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: 10541220
• 负责人: Elizabeth Helen Andersen
• 金额: $ 19.44万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541220
• 关键词: Affective; Affective Symptoms; Age Years; Aggressive behavior; Amygdaloid structure; Anger; Antidepressive Agents; Anxiety; Attenuated; Behavioral; Brain; Coupling; Crossover Design; Diagnostic; Dimensions; Disease; Distress; Double-Blind Method; Electroencephalography; Endocrine; Environment; Estradiol; Estradiol Receptors; Estrogens; Etiology; Exhibits; Feedback; Frequencies; Frustration; Future; Impairment; Intervention Studies; Link; Major Depressive Disorder; Measures; Mediating; 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; biological adaptation to stress; depressive symptoms; emotional stimulus; estrone-3-glucuronide; improved; indexing; middle age; mood symptom; neural; neural network; neuromechanism; neuropathology; neurophysiology; psychosis risk; recruit; 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 烦躁不安的出现，而不是抑郁的情绪，是痛苦和损害的主要来源， 围绝经期妇女易怒，表现愤怒的倾向，是一个维度的结构， 精神疾病，包括抑郁症、焦虑症和精神病。边缘神经网络失调是 神经病理学的核心是对威胁的异常反应和对非奖励的沮丧，这两个相互关联的 易怒的结构。在对非奖励的威胁反应和挫折中，皮质边缘系统的参与可能是 可靠的研究使用脑电图（EEG）。额叶和边缘神经元的功能耦合 神经网络依赖于θ（4-8Hz）和β（13- 30 Hz）频率的同步神经振荡， 比率（θ/β）是边缘介导的情感处理的额叶自上而下控制的指数。 绝经过渡期的特征在于雌二醇（E2）的显著变化，雌二醇（E2）是一种有效的调节剂， 涉及情感和奖励处理的边缘网络。易受E2正常变化的影响， 病因与生殖情绪障碍有关，40%的围绝经期妇女表现出 易受E2变化引发的情感症状的影响。尽管E2易感性的预测因子 变化（早期绝经过渡期和最近的压力生活事件），神经生理学 这种易感性的机制是未知的。本研究的主要目的是确定 神经生理基础的易感性E2波动和应激症状在围绝经期。 我们将研究30名45 - 55岁的围绝经期妇女，她们有很高的情感风险， 通过招募以下女性对E2变化的敏感性：1）报告出现显著易怒 同时进入更年期过渡; 2）处于早期更年期过渡阶段; 3）具有 最近有1+严重压力性生活事件。在基线（一周），我们将使用每日尿E1 G（高度相关） E2的代谢物），以指示E2变异性并确定E1 G变异性和应激性之间的关系 症状严重程度; E1 G变异性和任务诱导的威胁反应性（点探针任务）期间的θ/β比值， 挫折非奖励（点减法攻击范式）;和任务引起的θ/β比率， 易怒症状。在基线之后，我们将实验性地操纵E2环境以确定 E2在任务诱导的行为和神经生理反应中的作用，以及在易怒症状中的作用。使用 受试者内、随机、安慰剂对照、交叉设计，每名受试者将在两个 条件：经皮E2（0.1 mg/天）3周以稳定E2变异性，安慰剂3周。E1G 将在每种情况下评估变异性、易激惹症状和EEG测量。稳定E2变异性 透皮E2有望改善异常威胁和挫折与非奖励的振荡相关性 （降低θ/β比值），与更有效的额叶-边缘系统网络一致，并减少易怒。