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Background: Emotion regulation deficits have been highlighted as a transdiagnostic feature of multiple psychiatric disorders, including premenstrual dysphoric disorder (PMDD). In this study, we hypothesized that deficient prefrontal top-down regulation of key nodes of the salience network (SN) is a characteristic of PMDD, driven by increased levels of progesterone-derived neuroactive steroids.

Methods: Functional magnetic resonance imaging was used to investigate menstrual cycle–related variations in brain activity and connectivity during 2 emotional tasks (emotion generation and regulation) in 29 women with PMDD and 27 control women. We also examined whether differential brain activation between groups was related to serum levels of progesterone-derived neuroactive steroids and premenstrual symptom severity.

Results: Women with PMDD showed increased reactivity in key nodes of the SN and, at subthreshold level, in the default mode network during the luteal phase when passively viewing negative emotional stimuli. Intriguingly, SN hyperactivity in patients with PMDD was also apparent during the follicular phase and related to premenstrual symptom severity. Women with PMDD and control women had similar network connectivity patterns and activity in regions associated with the conscious control of emotion in PMDD. No link to progesterone-derived neuroactive steroids was found.

Conclusions: Multiple network aberrations during the luteal phase may explain the development of mood symptoms during the luteal phase. Furthermore, higher baseline (follicular) SN activity may render women with PMDD more susceptible to severe mood symptoms in response to hormonal fluctuations. What drives increased SN activity in the follicular phase is unknown, but innate and neuroplastic mechanisms have been proposed.