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

潜在威胁对情绪障碍认知控制影响的生物系统

• 批准号: 9766892
• 负责人: Neil Patrick Jones
• 金额: $ 67.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766892
• 关键词: Amygdaloid structure; Animals; Anterior; Anxiety; Anxiety Disorders; Atlases; Behavior; Behavioral; Biological; Biological Markers; Cell Nucleus; Cognitive; Comorbidity; Custom; Data; Depressed mood; Depressive disorder; Detection; Development; Diagnosis; Disease; Dopamine; Ecological momentary assessment; Endocrine; Exhibits; Family; Feeling; Female; Financial Hardship; Functional Magnetic Resonance Imaging; Functional disorder; Galvanic Skin Response; Goals; Heterogeneity; Image; Impaired cognition; Impairment; Individual; Intervention; Knowledge; Laboratories; Life; Maintenance; Major Depressive Disorder; Measures; Mediating; Mental Depression; Mood Disorders; Moods; Motivation; Neuropsychological Tests; Norepinephrine; Occupations; Pain; Participant; Pathway interactions; Patient Self-Report; Performance; Peripheral; Phenotype; Physiological; Physiology; Prefrontal Cortex; Productivity; Reaction Time; Regulation; Research; Role; Salivary; Secondary to; Signal Transduction; Societies; Specific qualifier value; Stress; Structure; Subgroup; System; Task Performances; Taxes; United States; Update; Ventral Tegmental Area; Woman; Work; acute stress; aged; alpha-amylase; anxiety states; anxious; biological adaptation to stress; biological systems; cognitive control; cognitive development; cognitive function; cognitive task; cost; depressive symptoms; economic cost; endophenotype; executive function; experience; functional disability; functional outcomes; indexing; locus ceruleus structure; men; negative affect; negative mood; neural circuit; neuromechanism; neuromelanin; noradrenergic; norepinephrine system; novel; prospective; recruit; relating to nervous system; response; social; years lived with disability

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.

7.项目总结/摘要 抑郁症需要在疼痛和痛苦中付出巨大的个人代价，经济代价约为102美元 每年损失10亿美元，这是因为工作效率下降。抑郁情绪和功能障碍的一个关键因素 抑郁症的损害是认知功能被破坏。认知功能障碍是一种持久的 不容易治疗的抑郁症的特征。初步调查显示急性应激反应的程度- 在认知任务中经历的诱导焦虑有可能解释前额叶皮层的异质性。 皮质（PFC）介导的认知控制缺陷的抑郁症。动物工作指出了动物的核心作用， 杏仁核中央核和蓝斑-去甲肾上腺素（LC-NE）系统作为介导应激- 诱导焦虑然而，压力诱导焦虑的具体生物学机制及其 情感障碍患者PFC损伤、抑郁情绪和功能结局下降的原因 仍然不清楚。阐明压力诱导焦虑的生物学机制及其对 认知控制可以为识别特定的个体铺平道路， 针对抑郁症的认知控制缺陷将是最有效的。本研究的目的1是评估 LC-NE系统对压力诱导的焦虑的可变性的贡献;目标2将检查 腹侧被盖区（VTA）-中皮层多巴胺能神经回路与认知控制的关系。实现 这些目标是140名年龄在30-50岁的患有抑郁症谱系障碍的男性和女性（即，主要 抑郁症、持续性抑郁症或其他特定的抑郁症）和40名健康人 控制将完成认知任务--对表示、维护和更新方面的负担， 认知控制-在潜在的威胁和非威胁条件下。激活神经回路 将使用功能性磁共振成像（fMRI）进行评估，以优化定位和评估活动 在LC、VTA和认知控制网络（即，在背外侧前额叶皮层内）。此外，本发明还提供了一种方法， 同时收集瞳孔测量，并用作LC激活的次要指标，因为其高 与LC神经放电相关。我们将使用内分泌（例如， 唾液α淀粉酶），生理学的（即，皮肤电导），和自我报告评估（即，状态焦虑）。 此外，行为表现和反应时间数据将用于评估压力对 认知控制目标3将确定压力诱导的焦虑和认知控制的神经生物标志物是否 在实验室环境中观察到的前瞻性预测抑郁和焦虑情绪和功能结果， 日常生活中的压力。参与者将被随访2周，并将被要求完成 随机评估他们的工作效率、社会/家庭功能和情绪， 压力的生理检测。因此，该建议将阐明LC-NE系统在认知中的作用， 控制障碍及其对功能障碍的影响。