Belinda Pletzer

Menstrual cycle and hormonal contraceptive use modulate human brain structure.

Sex differences in human brain structure have repeatedly been described, but results are inconsistent. However, these studies hardly controlled for cycle phase of women or the use of hormonal contraceptives. Our study shows that these factors are not negligible, but have a considerable influence on human brain structure. We acquired high-resolution structural images from the brains of 14 men, 14 women, who did not use, and 14 women, who did use hormonal contraceptives. Women, who did not use hormonal contraceptives, were scanned twice, once during their early follicular and once during their mid-luteal cycle-phase. Regional gray matter volumes were compared by voxel-based morphometry. Men had larger hippocampi, parahippocampal and fusiform gyri, amygdalae and basal ganglia than women. Women showed larger gray matter volumes in the prefrontal cortex, pre- and postcentral gyri. These sex-dependent effects were modulated by menstrual cycle phases and hormonal contraceptives. We found larger volumes in the right fusiform/parahippocampal gyrus during early follicular compared to mid-luteal cycle phase. Women using hormonal contraceptives showed significantly larger prefrontal cortices, pre- and postcentral gyri, parahippocampal and fusiform gyri and temporal regions, compared to women not using contraceptives.

50 years of hormonal contraception—time to find out, what it does to our brain

Hormonal contraceptives are on the market for more than 50 years and used by 100 million women worldwide. However, while endogenous steroids have been convincingly associated with change in brain structure, function and cognitive performance, the effects of synthetic steroids contained in hormonal contraceptives on brain and cognition have barely been investigated. In this article we summarize the sparse findings, describing brain structural, functional and behavioral findings from the literature and suggest that synthetic steroids may contribute to masculinizing as well as feminizing effects on brain and behavior. We try to identify methodological challenges, explain, how results on endogenous steroids may transfer into research on hormonal contraceptives and point out factors that need to be controlled in the study of hormonal contraceptive dependent effects. We conclude that there is a strong need for more systematic studies, especially on brain structural, functional and cognitive changes due to hormonal contraceptive use. The hormonal contraceptive pill is the major tool for population control. Hence, such behavioral changes could cause a shift in society dynamics and should not stay unattended.

Hormonal contraceptives masculinize brain activation patterns in the absence of behavioral changes in two numerical tasks.

The aim of the present study was to identify, whether and how oral hormonal contraceptives (OCs) alter womens number processing. Behavioral performance and brain activation patterns (BOLD-response) of 14 OC-users were evaluated during two distinct numerical tasks (number comparison, number bisection) and compared to 16 men (high testosterone), and 16 naturally cycling women, once during their follicular (low hormone levels) and once during their luteal cycle phase (high progesterone). For both tasks, reliable sex differences and menstrual cycle dependent modulation have previously been described. If progestogenic effects of the synthetic progestins contained in OC play a predominant role, OC-users should be comparable to luteal women. If androgenic effects of the synthetic steroids exert the progestogenic actions, OC-users should be comparable to men. Likewise, if neither of the above are the case, the reduction of endogenous steroids by OCs should make OC-users comparable to follicular women. Our findings suggest that OC-users resemble follicular women in their behavioral performance, but show male-like brain activation patterns during both tasks. Analysis of brain-behavior relationships suggests that OC-users differ from naturally cycling women in the way they recruit their neural resources to deal with challenges of the tasks. We conclude that OCs, which are used by 100 million women worldwide, may have profound effects on cognition that have not been recognized so far.

Impulsivity relates to striatal gray matter volumes in humans: evidence from a delay discounting paradigm

