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Increasing evidence suggests that endogenous sex steroid changes affect human brain functional connectivity, which could be obtained by resting-state fMRI (RS-fMRI). Nevertheless, RS studies on the menstrual cycle (MC) are underrepresented and yield inconsistent results. We attribute these inconsistencies to the use of various methods in exploratory approaches and small sample sizes. Hormonal fluctuations along the MC likely elicit subtle changes that, however, may still have profound impact on network dynamics when affecting key brain nodes. To address these issues, we propose a ROI-based multimodal analysis approach focusing on areas of high functional relevance to adequately capture these changes. To that end, sixty naturally cycling women underwent RS-fMRI in three different cycle phases and we performed the following analyses: (1) group-independent component analyses to identify intrinsic connectivity networks, (2) eigenvector centrality (EC) as a measure of centrality in the global connectivity hierarchy, (3) amplitude of low-frequency fluctuations (ALFF) as a measure of oscillatory activity and (4) seed-based analyses to investigate functional connectivity from the ROIs. For (2)(4), we applied a hypothesis-driven ROI approach in the hippocampus, caudate and putamen. In the luteal phase, we found (1) decreased intrinsic connectivity of the right angular gyrus with the default mode network, (2) heightened EC for the hippocampus, and (3) increased ALFF for the caudate. Furthermore, we observed (4) stronger putamenthalamic connectivity during the luteal phase and stronger fronto-striatal connectivity during the pre-ovulatory phase. This hormonal modulation of connectivity dynamics may underlie behavioural, emotional and sensorimotor changes along the MC. (VLID)4701922

Sex differences in spatial abilities are well documented, even though their underlying causes are poorly understood. Some studies assume a biological basis of these differences and study the relationship of sex hormone levels to spatial abilities. Other studies assume social influences and study the relationship of gender role (masculinity/femininity) to spatial abilities. Contemporary theories postulate a psychobiosocial model of sex differences in spatial abilities, in which both biological (e.g., hormonal) and psychosocial (e.g., gender role) variables interactively modulate spatial abilities. However, few studies have addressed both aspects simultaneously. Accordingly, the present study explores potential interactive effects between gender role and sex hormones on spatial performance. 41 men and 41 women completed a mental rotation and a virtual navigation task. Sex hormone levels and gender role were assessed in all participants. Sex differences favoring men were observed in both tasks. We found that neither sex hormones nor gender role alone emerged as mediators of these sex differences. However, several interactive effects between gender role and sex hormones were identified. Combined effects of masculinity and testosterone were observed for those variables that displayed sex differences. Participants with both, high masculinity and high testosterone showed the best performance. However, this association was further modulated by biological sex and progesterone levels. Furthermore, we observed an interactive effect of femininity, estradiol and testosterone on response times in both tasks. Consistent across both tasks and irrespective of biological sex, testosterone related to response times in participants with low estradiol levels, depending on their femininity. In participants with low femininity, testosterone was related to slower reaction times, while in participants with higher femininity, testosterone was related to faster reaction times. (VLID)4053429

The hybrid model of number magnitude processing suggests that multi-digit numbers are simultaneously processed holistically (whole number magnitudes) and in a decomposed manner (digit magnitudes). Thus, individual tendencies and situational factors may affect which type of processing becomes dominant in a certain individual in a given situation. The unit-decade compatibility effect has been described as indicative of stronger decomposed number processing. This effect occurs during the comparison of two-digit numbers. Compatible items in which the larger number contains the larger unit digit are easier to solve than incompatible items in which the larger number contains the smaller unit digit. We have previously described women show a larger compatibility effect than men. Furthermore, the compatibility effect is modulated by situational factors like the vertical spacing of the presented numbers. However, it has not been addressed whether situational factors and sex affect the unit-decade compatibility effect interactively. We have also demonstrated that the unit-decade compatibility effects relates to global-local processing, which in turn also affects spatial processing strategies. However, a link between spatial processing strategies and the unit-decade compatibility effect has not yet been established. In the present study we investigate, whether sex differences in the unit-decade compatibility effect (i) depend on the vertical spacing between numbers, (ii) are mediated via sex hormone levels of participants, and (iii) relate to sex differences in spatial processing strategies. 42 men and 41 women completed a two-digit number comparison task as well as a spatial navigation task. The number comparison task modulates compatibility and vertical spacing in a 2 2 design. The results confirm a larger compatibility effect in women compared to men and with dense compared to sparse spacing. However, no interactive effect was observed, suggesting that these factors modulate number magnitude processing independently. The progesterone/testosterone ratio was related to the compatibility effect, but did not mediate the sex difference in the compatibility effect. Furthermore, spatial processing strategies were related to the compatibility effect and did mediate the sex difference in the compatibility effect. Participants with a stronger focus on landmarks in the spatial navigation task showed a larger compatibility effect. P28261 (VLID)3406867

