Estradiol administration modulates neural emotion regulation.

Variations of sex hormones during the menstrual cycle can lead to changes in emotion processing. The ability to successfully regulate one's emotions is associated with better social abilities and mental health. While women show better performance in fear extinction learning under high estradiol (E2) compared to women under low E2 levels, little is known about the effect of E2 on emotion regulation. We explored whether E2 modulates emotion regulation in a functional magnetic resonance imaging paradigm and administered E2 valerate to 32 young naturally cycling women during their early follicular phase in a double-blind, placebo-controlled within-subject design. This standardized experimental control allowed us to explore the specific effect of E2 on emotion regulation while controlling for other hormones varying throughout the menstrual cycle. Behaviorally, no difference between conditions appeared. However, on the neural level, E2 administration was associated with lower activation in the right lingual- and left calcarine gyrus, right orbitofrontal cortex and left hippocampus relative to placebo. With respect to the main effect of down-regulation higher activation of the right superior frontal gyrus and left dorsomedial prefrontal cortex was seen; which is in accordance to previous literature. An interaction between drug condition and emotion regulation appeared for the left inferior frontal gyrus extending into the middle frontal gyrus indicating lower activation during down-regulation in the E2 condition than the placebo condition. On the behavioral level, women reported less negative affect in the E2 condition. The results fit well to a previously described psychoneuroendocrinological model in which E2 plays an important modulatory role on emotional processes and risk factors of mental health in women.

Shaping of the Female Human Brain by Sex Hormones: A Review.

Traditionally sex hormones have been associated with reproductive and developmental processes only. Since the 1950s we know that hormones can have organizational effects on the developing brain and initiate hormonal transition periods such as puberty. However, recent evidence shows that sex hormones additionally structure the brain during important hormonal transition periods across a woman's life including short-term fluctuations during the menstrual cycle. However, a comprehensive review focusing on structural changes during all hormonal transition phases of women is still missing. Therefore, in this review structural changes across hormonal transition periods (i.e., puberty, menstrual cycle, oral contraceptive intake, pregnancy and menopause) were investigated in a structured way and correlations with sex hormones evaluated. Results show an overall reduction in grey matter and region-specific decreases in prefrontal, parietal and middle temporal areas during puberty. Across the menstrual cycle grey matter plasticity in the hippocampus, the amygdala as well as temporal and parietal regions were most consistently reported. Studies reporting on pre- and post-pregnancy measurements revealed volume reductions in midline structures as well as prefrontal and temporal cortices. During perimenopause, the decline in sex hormones was paralleled with a reduction in hippocampal and parietal cortex volume. Brain volume changes were significantly correlated with estradiol, testosterone and progesterone levels in some studies, but directionality remains inconclusive between studies. These results indicate that sex hormones play an important role in shaping women's brain structure during different transition periods and are not restricted to specific developmental periods.

Sex hormones and human brain function.

Sex hormones have organizational and activational effects on the human brain and can interact with the neurotransmitter systems. These biologic mechanisms may have a far-reaching impact, with both behavioral consequences and structural as well as functional brain modulation. The impact of cycling hormone levels throughout the menstrual cycle on cognitive and emotion processing has especially received some attention recently. Therefore, the aim of this chapter is to give an overview of findings regarding the effects of estradiol and progesterone, but also testosterone, on functional brain domains comprising cognition, emotion, and reward processing.

Exploring Sex Differences in the Neural Correlates of Self-and Other-Referential Gender Stereotyping.

While general self-referential processes and their neural underpinnings have been extensively investigated with neuroimaging tools, limited data is available on sex differences regarding self- and other-referential processing. To fill this gap, we measured 17 healthy women and men who performed a self- vs. other-appraisal task during functional magnetic resonance imaging (fMRI) using gender-stereotypical adjectives. During the self-appraisal task, typical male (e.g., "dominant," "competitive") and female adjectives (e.g., "communicative," "sensitive") were presented and participants were asked whether these adjectives applied to themselves. During the other-appraisal task, a prototypical male (Brad Pitt) and female actor (Julia Roberts) was presented and participants were asked again to judge whether typical male and female adjectives applied to these actors. Regarding self-referential processes, women ascribed significantly more female compared to male traits to themselves. At the same time both women and men indicated a stronger desire to exhibit male over female traits. While fMRI did not detect general sex differences in the self- and other-conditions, some subtle differences were revealed between the sexes: both in right putamen and bilateral amygdala stronger gender-congruent activation was found which was however not associated with behavioral measures like the number of self-ascribed female or male attributes. Furthermore, sex hormone levels showed some associations with brain activation pointing to a different pattern in women and men. Finally, the self- vs. other-condition in general led to stronger activation of the anterior cingulate cortex while the other- vs. self-condition activated the right precuneus more strongly which is in line with previous findings. To conclude, our data lend support for subtle sex differences during processing of stereotypical gender attributes. However, it remains unclear whether such differences have a behavioral relevance. We also point to several limitations of this study including the small sample size and the lack of control for potentially different hormonal states in women.

Exploring the fMRI based neural correlates of the dot probe task and its modulation by sex and body odor.

