefrontal cortex (PFC) mediated cognitive control deficits in depression. Animal work points to the central role of the central nucleus of the amygdala and the locus coeruleus-norepinephrine (LC-NE) system as mediating stress- induced anxiety. However, the specific biological mechanisms underlying stress-induced anxiety and their contributions to PFC impairment, depressive mood, and decreased functional outcomes in mood disorders remain unclear. Clarifying the biological mechanisms underlying stress-induced anxiety and its effects on cognitive control may pave the way for identifying specific individuals for whom interventions that selectively target cognitive control deficits in depression will be most effective. Aim 1 of this study proposes to evaluate the contributions of the LC-NE system to variability in stress-induced anxiety; and Aim 2 will examine associations among LC, ventral tegmental area(VTA)-mesocortical dopaminergic circuit, and cognitive control. To achieve these aims 140 men and women aged 30-50 years presenting with depression spectrum disorders (i.e., major depressive disorder, persistent depressive disorder, or other specified depressive disorder) and 40 healthy controls will complete cognitive tasks—taxing the representation, maintenance, and updating aspects of cognitive control—under potentially threatening and non-threatening conditions. Activation of neural circuits will be assessed with functional magnetic resonance imaging (fMRI) optimized to localize and assess activity within the LC, VTA, and cognitive control networks (i.e., within the dorsolateral prefrontal cortex). In addition, concurrent pupillometry will be collected and used as a secondary index of LC activation, given its high correlation with LC neural firing. We will assess the magnitude of the stress-response using endocrine (e.g., salivary alpha amylase), physiological (i.e., skin conductance), and self-report assessments (i.e., state-anxiety). In addition, behavioral performance and reaction-time data will be used to assess the impact of stress on cognitive control. Aim 3 will determine if neural biomarkers of stress-induced anxiety and cognitive control observed in a laboratory setting prospectively predict depressed and anxious mood and functional outcomes in the context of stress in daily life. Participants will be followed for 2 weeks and will be asked to complete assessments of their work productivity, social/family functioning, and mood randomly and in response to physiological detection of stress. Thus, this proposal will clarify the role of the LC-NE system on cognitive dyscontrol and its influence on functional impairment.