Oral contraceptive (OC) effects on the brain have gained increasing interest, but are highly controversial. Previous studies suggest that OC users have larger hippocampi, parahippocampi, fusiform gyri and Cerebelli. Preliminary evidence from one of those studies even suggests an effect of previous contraceptive use on the hippocampi of women who are not current users of OCs. Furthermore, more recent studies postulate an involvement of previous OC treatment in later development of mood disorders. To address the question whether previous OC treatment affects womens brain structure later in life, high resolution structural images were obtained from 131 naturally cycling women. Among them, 52 women had never used OC before, 52 had previously used one OC for a continuous time period and 27 had previously used multiple contraceptives. The groups did not differ in gray matter volumes. Since endogenous sex hormones modulate gray matter volumes of the hippocampus and basal ganglia along the menstrual cycle, we hypothesize effects of OC use on these areas. Specifically, we hypothesize that a longer duration of previous OC treatment is related to larger hippocampi and larger basal ganglia. Indeed we found the duration of previous OC use to be positively correlated to hippocampal and basal ganglia volumes bilaterally. For the hippocampus, but not for the basal ganglia, this association disappeared after controlling for the time since discontinuation. These results suggest that for the hippocampus, but not for the basal ganglia, effects of previous contraceptive treatment are reversed after a time period comparable to treatment duration. These data question the immediate reversibility of OC effects on brain structure. Accordingly, some changes in the brain due to long-term contraceptive use, while subtle, may be long-lasting. P28261 W 1233-G17 (VLID)4339103

Sex differences in navigation performance have been attributed to sex differences in information processing during navigation. Perspective refers to the viewpoint of the navigator, with previous work suggesting that men tend to use an allocentric perspective, while women tend to use an egocentric perspective during navigation. Furthermore, different navigation strategies may be used when moving from point A to B, with previous work suggesting that men tend to use a Euclidian strategy, while women tend to use a landmark-based strategy. However, it has not been studied whether perspective and strategy affect sex differences in navigation interactively or independently of each other. The present study aimed to investigate the interactive effects of perspective and strategy on sex differences in a 3D navigation task. In different levels of the task, perspective and strategy were modulated in a 22 design via different instructions. Potential mediating effects of video gaming experience and sex hormone levels were addressed. We found that men outperformed women in all levels of the navigation task. However, the male advantage was more pronounced using the allocentric perspective compared to the egocentric perspective. When using the allocentric perspective, men showed better performance using a Euclidian strategy while women showed better performance using a landmark-based strategy. The strategy did not modulate performance under the egocentric perspective. Accordingly, sex differences in navigation were interactively modulated by perspective and strategy. These effects were not explained by sex differences in video gaming experience or sex hormone levels. (VLID)3568632

The unit-decade compatibility effect has challenged the model of holistic number magnitude processing, suggesting decomposed processing of multi-digit numbers. Recent evidence confirms that decomposed processing of decade and unit magnitudes occurs in parallel. However, the mode of presentation of multi-digit numbers may affect the processing mode (holistic vs. decomposed, parallel vs. sequential). We therefore investigated in two studies, whether presentation mode (vertical, horizontal, or consecutive) or the distance between two vertically presented numbers affects the unit-decade compatibility effect during number comparison. We found that the compatibility effect did not differ significantly between vertical and horizontal presentation, adding to previous results on perceptual generality, but was nonsignificant with consecutive presentation. However, the compatibility effect was significantly smaller, if numbers are spaced further apart. Thus, stimulus size and distance between numbers affect the processing of multi-digit numbers and should be reported in future studies.

