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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.

Traditional consolidation theory, which seeks to explain how new memories are incorporated into the preexisting neural architecture, stipulates that the hippocampus plays a time-limited role in this process. However, although there is abundant research showing that the hippocampus is necessary for the initial (encoding) phase, there is very little experimental evidence with human subjects proving that the structure ceases to play a role in the retrieval of episodic items from memory stores. To test this hypothesis, we investigated recall activation associated with recent memories (2.5 days) versus remote memories (mean of 8 years) using functional magnetic resonance imaging. In accordance with the multiple memory trace theory, recall of consolidated autobiographic information, represented by the remote condition, was not independent of the hippocampus. Both types of memory retrieval produced significant activation in parahippocampal, prefrontal, and midtemporal gyri, the parietal-temporal junction, and a medial region of cortex spanning the posterior cingulate and precuneus gyri. However, where recent events activated bilateral regions of the caudate nucleus, remote events yielded significantly greater activation within the hippocampus proper. The results challenge traditional consolidation theory, which would predict greater hippocampal activity for recent events. Furthermore, they highlight the interplay between multiple memory systems in the brain. We argue that our particular question format, which encouraged depth of recall and did not require a prescan interview, as well as our delineation of the recent and remote time periods, were the determining factors for the observed pattern of hippocampal activation.

IMPORTANCE Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause. OBJECTIVE To investigate whether MAO-A total distribution volume (V T), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years). DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11-labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years). MAIN OUTCOMES AND MEASURES Values of MAO-A V T in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain. RESULTS On average, MAO-A V T in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F 16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A V T (F 8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A V T in the prefrontal cortex (r = 0.54; P = .008). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A V T during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.