Research ReportStability of resting state networks in the female brain during hormonal changes and their relation to premenstrual symptoms
Introduction
Blood oxygen-level dependent (BOLD) contrast has been used for studying the brain in-vivo, through functional magnetic resonance imaging (fMRI), for more than 2 decades now (Belliveau et al., 1991). In the absence of a task, spontaneous low frequency (<0.1 Hz) fluctuations of BOLD signal occur throughout the brain. This signal exhibits temporal correlations in spatially distinct regions of the brain. Some patterns appear consistently and are referred to as resting state networks (RSN). It is hypothesized that these networks are related with unconstrained mental activity (Biswal et al., 1995, Mason et al., 2007, Raichle, 2011, Barkhof et al., 2014). Functional connectivity as measured by RS-fMRI is a new potential biomarker for several pathologies. Using RS-fMRI, alterations in RSNs have been described in a series of different diseases, showing the sensitivity of this technique. Examples of pathologies, which were recently studied using RS-fMRI are: Alzheimer׳s disease (Dennis and Thompson, 2014), Parkinson׳s disease (Baggio et al., 2015), obsessive compulsive disorder (Beucke et al., 2014), bipolar disorder (Magioncalda et al., 2015), depression (Sambataro et al., 2013, Sundermann et al., 2014), attention deficit hyperactivity disorder (ADHD) (dos Santos Siqueira et al., 2014), and anorexia nervosa (Boehm et al., 2014). However, different diseases seem to affect the same RSN, so specificity of RS-fMRI is lower. It is important to note that menstrual cycle phase and use of hormonal contraceptives is almost never controlled for in these studies, while it is not yet confirmed that it is justified to do so.
One RSN that is particularly studied is the default mode network (DMN), first described in 2001 (Raichle et al., 2001). It includes the medial prefrontal cortex, posterior cingulate cortex, lateral temporal cortex and inferior parietal lobule, and is attenuated during task performance (Buckner et al., 2008). The DMN is believed to be related to introspective and self-referential thought processes, and becomes deactivated during goal-directed behavior (Barkhof et al., 2014). In addition, significant gender differences are found in cognition related networks, like the executive control network (ECN) (Filippi et al., 2013). Hormonal factors are a plausible explanation for sex-differences, and hormones might influence the formation of these RSNs.
Previous task-based fMRI research has revealed several gender (Wrase et al., 2003, Schoning et al., 2007, Konrad et al., 2008, Weis et al., 2008, Pletzer et al., 2013), menstrual cycle (Fernandez et al., 2003, Gizewski et al., 2006, Konishi et al., 2008, Roberts et al., 2008, Rupp et al., 2009, Guapo et al., 2009, Zhu et al., 2010), and hormonal contraceptives (HC) (Bonenberger et al., 2013, Abler et al., 2013, Mareckova et al., 2014) effects on the BOLD signal. The amount of the literature on these hormonal effects on RS-fMRI is however significantly smaller. Aside from gender differences (Tomasi and Volkow, 2012, Filippi et al., 2013, Wetherill et al., 2014, Agcaoglu et al., 2015), only recently some authors evaluated the effect of menstrual cycle phase (Petersen et al., 2014, Hjelmervik et al., 2014), and use of HC (Petersen et al., 2014). Unfortunately, regarding the menstrual cycle effects on RSNs, the results of these studies are inconsistent; Petersen et al. (2014) found differences with cycle phase in the DMN and ECN, Hjelmervik et al. (2014) only assessed the ECN and did not find any differences. Regarding HC use, Petersen et al. (2014) did not find differences between the active and inactive pill phase, but did record alterations when comparing the natural menstrual cycle (NC) follicular phase with the inactive pill phase.
The purpose of this work was to evaluate the influence of both menstrual cycle phase, and HC use on the DMN and the ECN, in a longitudinal design. For the NC group, we included the time-point of ovulation, which was not assessed in previous studies. In the HC group we corrected for generation of the synthetic progestin component contained in the HC, as this may influence results or introduce heterogeneity within the HC group (Pletzer and Kerschbaum, 2014). Additionally, since the association of the DMN with mood disorders like depression and bipolar disorder (Sambataro et al., 2013, Sundermann et al., 2014, Magioncalda et al., 2014), we acquired data regarding premenstrual symptoms (PMS) in both our groups, through completion of a “daily rating of severity of problems” (DRSP) questionnaire (Endicott et al., 2006) during 2 cycles. To the best of our knowledge, it is the first time that possible PMS effects on RSNs are evaluated.
Section snippets
Results
As described in more detail in Section 4, data quality control was performed on both hormonal data, and MR data. Temporal SNR maps are used to assess RS-fMRI data quality. What we describe in this section results from the remaining data after quality control (NC group=18 subjects; HC group=19 subjects).
Discussion
Within the scientific community there is a rapidly growing interest in brain resting state networks (RSN) in health and disease, as measured through resting-state fMRI (RS-fMRI). Possible effects of menstrual cycle phase and use of hormonal contraception are often ignored in study designs. However, it has been shown in other subtopics of neuroimaging, such as voxel-based-morphometry (Pletzer et al., 2010, De Bondt et al., 2013a), diffusion tensor imaging (De Bondt et al., 2013b) and GABA
Subjects
A total of 65 healthy young women, with no history of neurological of psychiatric illness, were enrolled in this longitudinal study. The study was approved by the institutional review board, and all subjects signed a written informed consent form. Of our subjects, 38 women had a natural menstrual cycle (NC-group), while 27 women were taking second or third generation monophasic hormonal contraceptives (HC group). We purposefully did not include women who were taking fourth generation HC,
References (67)
- et al.
