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

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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.