Biology subjects

Jacobs, E. G.

Publications and source records attributed to Jacobs, E. G..

17 recordsLinked to original sources

bioRxiv2026

Menarche onset is an inflection point for mental health and brain development

Menarche is a normative milestone of female puberty, yet its role in adolescent mental health and brain development remains poorly understood. Using longitudinal data from 5,016 females (7 annual visits, ages 10-16 years) in the Adolescent Brain Cognitive Development Study, we found that menarche onset functions as an inflection point for the development of internalizing symptoms and gross brain morphometry. The onset of menarche, largely independent of timing and socio-environmental factors, preceded a significant spike in internalizing symptoms, while altering the rate of ongoing structural brain development. Following menarche onset, individuals with faster declines in gray matter volume and surface area also had heightened internalizing symptoms. These findings suggest that menarche is not only a reproductive milestone but a neuroendocrine driver of adolescent brain and mental health trajectories. This normative and easily identifiable marker could define a critical window for mental health screenings with greater precision than current age-based guidelines.

neuroscience↗

bioRxiv2026

The progression of sex differences in brain networks across the lifespan

Sex differences in brain connectivity are well documented, yet how these differences evolve across the human lifespan remains poorly understood. Rigorously assessing sex-dependent trajectories of brain network organization is challenging due to difficulty in acquiring, processing, and modeling high-dimensional connectomes. Here, we analyzed 15 types of functional and structural connectivity networks from 1286 healthy individuals aged 8-100+ years, using our new AI-based Krakencoder to derive a low-dimensional multimodal "fusion" connectome representation. Sex differences were minimal in early childhood, pronounced in young to mid-adulthood, and diverged across modalities in later life: functional connectivity grew less distinct and structural connectivity grew more distinct from midlife onward. Functional differences were driven predominantly by higher-order association networks (default mode, control), while structural differences concentrated in lower-order cerebellar and subcortical pathways. These findings provide a lifespan-wide, multimodal map of sex differences in brain networks which may help inform sex-specific vulnerability and resilience to brain disorders.

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bioRxiv2026

Neurobiological Signatures of Endometriosis: Characterizing Pain, Cognition, and Brain Morphology

Endometriosis affects approximately 10% of reproductive-age women worldwide and is associated with substantial pain and mental health burden, yet its neurobiological correlates remain poorly characterized. Neuroimaging studies of endometriosis are particularly limited. Here we present a comprehensive, multidimensional investigation of the neurobiology of endometriosis, integrating structural and diffusion neuroimaging, biofluid measures, neuropsychological testing, and detailed health and psychosocial phenotyping in individuals with and without endometriosis. Compared with controls, individuals with endometriosis exhibited higher levels of pain, depression, and anxiety and performed worse across multiple cognitive domains. Global and regional brain morphometric measures did not differ between groups; however, endometriosis-specific pain was associated with altered gray matter volume and white matter microstructure across distributed pain-related neural circuits. These findings identify pain-related neurobiological signatures of endometriosis and establish a foundation for mechanistic and translational studies of its central nervous system effects.

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bioRxiv2024

Idiosyncrasy and generalizability of contraceptive- and hormone-related functional connectomes across the menstrual cycle

Neuroendocrinology has received little attention in human neuroscience research, resulting in a dearth of knowledge surrounding potent and dynamic modulators of cognition and behavior, as well as brain structure and function. This work addresses one such phenomenon by studying functional connectomics related to ovarian hormone fluctuations throughout the adult menstrual cycle. To do so, we used functional magnetic resonance imaging (fMRI) and hormone assessments from two dense, longitudinal datasets to assess variations in functional connectivity with respect to endogenous and exogenous endocrine factors throughout the menstrual cycle. First, we replicated prior findings that common, group-level and individual specific factors have similar relative contributions to functional brain network organization. Second, we found widespread connectivity related to hormonal contraceptive (HC) use, in addition to sparser estradiol- and progesterone-related connectivity, and differential generalizability of these subnetworks that suggests progestin-specific impacts on functional connectivity in HC users. These results provide novel insight into within-individual changes in brain organization across the menstrual cycle and the extent to which these changes are shared between individuals, illuminating understudied phenomena in reproductive health and important information for all neuroimaging studies that include participants who menstruate. Author SummaryEndocrine modulation of brain function across the menstrual cycle is poorly understood. Human neuroimaging research on the menstrual cycle has long relied on group- and or coarse, within-individual cycle stage-differences, overlooking considerable individual differences in brain organization, the menstrual cycle, and hormone concentrations. Here, we take a multi-dataset approach to identify idiosyncratic contraceptive- and hormone-related functional connectivity from within-individual neuroendocrine dynamics and then test the generalizability of this connectivity to other individuals. In doing so, we identified idiosyncratic hormone-responsive subnetworks that are somewhat generalizable to other individuals, though this generalizability is complicated by hormonal contraceptive use, potentially reflecting differential connectivity between contraceptive formulations. Thus, this work illuminates individual similarities and differences in neuroendocrine dynamics across the menstrual cycle.