Time-stable personality traits, such as impulsivity and its relationship with functional and structural brain alterations, have gained much attention in the recent literature. Evidence from functional neuroimaging data implies an association between impulsivity and cortical as well as subcortical areas of the reward system. Discounting future rewards during impulsive decisions can be related to activation in the orbitofrontal cortex and striatum. Cortical structural changes in prefrontal regions have been found for introspective impulsivity measures. The present study focuses on brain regions associated with delay discounting to investigate structural manifestations of trait impulsivity. To test this, seventy subjects underwent structural magnetic resonance imaging (MRI) followed by a behavioral delay discounting task outside of the scanner to measure impulsivity with questions like: “Would you like to have 3€ immediately or 10€ in 5 days?”. The amount of smaller-but-sooner decisions was calculated and used as a measure of behavioral impulsivity. Furthermore, we estimated subject’s individual delay discounting parameter K reflecting the tendency to discount future rewards. Behaviorally, we found strong evidence in favor of a discounting utility model compared to a standard hyperbolic model of choice valuation. Neuronally, we focused on cortical and subcortical brain structure and investigated the association of behavioral impulsivity with delay discounting tendencies and gray matter volume. Voxel-based morphometric analyses showed positive correlations between delay discounting and gray matter volume in the striatum. Additional analyses using Freesurfer provided evidence for a positive correlation between delay discounting and gray matter volume of the caudate. Taken together, our study provides strong evidence for a structural manifestation of time-stable trait impulsivity in the human brain.

Menstrual cycle variations in the BOLD-response to a number bisection task: implications for research on sex differences.

Numerical processing involves either number magnitude processing, which has been related to spatial abilities and relies on superior parietal regions, or arithmetic fact retrieval, which has been related to verbal abilities and involves the inferior parietal lobule. Since men score better in spatial and women in verbal tasks, we assume that women have advantages in fact retrieval, while men have benefits in number magnitude processing. According to findings on menstrual cycle variations in spatial and verbal abilities, fact retrieval should improve during the luteal phase and magnitude processing during the follicular phase. To dissociate sex- and menstrual cycle-dependent effects on fact retrieval and number magnitude processing, we applied a number bisection task in 15 men and 15 naturally cycling women. Multiplicative items (e.g. 12_15_18) are part of a multiplication series and can be solved by fact retrieval, while non-multiplicative items (e.g. 11_14_17) are not part of a multiplication series and require number magnitude processing. In men and women in their luteal phase, error rates were higher and deactivation of the medial prefrontal cortex and the bilateral inferior parietal lobules was stronger for non-multiplicative compared to multiplicative items (positive multiplicativity effect), while in the follicular phase women showed higher error rates and stronger deactivation in multiplicative compared to non-multiplicative items (negative multiplicativity effect). Thus, number magnitude processing improves, while arithmetic fact retrieval impairs during the follicular phase. While a female superiority in arithmetic fact retrieval could not be confirmed, we observed that sex differences are significantly modulated by menstrual cycle phase.

Mathematics anxiety reduces default mode network deactivation in response to numerical tasks.

Mathematics anxiety is negatively related to mathematics performance, thereby threatening the professional success. Preoccupation with the emotional content of the stimuli may consume working memory resources, which may be reflected in decreased deactivation of areas associated with the default mode network (DMN) activated during self-referential and emotional processing. The common problem is that math anxiety is usually associated with poor math performance, so that any group differences are difficult to interpret. Here we compared the BOLD-response of 18 participants with high (HMAs) and 18 participants with low mathematics anxiety (LMAs) matched for their mathematical performance to two numerical tasks (number comparison, number bisection). During both tasks, we found stronger deactivation within the DMN in LMAs compared to HMAs, while BOLD-response in task-related activation areas did not differ between HMAs and LMAs. The difference in DMN deactivation between the HMA and LMA group was more pronounced in stimuli with additional requirement on inhibitory functions, but did not differ between number magnitude processing and arithmetic fact retrieval.

Sex-specific strategy use and global-local processing: a perspective toward integrating sex differences in cognition

This article reviews the literature on sex-specific strategy use in cognitive tasks with the aim to carve out a link between sex differences in different cognitive tasks. I conclude that male strategies are commonly holistic and oriented toward global stimulus aspects, while female strategies are commonly decomposed and oriented toward local stimulus aspects. Thus, the strategies observed in different tasks, may depend on sex differences in attentional focus and hence sex differences in global-local processing. I hypothesize that strategy use may be sex hormone dependent and hence subject to change over the menstrual cycle as evidenced by findings in global-local processing and emotional memory. Furthermore, I propose sex hormonal modulation of hemispheric asymmetries as one possible neural substrate for this theory, thereby building on older theories, emphasizing the importance of sex differences in brain lateralization. The ideas described in the current article represent a perspective toward a unifying approach to the study of sex differences in cognition and their neural correlates.

