Abstract
Increasing evidence suggests that endogenous sex steroid changes affect human brain functional connectivity, which could be obtained by resting-state fMRI (RS-fMRI). Nevertheless, RS studies on the menstrual cycle (MC) are underrepresented and yield inconsistent results. We attribute these inconsistencies to the use of various methods in exploratory approaches and small sample sizes. Hormonal fluctuations along the MC likely elicit subtle changes that, however, may still have profound impact on network dynamics when affecting key brain nodes. To address these issues, we propose a ROI-based multimodal analysis approach focusing on areas of high functional relevance to adequately capture these changes. To that end, sixty naturally cycling women underwent RS-fMRI in three different cycle phases and we performed the following analyses: (1) group-independent component analyses to identify intrinsic connectivity networks, (2) eigenvector centrality (EC) as a measure of centrality in the global connectivity hierarchy, (3) amplitude of low-frequency fluctuations (ALFF) as a measure of oscillatory activity and (4) seed-based analyses to investigate functional connectivity from the ROIs. For (2)–(4), we applied a hypothesis-driven ROI approach in the hippocampus, caudate and putamen. In the luteal phase, we found (1) decreased intrinsic connectivity of the right angular gyrus with the default mode network, (2) heightened EC for the hippocampus, and (3) increased ALFF for the caudate. Furthermore, we observed (4) stronger putamen–thalamic connectivity during the luteal phase and stronger fronto-striatal connectivity during the pre-ovulatory phase. This hormonal modulation of connectivity dynamics may underlie behavioural, emotional and sensorimotor changes along the MC.
Highlights
Sex hormones are well known for their structural and functional implications in the central nervous system (McEwen and Milner 2017)
For the final sample and as expected, estradiol levels were significantly higher during the pre-ovulatory phase compared to menses (b = 0.62, SEb = 0.10, t(118) = 6.33, p < 0.001) and luteal phase (b = − 0.32, SEb = 0.11, t(59) = − 2.92, p < 0.01), as well as during the luteal phase compared to menses (b = 0.28, SEb = 0.10, t(118) = 2.91, p < 0.01) (Table 3)
Progesterone levels were significantly higher during the luteal phase compared to menses (b = 1.23, SEb = 0.12, t(118) = 10.54, p < 0.001) and pre-ovulatory phase (b = 0.92, SEb = 0.11, t(59) = 8.17, p < 0.001), but did not differ between the pre-ovulatory phase and menses, as expected (b = 0.20, SEb = 0.12, t(118) = 1.70, p = 0.09) (Table 3, Fig. 1)
Summary
Sex hormones are well known for their structural and functional implications in the central nervous system (McEwen and Milner 2017). Progesterone has been shown to increase dendritic spine number and density in cortical neuron cultures (Sanchez et al 2013; Acharya et al 2017) This suggests similar mechanism of action for both sex hormones, animal data strongly indicate that the effects are context dependent and progesterone might facilitate some of these estrogenic actions, while modulating or opposing others (McEwen and Milner 2017). Higher brain activity has been observed in hippocampus before ovulation and in basal ganglia during the luteal phase (Pletzer et al 2019) Both at rest and during different tasks, increased functional cortico-subcortical connectivity has been reported during the higher hormone phases (Peper et al 2011; Arélin et al 2015). The fact that the majority of these changes occur irrespective of the task, suggests a menstrual cycle modulation of common underlying functional networks
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