Lateralization of resting state networks and relationship to age and gender
NeuroImage
(2015) - et al.
Changes in structural and functional connectivity among resting-state networks across the human lifespan
NeuroImage
(2014) The role of physiological noise in resting-state functional connectivity
NeuroImage
(2012)- et al.
Prefrontal GABA concentration changes in women-influence of menstrual cycle phase, hormonal contraceptive use, and correlation with premenstrual symptoms
Brain Res.
(2015) - et al.
Regional gray matter volume differences and sex-hormone correlations as a function of menstrual cycle phase and hormonal contraceptives use
Brain Res.
(2013) - et al.
Effects of sex hormonal levels and phases of the menstrual cycle in the processing of emotional faces
Psychoneuroendocrinology
(2009) - et al.
Fasting plasma insulin and the default mode network in women at risk for Alzheimer׳s disease
Neurobiol. Aging
(2013) - et al.
Oral contraceptive pill use and menstrual cycle phase are associated with altered resting state functional connectivity
NeuroImage
(2014) - et al.
Menstrual cycle and hormonal contraceptive use modulate human brain structure
Brain Res.
(2010) - et al.
Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal
Eur. Neuropsychopharmacol.: J. Eur. Coll. Neuropsychopharmacol.
(2013)
Menstrual cycle phase modulates cognitive control over male but not female stimuli
Brain Res.
Neural activation in the orbitofrontal cortex in response to male faces increases during the follicular phase
Horm. Behav.
Metabolic profiles of endogenous and ethynyl steroids in plasma and urine from women during administration of oral contraceptives
J. Steroid Biochem.
Functional anatomy of visuo-spatial working memory during mental rotation is influenced by sex, menstrual cycle, and sex steroid hormones
Neuropsychologia
Hormone withdrawal symptoms in oral contraceptive users
Obstet. Gynecol.
Sex differences in resting state neural networks of nicotine-dependent cigarette smokers
Addict. Behav.
Anti-correlated networks, global signal regression, and the effects of caffeine in resting-state functional MRI
NeuroImage
Gender differences in the processing of standardized emotional visual stimuli in humans: a functional magnetic resonance imaging study
Neurosci. Lett.
Brain activation evoked by erotic films varies with different menstrual phases: an fMRI study
Behav. Brain Res.
Neural correlates of erotic stimulation under different levels of female sexual hormones
PloS One
Cognitive impairment and resting-state network connectivity in Parkinson׳s disease
Hum. Brain Mapp.
Resting-state functional MR imaging: a new window to the brain
Radiology
Functional mapping of the human visual cortex by magnetic resonance imaging
Science
Default mode network subsystem alterations in obsessive–compulsive disorder
Br. J. Psychiatry: J. Ment. Sci.
Functional connectivity in the motor cortex of resting human brain using echo-planar MRI
Magn. Reson. Med.: Off. J. Soc. Magn. Reson. Med./Soc. Magn. Reson. Med.
Increased resting state functional connectivity in the fronto-parietal and default mode network in anorexia nervosa
Front. Behav. Neurosci.
It׳s all about money: oral contraception alters neural reward processing
Neuroreport
The brain׳s default network: anatomy, function, and relevance to disease
Ann. NY Acad. Sci.
A method for making group inferences from functional MRI data using independent component analysis
Hum. Brain Mapp.
Mood changes and menstrual symptoms with different gestagen/estrogen combinations. A double blind comparison with a placebo
Acta Psychiatr. Scand. Suppl.
Does the use of hormonal contraceptives cause microstructural changes in cerebral white matter? Preliminary results of a DTI and tractography study
Eur. Radiol.
Functional brain connectivity using fMRI in aging and Alzheimer׳s disease
Neuropsychol. Rev.
Abnormal functional resting-state networks in ADHD: graph theory and pattern recognition analysis of fMRI data
BioMed Res. Int.
Cited by (45)
Electroencephalography findings in menstrually-related mood disorders: A critical review
2024, Frontiers in NeuroendocrinologySex steroids and the female brain across the lifespan: insights into risk of depression and Alzheimer's disease
2023, The Lancet Diabetes and EndocrinologyHormonal contraceptives and the brain: A systematic review on 60 years of neuroimaging, EEG, and biochemical studies in humans and animals
2023, Frontiers in NeuroendocrinologyHormone-based models for comparing menstrual cycle and hormonal contraceptive effects on human resting-state functional connectivity
2022, Frontiers in NeuroendocrinologyCitation Excerpt :Network analyses relying on ICA have produced contradictory results (Table 2). De Bondt et al. (2015b) found no effect of OCs on DMN or ECN rsFC (Ns = 18 NC, 19 OC). Petersen et al. (2014) found lower connectivity in OC users taking active OCs compared to follicular women when evaluating DMN and ECN connectivity.
Neuroimaging the menstrual cycle: A multimodal systematic review
2021, Frontiers in NeuroendocrinologyCitation Excerpt :Similarly, the functional connectivity of the medial and orbital PFC within the frontoparietal network and the default mode network correlated positively with allopregnanolone levels (Syan et al., 2017). Resting-state fMRI studies suggest an influence of E2 on the functional connectivity of prefrontal regions as well, although the findings appear less consistent (De Bondt et al., 2015b; Pletzer et al., 2016; Weis et al., 2017). In contrast, structural findings point to a neurotrophic influence of E2 on prefrontal regions, as positive correlations were found between E2 levels and both prefrontal grey matter volume and cortical thickness (De Bondt et al., 2013a; Lisofsky et al., 2015b; Petersen et al., 2015).
The scientific body of knowledge – Whose body does it serve? A spotlight on oral contraceptives and women's health factors in neuroimaging
2021, Frontiers in Neuroendocrinology