Background: Global-local stimuli are hierarchical structures consisting of a larger global structure which is composed of smaller local stimuli. Numbers are also constructed hierarchically, with multi-digit numbers being made up from single digits. During two-digit number comparison, compatible items (larger number contains larger unit digit, e.g., 53 vs. 68) are processed faster and more accurately than incompatible items (smaller number contains larger unit digit, e.g., 58 vs. 63). This so-called unit-decade-compatibility effect has challenged the holistic model of number processing and suggests that the processing of number magnitudes occurs at least in part, decomposed, i.e., separately for each digit. Thus, the compatibility effect is indicative of how decomposed numbers are processed, thereby sharing similarities with traditional global-local processing of hierarchical stimuli. The goal of this study was to investigate whether factors that have been shown to reliably influence global-local processing also affect the compatibility effect during number comparison. Those include visual hemifield, sex, and menstrual cycle phase in women. Method: One hundred sixty participants, 77 naturally cycling women and 83 men, completed a two-digit number comparison task twice, with test-sessions time-locked to the early follicular or mid-luteal cycle phase in women. Number comparison stimuli were presented to the right or left hemifield, respectively. Results: We observed a stronger compatibility effect in the right visual hemifield compared to left visual hemifield and in women compared to men, but no evidence for an influence of menstrual cycle phase in women could be found. Conclusion: Hemispheric asymmetries in holistic versus decomposed number processing could be demonstrated for the first time, suggesting a similar hemispheric modulation for number magnitude processing as for global-local processing. (VLID)2677931

Animal studies have robustly shown hormone related changes in spine density in various brain areas, specifically the hippocampus. Literature on hormone dependent gray matter volume changes in humans is however less consistent. While various areas have been reported to change along the menstrual cycle in women, many do not survive multiple-comparisons correction and only hippocampal changes have been replicated. We attribute these problems to small sample sizes and inconsistent definitions of menstrual cycle phases. In the present study a large sample of 55 women was scanned three times along their menstrual cycle in concisely defined time windows of hormonal changes. Accordingly this is the first study using a large enough sample size to assess menstrual cycle dependent changes in human brain structure with sufficient power. Results confirm a significant estradiol-dependent pre-ovulatory increase in gray matter volumes of the bilateral hippocampus, but also show a significant, progesterone-dependent increase in gray matter volumes of the right basal ganglia after ovulation. No other areas were affect by hormonal changes along the menstrual cycle. These hormone driven menstrual cycle changes in human brain structure are small, but may be the underlying cause of menstrual cycle dependent changes in cognition and emotion. P28261 W1233-G17 (VLID)3113365

Longitudinal menstrual cycle studies allow to investigate the effects of ovarian hormones on brain organization. Here, we use spectral dynamic causal modelling (spDCM) in a triple network model to assess effective connectivity changes along the menstrual cycle within and between the default mode, salience and executive control networks (DMN, SN, and ECN). Sixty healthy young women were scanned three times along their menstrual cycle, during early follicular, pre-ovulatory and mid-luteal phase. Related to estradiol, right before ovulation the left insula recruits the ECN, while the right middle frontal gyrus decreases its connectivity to the precuneus and the DMN decouples into anterior/posterior parts. Related to progesterone during the mid-luteal phase, the insulae (SN) engage to each other, while decreasing their connectivity to parietal ECN, which in turn engages the posterior DMN. When including the most confident connections in a leave-one out cross-validation, we find an above-chance prediction of the left-out subjects’ cycle phase. These findings corroborate the plasticity of the female brain in response to acute hormone fluctuations and may help to further understand the neuroendocrine interactions underlying cognitive changes along the menstrual cycle., Hidalgo-Lopez et al. use dynamic causal modelling to investigate changes in effective connectivity related to menstrual phase and hormonal levels in healthy women. Their results provide further insight into how the brain responds to hormone fluctuations throughout the menstrual cycle.