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

项目总结 易怒情绪的出现，而不是抑郁情绪的出现，是痛苦和损害的主要来源。 围绝经期妇女。易怒，即表现出愤怒的倾向，是一个可以看到的维度结构 精神障碍，包括抑郁、焦虑和精神病。边缘神经网络的调节失调 对威胁的异常反应和对非奖励的沮丧是神经病理学的中心，这两种反应相互关联 易怒的结构。在威胁反应和对非奖励的挫折感中，皮质-边缘参与可能是 使用脑电(EEG)进行了可靠的研究。额叶和边缘神经的功能耦合 网络依赖于theta(4-8赫兹)和β(13-30赫兹)频率的同步神经振荡，其 比率(theta/beta)是边缘介导的情感加工的前额自上而下控制的指标。 更年期过渡的特点是雌二醇(E2)的变化很大，雌二醇是一种强有力的调节因子 边缘网络参与情感和奖赏的处理。对E2正常变化的脆弱性是 病因与生殖情绪障碍有关，40%的围绝经期妇女表现出 对由雌二醇变化引发的情感症状的易感性。尽管这种对E2易感性的预测因素 确定的变化(早期绝经过渡期和最近的应激性生活事件)，神经生理学 这种易感性的机制尚不清楚。这项研究的主要目标是确定 围绝经期对雌二醇波动和应激症状易感性的神经生理学基础。 我们将研究30名围绝经期妇女，年龄在45-55岁之间，她们患情感性精神疾病的几率很高。 通过招募以下女性对E2变化的易感性：1)报告出现明显的易怒 同时进入更年期过渡阶段；2)处于更年期早期过渡阶段；3)有 最近有1+次严重的压力生活事件。在基线(一周)时，我们将使用每日尿E1G(高度相关 E2的代谢物)以指示E2的变异性并确定：E1G变异性和应激性之间的关系 症状严重性；任务诱导的威胁反应(点探测任务)期间的E1G变异性和β/β比率 挫折感与非奖励性(点减攻击范式)；任务诱发的β/β比 易怒症状。在基线之后，我们将试验性地操纵E2环境以确定 雌二醇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，每个参与者将在两个 条件：服用3周的透皮雌二醇组(0.1毫克/天)以稳定E2的变异性，并服用安慰剂3周。E1G 将在每种情况下评估变异性、易怒症状和脑电测量。稳定雌二醇性变异性 透皮雌激素有望改善异常威胁和挫折感与非奖励的振荡相关性 (降低theta/beta比率)，与更有效的额叶-边缘网络一致，并减少易怒。

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.