Hormonal Cycles, Brain Network Connectivity, and Windows of Vulnerability to Affective Disorder

Abstract

The rate of affective disorder is substantially higher in women than in men, and considerable evidence points to the actions of ovarian hormones in mediating this disparity. In this Opinion, we discuss the hypothesis that cyclic changes in ovarian hormone levels produce cyclic alterations in connectivity between the intrinsic networks of the brain. These alterations produce specific temporal windows within the menstrual cycle when internetwork connectivity is increased, associated with increased stress reactivity and better memory for unpleasant, arousing events, leading to increased negative mood and susceptibility to affective disorder. Our windows of vulnerability model offers insights for both treatment of affective disorder and research on sex differences in the brain.

Figure 1,. Key Figure: Windows of Vulnerability Model:

Panel A: Schematic of the mid-luteal window of vulnerability in the context of hormone levels across the menstrual cycle. Increased risk of affective disorder occurs midway between ovulation and next menstruation, when progesterone levels are at peak, and estradiol levels are moderate. Panel B: Effects of ovarian hormones on brain, body and memory, leading to increased affective vulnerability. (a) Elevated ovarian hormone levels in the midluteal phase alter connectivity between the salience network and default mode network. (b) Increased inter-network connectivity promotes greater neural, hormonal, and autonomic stress responses. (c) Increased inter-network connectivity also promotes encoding, consolidation and retrieval of negative experiences. (d) Enhanced stress responses cause negative experiences to be experienced as more arousing, further promoting affective memory enhancement. (e) Enhanced encoding, consolidation and retrieval of negative events produce distortions of memory, which promote experiences of intense negative affect.

Figure 2:. Ovarian Hormone Influence Salience Network Connectivity:

a) Default mode (yellow) and salience (blue) networks [122] b) Exogenous progesterone increases connectivity between amygdala and medial prefrontal cortex [75]. c) Exogenous progesterone increases connectivity between amygdala and anterior mid-cingulate [75]. d) Treatment with oral contraceptives increases connectivity of anterior mid-cingulate to precuneus [73]. e) Regions of greater connectivity to left amygdala in luteal vs. follicular phase, including cerebellum, precuneus (center) and lateral prefrontal cortex [73].

Figure 3:. Ovarian Hormones Influence Stress Reactivity:

a) Enhanced amygdala signal to negative images in luteal vs. follicular phase [84]. b) Cortisol response to cold pressor stress in early follicular (EF), late follicular (LF) and mid-luteal (ML) phases. Cortisol response is significantly elevated in ML [94]. c) Ratio of high frequency to low frequency heart rate variability before and after mirror-tracing (MT) and mental arithmetic (MA) tasks in follicular and luteal phases. LF/HF ratio is significantly greater in luteal phase [89]. d-f) Comparison of follicular and luteal women’s response during cold pressor stress in terms of d) noradrenaline response e) subjective depression f) subjective anxiety [92]