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bioRxiv2024

The estrous cycle modulates hippocampal spine dynamics, dendritic processing, and spatial coding

AbstractHistological evidence suggests that the estrous cycle exerts a powerful effect on CA1 neurons in mammalian hippocampus. Decades have passed since this landmark observation, yet how the estrous cycle shapes dendritic spine dynamics and hippocampal spatial coding in vivo remains a mystery. Here, we used a custom hippocampal microperiscope and two-photon calcium imaging to track CA1 pyramidal neurons in female mice over multiple cycles. Estrous cycle stage had a potent effect on spine dynamics, with heightened density during periods of greater estradiol (proestrus). These morphological changes were accompanied by greater somatodendritic coupling and increased infiltration of back-propagating action potentials into the apical dendrite. Finally, tracking CA1 response properties during navigation revealed enhanced place field stability during proestrus, evident at the single-cell and population level. These results establish the estrous cycle as a driver of large-scale structural and functional plasticity in hippocampal circuits essential for learning and memory.

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bioRxiv2024

Exploring sex-specific neuroendocrine influences on the sensorimotor-association axis in single individuals

Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization - the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Our findings revealed modest effects that differed between participants, hinting at subtle -potentially sex-specific- associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples.

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bioRxiv2024

Circadian rhythms tied to changes in brain morphology in a densely-sampled male

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones. Significance StatementThough rhythmic changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species, this relationship has not been well characterized in humans. In this precision neuroimaging study, we found that global and regional brain morphology and steroid hormone levels exhibit tandem circadian rhythms. These findings provide high-resolution insight into the anatomical signature of diurnal changes in brain morphology and steroid hormone production in a human male and reveal the metronomic regularity of these rhythms over time.

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bioRxiv2023

Neuroanatomical changes observed over the course of a human pregnancy

Pregnancy is a period of profound hormonal and physiological change experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation have not been studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through two years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, which stand in contrast to increases in white matter microstructural integrity, ventricle volume, and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as the first comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to stimulate further exploration and discovery.

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bioRxiv2023

Diurnal fluctuations in steroid hormones tied to variation in intrinsic functional connectivity in a densely sampled male

Most of mammalian physiology is under the control of biological rhythms, including the endocrine system with time-varying hormone secretion. Precision neuroimaging studies provide unique insights into the means through which our endocrine system regulates dynamic properties of the human brain. Recently, we established estrogens ability to drive widespread patterns of connectivity and enhance the functional efficiency of large-scale brain networks in a woman sampled every 24h across 30 consecutive days, capturing a complete menstrual cycle. Steroid hormone production also follows a pronounced sinusoidal pattern, with a peak in testosterone between 6-7am and nadir between 7-8pm. To capture the brains response to diurnal changes in hormone production, we carried out a companion precision imaging study of a healthy adult man who completed MRI and venipuncture every 12-24 hours across 30 consecutive days. Results confirmed robust diurnal fluctuations in testosterone, cortisol, and estradiol. Standardized regression analyses revealed predominantly positive associations between testosterone, cortisol, and estradiol concentrations and whole-brain patterns of coherence. In particular, functional connectivity in Dorsal Attention and Salience/Ventral Attention Networks were coupled with diurnally fluctuating hormones. Further, comparing dense-sampling datasets between a man and naturally-cycling woman revealed that fluctuations in sex hormones are tied to patterns of whole-brain coherence to a comparable degree in both sexes. Together, these findings enhance our understanding of steroid hormones as rapid neuromodulators and provide evidence that diurnal changes in steroid hormones are tied to patterns of whole-brain functional connectivity. Significance StatementDiurnal variation is an essential biorhythm, yet the relationship between diurnal fluctuations in steroid hormones and the functional architecture of the human brain is virtually unknown. This precision neuroimaging study suggests that endogenous fluctuations in testosterone, estradiol, and cortisol concentrations are tied to rhythmic changes in coherence across the brain. Precision imaging studies that track individuals across major endocrine transitions (e.g. the diurnal cycle and menstrual cycle) demonstrate steroid hormones ability to modulate the functional architecture of the brain in both sexes, and provide a starting point for future studies to probe the functional significance of these rhythms for behavior.

