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1The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone 2 production that occurs in most mammalian species. In rodents and nonhuman primates, 3 estrogen and progesterone's impact on the brain is evident across a range of 4 spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of 5 the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we 6 examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain 7 networks at rest in a woman who underwent brain imaging and venipuncture for 30 8 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's 9 widespread influence on cortical dynamics. Time-lagged analyses examined the 10 directionality of these relationships and reveal estrogen's ability to drive connectivity 11 across major functional brain networks, including the Default Mode and Dorsal Attention 12 Networks, whose hubs are densely populated with estrogen receptors. These results 13 reveal the rhythmic nature in which brain networks reorganize across the human 14 menstrual cycle. Neuroimaging studies that densely sample the individual connectome 15 have begun to transform our understanding of the brain's functional organization. As 16 these results indicate, taking endocrine factors into account is critical for fully 17 understanding the intrinsic dynamics of the human brain. The brain is an endocrine organ whose day-to-day function is intimately tied to the action 20 of neuromodulatory hormones [1][2][3][4] . Yet, the study of brain-hormone interactions in human 21 neuroscience has often been woefully myopic in scope: the classical approach of 22 interrogating the brain involves collecting data at a single time point from multiple 23 subjects and averaging across individuals to provide evidence for a 24 hormone-brain-behavior relationship. This cross-sectional approach obscures the rich, 25 rhythmic nature of endogenous hormone production. A promising trend in network 26 neuroscience is to flip the cross-sectional model by tracking small samples of individuals 27 over timescales of weeks, months, or years to provide insight into how biological, 28 behavioral, and state-dependent factors influence intra-and inter-individual variability in 29 the brain's intrinsic network organization [5][6][7] . Neuroimaging studies that densely sample 30 the individual connectome are beginning to transform our understanding of the dynamics 31 of human brain organization. However, these studies commonly overlook sex steroid 32 hormones as a source of variability-a surprising omission given that sex hormones are 33 powerful neuromodulators that display stable circadian, infradian, and circannual 34 rhythms in nearly all mammalian species. In the present study, we illustrate robust, 35 time-dependent interactions between the sex steroid hormones 17β-estradiol and 36 progesterone and the functional network organization of the brain over a complete 37 menstrual cycle, offering compell...

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Sex steroid hormones have been shown to alter regional brain activity, but the extent to which they modulate connectivity within and between large-scale functional brain networks over time has yet to be characterized. Here, we applied dynamic community detection techniques to data from a highly sampled female with 30 consecutive days of brain imaging and venipuncture measurements to characterize changes in resting-state community structure across the menstrual cycle. Four stable functional communities were identified, consisting of nodes from visual, default mode, frontal control, and somatomotor networks. Limbic, subcortical, and attention networks exhibited higher than expected levels of nodal flexibility, a hallmark of between-network integration and transient functional reorganization. The most striking reorganization occurred in a default mode subnetwork localized to regions of the prefrontal cortex, coincident with peaks in serum levels of estradiol, luteinizing hormone, and follicle stimulating hormone. Nodes from these regions exhibited strong intra-network increases in functional connectivity, leading to a split in the stable default mode core community and the transient formation of a new functional community. Probing the spatiotemporal basis of human brain–hormone interactions with dynamic community detection suggests that hormonal changes during the menstrual cycle result in temporary, localized patterns of brain network reorganization.