The dot probe task implicitly cues attention via emotional information, an effect which is especially pronounced for threat-related cues. However, several questions remain unexplored. The first one is whether chemosignals like the androgen-derivative androstadienone can influence such attentional biases. Second, few studies have addressed sex differences regarding attentional biases. Finally, the neural correlates of these potential behavioral effects based on functional magnetic resonance imaging (fMRI) are not known. In two experiments we aimed to answer these questions. A total of 159 healthy individuals (58 oral-contraceptive-users, 42 luteal women, 59 men) were tested. In experiment 1 (behavioral study) we examined attentional biases behaviorally, while in experiment 2 (fMRI study) the dot probe task was complemented by fMRI. Our results provide robust evidence that in healthy participants fearful but not angry or happy faces lead to a strong general attentional bias. Elucidating the neural basis of this effects points to an early processing advantage in bilateral thalamus for valid compared to invalid cued fear. However, this finding was limited to those participants with the strongest attentional biases and was not linked to behavioral measures. Furthermore, no consistent sex or group differences existed neither did the putative human chemosignal androstadienone reliably modulate attentional biases or change neural processing.

The human body odor compound androstadienone increases neural conflict coupled to higher behavioral costs during an emotional Stroop task.

The androgen derivative androstadienone (AND) is a substance found in human sweat and thus may act as human chemosignal. With the current experiment, we aimed to explore in which way AND affects interference processing during an emotional Stroop task which used human faces as target and emotional words as distractor stimuli. This was complemented by functional magnetic resonance imaging (fMRI) to unravel the neural mechanism of AND-action. Based on previous accounts we expected AND to increase neural activation in areas commonly implicated in evaluation of emotional face processing and to change neural activation in brain regions linked to interference processing. For this aim, a total of 80 healthy individuals (oral contraceptive users, luteal women, men) were tested twice on two consecutive days with an emotional Stroop task using fMRI. Our results suggest that AND increases interference processing in brain areas that are heavily recruited during emotional conflict. At the same time, correlation analyses revealed that this neural interference processing was paralleled by higher behavioral costs (response times) with higher interference related brain activation under AND. Furthermore, AND elicited higher activation in regions implicated in emotional face processing including right fusiform gyrus, inferior frontal gyrus and dorsomedial cortex. In this connection, neural activation was not coupled to behavioral outcome. Furthermore, despite previous accounts of increased hypothalamic activation under AND, we were not able to replicate this finding and discuss possible reasons for this discrepancy. To conclude, AND increased interference processing in regions heavily recruited during emotional conflict which was coupled to higher costs in resolving emotional conflicts with stronger interference-related brain activation under AND. At the moment it remains unclear whether these effects are due to changes in conflict detection or resolution. However, evidence most consistently suggests that AND does not draw attention to the most potent socio-emotional information (human faces) but rather highlights representations of emotional words.

Bayesian informed evidence against modulation of androstadienone-effects by genotypic receptor variants and participant sex: A study assessing Stroop interference control, mood and olfaction.

The androgen derivative androstadienone (AND) is present in human sweat and may act as human chemosignal. Though effects of AND have been reported with respect to emotional and cognitive processes, results have been highly inconsistent. For this reason, it is likely that AND-action is dependent on modulatory factors. Here we wanted to specifically investigate the impact of genotypic variations of the AND-receptor OR7D4, as well as the influence of participant sex and concomitant hormonal fluctuations on AND-action during emotional interference processing, olfactory performance and mood assessments. To this end 80 healthy individuals (women taking oral contraceptives; naturally cycling women measured during the luteal phase and men) were tested twice on two consecutive days (AND vs. placebo exposure) with an emotional Stroop task. Also, olfactory performance and mood was assessed. Participants provided saliva samples to measure testosterone, progesterone and estradiol and a blood sample to assess genotypic variations of the AND-receptor OR7D4. We found a small task-dependent reduction of overall error rates under AND but no modulation of effects by genetic variation or group (female OC, female NC, male) with respect to olfactory performance and mood. Additional analyses with help of Bayesian statistics gave strong evidence in favor of specific null hypotheses suggesting that the action of AND was not modulated by either genotypic variations or sex of participants with respect to interference control (bias indices), olfactory self-reports and mood parameters. Additional effects of AND in connection with hormonal fluctuations are reported.

The human body odor compound androstadienone leads to anger-dependent effects in an emotional Stroop but not dot-probe task using human faces.

The androgen derivative androstadienone is a substance found in human sweat and thus is a putative human chemosignal. Androstadienone has been studied with respect to effects on mood states, attractiveness ratings, physiological and neural activation. With the current experiment, we aimed to explore in which way androstadienone affects attention to social cues (human faces). Moreover, we wanted to test whether effects depend on specific emotions, the participants' sex and individual sensitivity to smell androstadienone. To do so, we investigated 56 healthy individuals (thereof 29 females taking oral contraceptives) with two attention tasks on two consecutive days (once under androstadienone, once under placebo exposure in pseudorandomized order). With an emotional dot-probe task we measured visuo-spatial cueing while an emotional Stroop task allowed us to investigate interference control. Our results suggest that androstadienone acts in a sex, task and emotion-specific manner as a reduction in interference processes in the emotional Stroop task was only apparent for angry faces in men under androstadienone exposure. More specifically, men showed a smaller difference in reaction times for congruent compared to incongruent trials. At the same time also women were slightly affected by smelling androstadienone as they classified angry faces more often correctly under androstadienone. For the emotional dot-probe task no modulation by androstadienone was observed. Furthermore, in both attention paradigms individual sensitivity to androstadienone was neither correlated with reaction times nor error rates in men and women. To conclude, exposure to androstadienone seems to potentiate the relevance of angry faces in both men and women in connection with interference control, while processes of visuo-spatial cueing remain unaffected.