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bioRxiv2023

Menstrual cycle-driven hormone concentrations co-fluctuate with white and grey matter architecture changes across the whole brain

Cyclic fluctuations in hypothalamic-pituitary-gonadal axis (HPG-axis) hormones exert powerful behavioral, structural, and functional effects through actions on the mammalian central nervous system. Yet, very little is known about how these fluctuations alter the structural nodes and information highways of the human brain. In a study of 30 naturally cycling women, we employed multidimensional diffusion and T1-weighted imaging during three estimated menstrual cycle phases (menses, ovulation, mid-luteal) to investigate whether HPG-axis hormone concentrations co-fluctuate with alterations in white matter (WM) microstructure, cortical thickness (CT), and brain volume. Across the whole brain, 17{beta}-estradiol and luteinizing hormone (LH) concentrations were directly proportional to diffusion anisotropy (FA), while follicle-stimulating hormone (FSH) was directly proportional to cortical thickness. Within several individual regions, FSH and progesterone demonstrated opposing associations with mean diffusivity and cortical thickness. These regions mainly reside within the temporal and occipital lobes, with functional implications for the limbic and visual systems. Lastly, progesterone was associated with increased tissue and decreased CSF volumes, with total brain volume remaining unchanged. These results are the first to report simultaneous brain-wide changes in human WM microstructure and cortical thickness coinciding with menstrual cycle-driven hormone rhythms. Strong brain-hormone interaction effects may not be limited to classically known HPG-axis receptor-dense regions.

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bioRxiv2023

The influence of chronological age and menopause status on the functional neural correlates of spatial context memory in middle-aged females.

Reductions in the ability to encode and retrieve past experiences in rich spatial contextual detail (episodic memory) are apparent by midlife - a time when most females experience spontaneous menopause. Yet, little is known about how menopause status affects episodic memory-related brain activity at encoding and retrieval in middle-aged pre- and post-menopausal females, and whether any observed group differences in brain activity and memory performance correlate with chronological age within group. We conducted an event-related task fMRI study of episodic memory for spatial context to address this knowledge gap. Multivariate behavioral partial least squares (PLS) was used to investigate how chronological age and retrieval accuracy correlated with brain activity in 31 premenopausal (age range: 39.55 - 53.30 yrs, Mage = 44.28 yrs, SDage = 3.12 yrs) and 41 postmenopausal females (age range: 46.70 to 65.14 yrs, Mage = 57.56 yrs, SDage = 3.93 yrs). We found that postmenopausal status, and advanced age within post-menopause, was associated with lower spatial context memory. The fMRI analysis showed that only in postmenopausal females, advanced age was correlated with decreased activity in occipitotemporal, parahippocampal, and inferior parietal during encoding and retrieval, and poorer spatial context memory performance. In contrast, only premenopausal females exhibited an overlap in encoding and retrieval activity in angular gyrus, midline cortical regions, and prefrontal cortex, which correlated with better spatial context retrieval accuracy. These results highlight how menopause status and chronological age, nested within menopause group, affect episodic memory and its neural correlates at midlife. Significance StatementThis is the first fMRI study to examine how pre- and post-menopause status affects the neural correlates of episodic memory encoding and retrieval, and how chronological age contributes to any observed group similarities and differences. We found that both menopause status (endocrine age) and chronological age affect spatial context memory and its neural correlates. Menopause status directly affected the direction of age- and performance-related correlations with brain activity in inferior parietal, parahippocampal and occipitotemporal cortices across encoding and retrieval. Moreover, we found that only premenopausal females exhibited cortical reinstatement of encoding-related activity in midline cortical, prefrontal, and angular gyrus, at retrieval. This suggests that spatial context memory abilities may rely on distinct brain systems at pre-compared to post-menopause.

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bioRxiv2022

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and non-users

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine neurotransmission. Yet little is known about hormonal regulation of the dopamine system in the human brain. Using Positron Emission Tomography (PET), we address this gap by comparing hormonal contraceptive users and non-users across multiple aspects of dopamine function: dopamine synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and dopamine release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n=21 naturally cycling; n=15 hormonal contraceptive users), and men (n=20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater dopamine synthesis capacity than naturally cycling participants, particularly in dorsal caudate, and greater cognitive flexibility. Further, across individuals the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or dopamine release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to womens hormone status. Hormonal contraception (in the form of pill, shot, implant, ring or IUD) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the dopamine system. Findings from this study begin to address this critical gap in womens health.