Sex Differences in the Processing of Global vs. Local Stimulus Aspects in a Two-Digit Number Comparison Task – An fMRI Study

It has been debated for several decades, whether number magnitudes are processed global/holistically (whole number magnitudes) or in a local/decomposed fashion (digit magnitudes). However, while it has been suggested that men attend stronger to the global level, while women attend stronger to the local level, the question has never been studied with regards to sex differences. In two-digit number comparison men should engage a more holistic processing strategy, while women should engage a more decomposed strategy. To test this hypothesis, we employed number comparison stimuli of varying decade crossing and unit-decade compatibility in men (n = 16) and women (n = 16) during their early follicular and mid-luteal cycle phase. In within-decade (WD) items both numbers had the same decade digits. Non-WD items were unit-decade-compatible, if the smaller number contained the smaller unit-digit and incompatible otherwise. In incompatible items the two local features require different responses. Thus, processing of the local level should result in a compatibility effect in RT and recruitment of differential neural networks for compatible and incompatible items. The results support the view of a holistic strategy in men and a decomposed strategy in women. In men RT and BOLD-response did not differ for incompatible compared to compatible items. Women respond slower to incompatible compared to compatible items. They show a BOLD-response compatibility effect in regions of the default mode network during their follicular phase and in prefrontal areas involved in inhibitory control during their luteal phase. Furthermore, lateralization indices interacted with decade crossing and menstrual cycle phase in a way consistent with the hypothesis of progesterone-mediated interhemispheric decoupling.

Differential effects of androgenic and anti-androgenic progestins on fusiform and frontal gray matter volume and face recognition performance

Effects of oral hormonal contraceptives (OC) on human brain structure and behavior have only recently become a focus of research. Two explorative reports observed larger regional gray matter (GM) volumes in OC users within the prefrontal cortex, ACC and fusiform gyri, as well as parahippocampal gyri, hippocampus and cerebellum. These studies did however not control for the androgenicity of the progestin compound of OC, did not take into consideration how long OC users had been on their OC, and did not control for age differences between the OC group and the naturally cycling group. We compared 20 naturally cycling women during their early follicular cycle phase to 18 users of OC containing androgenic progestins and 22 users of OC containing anti-androgenic progestins. When controlling for age, we found that in users of anti-androgenic progestins relative GM volumes within the bilateral fusiform gyri, fusiform face area (FFA), parahippocampal place area (PPA) and cerebellum, were significantly larger than in naturally cycling women, while in users of androgenic progestins, relative as well as absolute volumes within the bilateral middle and superior frontal gyri were significantly smaller compared to naturally cycling women. These morphological changes were related to performance in a face recognition task. Face recognition performance was significantly better in users of anti-androgenic progestins compared to the other groups and significantly related to absolute as well as relative GM volumes in the FFA and PPA. Total GM volume, as well as absolute GM volumes within the bilateral fusiform gyri, FFA, hippocampus, parahippocampus, PPA, middle frontal gyri and ACC were significantly larger, the longer the duration of OC use, particularly in users of androgenic progestins. Morphological differences between active and inactive pill phase were observed in users of androgenic progestins. These findings suggest differential effects of androgenic and anti-androgenic progestins on human brain structure.

Predictors of performance in a real-life statistics examination depend on the individual cortisol profile

In standardized stress conditions, cortisol responders and non-responders differ in their memory performance. To evaluate this association in a real-life situation, we investigated whether the individual cortisol response profile predicts the performance in an examination in statistics in 112 healthy participants. In addition, basic arithmetic abilities as well as mathematics anxiety were evaluated. We collected a baseline saliva sample before the examination day as well as pre- and post-examination samples. Participants were attributed to one of four cortisol profiles depending on their cortisol change in anticipation of the examination. 52% of participants showed an increase (A-profile) and 43% a decrease (D-profile) in cortisol before the examination. Cortisol changes did not predict performance in the examination. However, only in A-profile individuals, mathematics anxiety and arithmetic abilities predicted statistics performance. We conclude that in real-life situations, cortisol facilitates the influence of mathematics anxiety and mathematical abilities on examination performance.