It is well established that women exhibit a significantly higher rate of affective disorders than men do. This difference is particularly strong in post-traumatic stress disorder, where women are more than twice as likely to experience PTSD than men. Recent evidence suggests that women?s susceptibility to PTSD varies with their levels of ovarian hormones. During the luteal phase, when progesterone is elevated, women are more than three times as likely to develop PTSD symptoms after trauma. Similarly, women are twice as likely as men to be diagnosed with depression, and depressive symptoms also vary by menstrual phase. Both of these disorders involve alterations of memory, stress responses, and resting connectivity in the brain?s intrinsic networks. In PTSD, individuals experience intrusive memories of traumatic events, while individuals with depression show a marked negative retrieval bias. Stress-evoked release of the stress hormone cortisol is also elevated in both disorders. Similarly, resting connectivity between the default mode network, a group of structures engaged during the retrieval of memories, and the salience network, a group of structures involved in processing emotion, is elevated in individuals suffering from both disorders. Recent research indicates that affective memory, stress responsiveness, and resting connectivity are all influenced by changes in ovarian hormone levels. Negative memories acquired during the progesterone-rich luteal phase are better retained than during other menstrual phases. Increased progesterone is also associated with increased stress-evoked cortisol secretion. Similarly, ingestion of progesterone pills increases the connectivity between key nodes of default and salience networks. No study to date, however, has assessed the influence of changes in ovarian hormones on inter-network connectivity over the menstrual cycle. We hypothesize that changes in hormone levels over the menstrual cycle produce natural windows of vulnerability to traumatic life events, during which changes in the connectivity of the brain facilitate stress responses and enhance memory for negative experiences. To test this hypothesis, we will measure resting connectivity, stress hormone levels, physiological responses, and memory for negative material learned at hormonally distinct phases of the menstrual cycle. We predict that connectivity between resting and default mode networks will be at highest levels during the luteal phase, and that material learned in a negative emotional state will be best retained during the luteal phase. Additionally, we predict that the amount of connectivity between these two networks will significantly predict the enhancement of memory by negative affect, as well as the physiological response to negative mood induction. The results of this study could help to identify periods of maximum vulnerability trauma, thus facilitating prevention, as well as point to new and more targeted drug treatments.

Public Health Relevance

This study will compare the connectivity between brain networks involved in emotion and memory over the course of the menstrual cycle, compare memory for emotional material learned in different phases of the menstrual cycle, and test for changes in stress hormone activity and negative mood between cycle phases. Based on earlier data, we predict that changes in brain connectivity between menstrual phases will cause windows of vulnerability to negative experience, where memory for emotional material is increased when progesterone levels are high. These findings will help to understand sex differences in post-traumatic stress disorder, and specifically explain why women traumatized during the high-progesterone luteal phase of the menstrual cycle are significantly more likely to develop PTSD than women traumatized at other times.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Cognition and Perception Study Section (CP)
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Vicentic, Aleksandra
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Massachusetts General Hospital
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Barrett, Lisa Feldman; Khan, Zulqarnain; Dy, Jennifer et al. (2018) Nature of Emotion Categories: Comment on Cowen and Keltner. Trends Cogn Sci 22:97-99
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