Progesterone mediates brain functional connectivity changes during the menstrual cycle-a pilot resting state MRI study

Abstract

The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC) mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal Resting-state functional Magnetic Resonance Imaging (rs-fMRI) design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

Keywords: RS-fMRI; estradiol; functional connectivity; menstrual cycle; progesterone.

Figure 1

Estradiol, progesterone and LH fluctuation across the menstrual cycle. Characteristic patterns of serum estradiol (red line), progesterone (black line) and LH (green line) levels are displayed across two menstrual cycles. The depicted data represents days of cycle with corresponding z-standardized, single hormone values, matching the single scan time points in chronological order. As expected, estradiol shows a first prominent peak in the periovulatory phase, followed by a second peak in the late luteal phase. LH surges after the peak of estrogen, shortly before ovulation. Progesterone levels are low during the follicular phase and high during the luteal phase.

Figure 2

Progesterone-modulated functional connectivity in bilateral dorsolateral prefrontal cortex and hippocampus. The whole brain Eigenvector Centrality Mapping (EC) analysis reveals a significant correlation of progesterone with bilateral dorsolateral prefrontal cortex (DLPFC) (p < 0.001 unc.; left panel). In the seed based analysis, these progesterone-modulated intrinsic connectivity-changes in right and left DLPFC were found to connect with bilateral hippocampus (right panel). For the left DLPFC (top panel), connectivity-changes to bilateral hippocampus were observed at a threshold of p < 0.005 (signal change depicted in red). The right DLPFC also showed progesterone-modulated connectivity with bilateral hippocampus modulated by progesterone at both thresholds: p < 0.001 (unc.; signal change depicted in yellow) and p < 0.005 (unc.; signal change depicted in red).

Figure 3

Progesterone-modulated functional connectivity in bilateral sensorimotor cortex and hippocampus. The whole brain Eigenvector Centrality Mapping (EC) analysis reveals a significant correlation of progesterone with bilateral sensorimotor cortex (p < 0.001 unc.; left panel). In the seed based analysis (right panel), these progesterone-modulated intrinsic connectivity-changes in right and left sensorimotor cortex were found to connect with the left hippocampus (signal change depicted in yellow) at a threshold of p < 0.001 (unc.); for p < 0.005 (unc.) a bilateral effect with both hippocampi could be demonstrated (signal change depicted in red).