Identifying neurophysiological mechanisms of susceptibility to estradiol fluctuation and irritability symptoms in the menopause transition: An experimental approach

确定更年期过渡期雌二醇波动和烦躁症状易感性的神经生理学机制：实验方法

• 批准号: 10348341
• 负责人: Elizabeth Helen Andersen
• 金额: $ 23.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348341
• 关键词: Affective; Affective Symptoms; Age-Years; Aggressive behavior; Amygdaloid structure; Anger; Antidepressive Agents; Anxiety; Attenuated; Behavioral; Brain; Coupling; Crossover Design; Dimensions; Disease; Distress; Double-Blind Method; Electroencephalography; Endocrine; Environment; Estradiol; Estrogens; Etiology; Exhibits; Feedback; Frequencies; Frustration; Future; Impairment; Intervention Studies; Link; Major Depressive Disorder; Measures; Mediating; Menopause; Mental Depression; Mental disorders; Methods; Modeling; Mood Disorders; Participant; Perimenopause; Placebo Control; Placebos; Predisposition; Premature Menopause; Prevention Research; Probability; Psychopathology; Psychoses; Randomized; Reporting; Research; Risk; Role; Sampling; Serum; Severities; Source; Stimulus; Stress; Stressful Event; Symptoms; System; Testing; Woman; attentional bias; base; biological adaptation to stress; depressive symptoms; emotional stimulus; estrone-3-glucuronide; improved; indexing; middle age; mood symptom; neural network; neuromechanism; neuropathology; neurophysiology; psychosis risk; receptor; recruit; relating to nervous system; reproductive; response; reward processing; stem; targeted biomarker; trend; urinary; Affective; Affective Symptoms; Age-Years; Aggressive behavior; Amygdaloid structure; Anger; Antidepressive Agents; Anxiety; Attenuated; Behavioral; Brain; Coupling; Crossover Design; Dimensions; Disease; Distress; Double-Blind Method; Electroencephalography; Endocrine; Environment; Estradiol; Estrogens; Etiology; Exhibits; Feedback; Frequencies; Frustration; Future; Impairment; Intervention Studies; Link; Major Depressive Disorder; Measures; Mediating; Menopause; Mental Depression; Mental disorders; Methods; Modeling; Mood Disorders; Participant; Perimenopause; Placebo Control; Placebos; Predisposition; Premature Menopause; Prevention Research; Probability; Psychopathology; Psychoses; Randomized; Reporting; Research; Risk; Role; Sampling; Serum; Severities; Source; Stimulus; Stress; Stressful Event; Symptoms; System; Testing; Woman; attentional bias; base; biological adaptation to stress; depressive symptoms; emotional stimulus; estrone-3-glucuronide; improved; indexing; middle age; mood symptom; neural network; neuromechanism; neuropathology; neurophysiology; psychosis risk; receptor; recruit; relating to nervous system; reproductive; response; reward processing; stem; targeted biomarker; trend; urinary