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bioRxiv2021

High-amplitude network co-fluctuations linked to variation in hormone concentrations over menstrual cycle

Many studies have shown that the human endocrine system modulates brain function, reporting associations between fluctuations in hormone concentrations and both brain activity and connectivity. However, how hormonal fluctuations impact fast changes in brain network structure over short timescales remains unknown. Here, we leverage "edge time series" analysis to investigate the relationship between high-amplitude network states and quotidian variation in sex steroid and gonadotropic hormones in a single individual sampled over the course of two endocrine states, across a natural menstrual cycle and under a hormonal regimen. We find that the frequency of high-amplitude network states are associated with follicle-stimulating and luteinizing hormone, but not the sex hormones estradiol and progesterone. Nevertheless, we show that scan-to-scan variation in the co-fluctuation patterns expressed during network states are robustly linked with the concentration of all four hormones, positing a network-level target of hormonal control. We conclude by speculating on the role of hormones in shaping ongoing brain dynamics.

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bioRxiv2020

Dynamic community detection reveals transient reorganization of functional brain networks across a female menstrual cycle

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 ovulation results in a temporary, localized patterns of brain network reorganization. Author SummarySex steroid hormones influence the central nervous system across multiple spatiotemporal scales. Estrogen and progesterone concentrations rise and fall throughout the menstrual cycle, but it remains poorly understood how day-to-day fluctuations in hormones shape human brain dynamics. Here, we assessed the structure and stability of resting-state brain network activity in concordance with serum hormone levels from a female who underwent fMRI and venipuncture for 30 consecutive days. Our results reveal that while network structure is largely stable over the menstrual cycle, there is temporary reorganization of several largescale functional brain networks during the ovulatory window. In particular, a default mode subnetwork exhibits increased connectivity with itself and with regions from temporoparietal and limbic networks, providing novel perspective into brain-hormone interactions.

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bioRxiv2020

Dynamic cerebellar network organization across the human menstrual cycle

The cerebellum contains the vast majority of neurons in the brain and houses distinct functional networks that constitute at least two homotopic maps of the cerebrum. While the functional organization of the human cerebellum has been characterized, the influence of sex steroid hormones on intrinsic cerebellar network dynamics has yet to be established. Here, we investigated the extent to which endogenous fluctuations in estradiol and progesterone alter functional cerebellar networks at rest in a woman densely sampled over a complete menstrual cycle (30 consecutive days). Edgewise regression analysis revealed negative associations between sex hormones and cerebellar coherence, with progesterone showing more pronounced negative associations relative to estradiol. Graph theory metrics probed sex hormones influence on topological brain states, revealing relationships between sex hormones and intra- and inter-network integration in Ventral Attention, Dorsal Attention, and Somato-Motor Networks. Together, these results suggest that the intrinsic dynamics of the cerebellum are intimately tied to day-by-day changes in sex hormones.

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bioRxiv2020

Progesterone shapes medial temporal lobe volume across the human menstrual cycle

The rhythmic production of sex steroid hormones is a central feature of the mammalian endocrine system. In rodents and nonhuman primates, sex hormones are powerful regulators of hippocampal subfield morphology. However, it remains unknown whether intrinsic fluctuations in sex hormones alter hippocampal morphology in the human brain. In a series of dense-sampling studies, we used high-resolution imaging of the medial temporal lobe (MTL) to determine whether endogenous fluctuations (Study 1) and exogenous manipulation (Study 2) of sex hormones alter MTL volume over time. Across the menstrual cycle, intrinsic fluctuations in progesterone were associated with volumetric changes in CA2/3, entorhinal, perirhinal, and parahippocampal cortex. Chronic progesterone suppression abolished these cycle-dependent effects and led to pronounced volumetric changes in entorhinal cortex and CA2/3 relative to freely cycling conditions. No associations with estradiol were observed. These results establish progesterones ability to rapidly and dynamically shape MTL morphology across the human menstrual cycle. HighlightsO_LISex hormones are powerful regulators of hippocampal plasticity in mammals. C_LIO_LIThe impact of hormone fluctuations on hippocampal morphology in humans is unknown. C_LIO_LIHigh resolution imaging of the MTL was conducted across two 30-day periods. C_LIO_LIProgesterone dynamically shapes MTL volume across the human menstrual cycle. C_LIO_LIChronic progesterone suppression abolishes cycle-dependent changes. C_LI

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bioRxiv2019

Functional reorganization of brain networks across the human menstrual cycle

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterones impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterones widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded--and perhaps driven--by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brains functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain. HighlightsO_LIIntrinsic fluctuations in sex hormones shape the brains functional architecture. C_LIO_LIEstradiol facilitates tighter coherence within whole-brain functional networks. C_LIO_LIProgesterone has the opposite, reductive effect. C_LIO_LIOvulation (via estradiol) modulates variation in topological network states. C_LIO_LIEffects are pronounced in network hubs densely populated with estrogen receptors. C_LI

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