PROJECT SUMMARY The emergence of irritability, not depressed mood, is the primary source of distress and impairment for perimenopausal women. Irritability, the predisposition to exhibit anger, is a dimensional construct seen across psychiatric disorders, including depression, anxiety, and psychosis. Dysregulation of limbic neural networks is central to the neuropathology of aberrant responses to threat and frustration to non-reward, two interconnected constructs of irritability. Cortico-limbic engagement during threat reactivity and frustration to non-reward can be reliably studied using electroencephalography (EEG). The functional coupling of frontal and limbic neural networks relies on synchronous neural oscillations in theta (4-8Hz) and beta (13-30Hz) frequencies, and their ratio (theta/beta) is an index of frontal top-down control of limbic-mediated affective processing. The menopause transition is characterized by substantial variability in estradiol (E2), a potent modulator of limbic networks involved in affective and reward processing. Vulnerability to normal changes in E2 is etiologically relevant to reproductive mood disorders, with 40% of perimenopausal women showing susceptibility to affective symptoms triggered by changes in E2. Although predictors of this susceptibility to E2 change are identified (early menopause transition stage and recent stressful life events), the neurophysiologic mechanisms of this susceptibility are unknown. The primary objective of this research is to determine the neurophysiological basis of susceptibility to E2 fluctuations and irritability symptoms in the perimenopause. We will study 30 perimenopausal women, 45 – 55 years of age, who have high probability for affective susceptibility to changes in E2 by recruiting women who: 1) report the emergence of significant irritability concurrent with entering the menopause transition; 2) are in the early menopause transition stage; and 3) have had 1+ recent severe stressful life event. At baseline (one week) we will use daily urinary E1G (highly correlated metabolite of E2) to index E2 variability and determine relationships between: E1G variability and irritability symptom severity; E1G variability and theta/beta ratios during task-induced threat reactivity (Dot Probe task) and frustration to non-reward (Point Subtraction Aggression Paradigm); and task-induced theta/beta ratios and irritability symptoms. Following baseline, we will experimentally manipulate the E2 environment to determine the role of E2 in task-induced behavioral and neurophysiological responses, and in irritability symptoms. Using a within-subjects, randomized, placebo-controlled, cross-over design, each participant will be studied under two conditions: 3 weeks on transdermal E2 (0.1 mg/day) to stabilize E2 variability and 3 weeks on placebo. E1G variability, irritability symptoms, and EEG measures will be assessed in each condition. Stabilizing E2 variability with transdermal E2 is expected to improve oscillatory correlates of aberrant threat and frustration to non-reward (decrease theta/beta ratios), consistent with more efficient frontal-limbic networks, and reduce irritability.

项目摘要 烦躁的出现，而不是情绪低落，是困扰和损害的主要来源 绝经妇女。易怒，展示愤怒的倾向，是一个横跨的维度结构 精神疾病，包括抑郁，动画和精神病。边缘神经网络的失调是 对非回报的威胁和挫败感异常反应的神经病理学的中心，两个相互联系 烦躁的结构。威胁反应性和对非回报的沮丧期间的Cortico-limbic参与可能是 使用脑电图（EEG）可靠地研究了。额叶和边缘中性的功能耦合 网络依赖于Theta（4-8Hz）和beta（13-30Hz）频率的同步神经振荡及其 比率（theta/beta）是边缘介导的情感处理的额叶自上而下控制的指数。 更年期过渡的特征是雌二醇（E2）的实质性变化，这是一个潜在的调节剂 与情感和奖励处理有关的边缘网络。 E2中正常变化的脆弱性为 病因与生殖情绪障碍有关，有40％的围绝经妇女显示 E2变化触发的情感症状的敏感性。尽管预测了这种对E2的敏感性 鉴定了变化（早期更年期过渡阶段和最近的压力性生活事件），神经生理学 这种敏感性的机制尚不清楚。这项研究的主要目的是确定 神经生理学的基础是围栏中E2波动和易怒症状的敏感性。 我们将研究30名45至55岁的围绝经妇女，她们对情感的可能性很高 通过招募妇女：1）报告出现明显易怒的妇女，对E2变化的敏感性 同时进入更年期过渡； 2）处于更年期过渡阶段； 3）有 最近有1个以上的严重压力寿命事件。在基线（一周）时，我们将使用每日尿液E1G（高度相关） E2的代谢产物）以索引E2变异性并确定：E1G变异性和易怒之间的关系 症状严重程度；任务引起的威胁反应性（DOT探针任务）和 对非回报的挫败感（点减法攻击范式）；以及任务引起的theta/beta比率和 易怒症状。基线之后，我们将通过实验操纵E2环境来确定 E2在任务引起的行为和神经生理学反应以及易怒症状中的作用。使用 主题内，随机，安慰剂对照，跨界设计，每个参与将在两个下进行研究 条件：透皮E2（0.1 mg/day）的3周以稳定E2变异性，安慰剂3周。 e1g 在每种情况下，将评估可变​​性，易怒症状和脑电图测量值。稳定E2变异性 随着透皮e2的预计将改善异常威胁和沮丧的振荡相关性 （降低theta/beta比），与更有效的额叶网络一致，并降低易怒。