Effects of estrogen on spatial navigation and memory.

RATIONALE: Animal studies suggest that the so-called "female" hormone estrogen enhances spatial navigation and memory. This contradicts the observation that males generally out-perform females in spatial navigation and tasks involving spatial memory. A closer look at the vast number of studies actually reveals that performance differences are not so clear. OBJECTIVES: To help clarify the unclear performance differences between men and women and the role of estrogen, we attempted to isolate organizational from activational effects of estrogen on spatial navigation and memory. METHODS: In a double-blind, placebo-controlled study, we tested the effects of orally administered estradiol valerate (E2V) in healthy, young women in their low-hormone menstrual cycle phase, compared to healthy, young men. Participants performed several first-person, environmentally rich, 3-D computer games inspired by spatial navigation and memory paradigms in animal research. RESULTS: We found navigation behavior suggesting that sex effects dominated any E2 effects with men performing better with allocentric strategies and women with egocentric strategies. Increased E2 levels did not lead to general improvements in spatial ability in either sex but to behavioral changes reflecting navigation flexibility. CONCLUSION: Estrogen-driven differences in spatial cognition might be better characterized on a spectrum of navigation flexibility rather than by categorical performance measures or skills.

The effect of short-term increase of estradiol levels on sexual desire and orgasm frequency in women and men: A double-blind, randomized, placebo-controlled trial.

Estradiol (E2) has been implicated in sexual functioning in both sexes. E2 levels change distinctively over the menstrual cycle, peaking around ovulation. Data on short-term effects of fluctuating E2 levels on sexual desire are however sparse and mostly based on observational studies. To fill this gap, we ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of a short-term increase in E2 on sexual desire and orgasm frequency in healthy, young men and women. Circulating E2 levels were elevated through estradiol valerate (E2V) administered over two consecutive days to simulate the rise in E2 levels around ovulation. E2V had no effect on orgasm frequency and only minor effects on sexual desire. On average, the administered E2V dampened change in sexual desire compared to untreated participants with comparable baseline sexual desire in such a way that sexual desire was slightly reduced even in those with higher baseline sexual desire. These findings suggest that short-term increases in E2 have little effect on sexual function and are unlikely to explain the increase in sexual desire around ovulation.

Effects of 24-hour oral estradiol-valerate administration on hormone levels in men and pre-menopausal women.

In order to translate the findings from the vast animal literature on the effect of 17ß-estradiol (E2) on brain and behavior to humans, a placebo-controlled pharmacological enhancement of E2 levels for at least 24 h is necessary. However, an exogenous increase in E2 for such a prolonged period might affect the endogenous secretion of other (neuroactive) hormones. Such effects would be of relevance for the interpretation of the effects of this pharmacological regimen on cognition and its neural correlates as well as be of basic scientific interest. We therefore administered a double dose of 12 mg of estradiol-valerate (E2V) to men and of 8 mg to naturally cycling women in their low-hormone phase, and assessed the concentration of two steroids critical to hormone regulation: follicle stimulating hormone (FSH) and luteinizing hormone (LH). We also assessed any changes in concentration of the neuroactive hormones progesterone (P4), testosterone (TST), dihydrotestosterone (DHT) and immune-like growth factor 1 (IGF-1). This regimen resulted in similar E2 levels in both sexes (saliva and serum). FSH and LH levels in both sexes were down-regulated to the same degree. P4 concentration decreased in both sexes only in serum but not saliva. TST and DHT levels dropped only in men whereas sex-hormone binding globulin was not affected. Finally, the concentration of IGF-1 decreased in both sexes. Based on previous studies on the effects of these neuroactive hormones, only the degree of downregulation of TST and DHT levels in men might have an impact on brain and behavior, which should be considered when interpreting the effects of the presented E2V regimes.

Effects of circulating estradiol on physiological, behavioural, and subjective correlates of anxiety: A double-blind, randomized, placebo-controlled trial.

Anxiety-related behaviours as well as the prevalence of anxiety disorders show a large sex difference in humans. Clinical studies in humans as well as behavioural studies in rodents suggest that estradiol may have anxiolytic properties. In line with this, anxiety symptoms fluctuate with estradiol levels along the menstrual cycle. However, the influence of estradiol on subjective, behavioural, as well as physiological correlates of anxiety has never been systematically addressed in humans. We ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of estradiol on anxiety in men and women. In healthy volunteers, circulating estradiol levels were elevated through estradiol administration over two consecutive days to simulate the rise in estradiol levels around ovulation. Subjective, behavioral, as well as, physiological correlates of anxiety were assessed using a virtual reality elevated plus-maze (EPM). Estradiol treatment reduced the physiological stress response with blunted heart rate response and lower cortisol levels compared to placebo treatment in both sexes. In contrast, respiration frequency was only reduced in women after estradiol treatment. Behavioural measures of anxiety as well as subjective anxiety on the EPM were not affected by estradiol treatment. In general, women showed more avoidance and less approach behavior and reported higher subjective anxiety levels on the EPM than men. These results highlight the limited anxiolytic properties of circulating levels of estradiol in humans, which influence physiological markers of anxiety but not approach and avoidance behaviour or subjective anxiety levels.

Self-referential processes and resting-state connectivity in breast cancer patients before and 1 year after chemotherapy.

Modifications in the processing of information relevant to oneself have been reported in breast cancer (BC) patients. Here, we characterize the longitudinal changes to self-representations in BC patients and how they are related to intrinsic functional brain connectivity. We tested 16 BC patients before (T1) and 1 year after the end of chemotherapy (T2) along with 24 healthy control participants (HC) at similar time points. Participants underwent resting-state fMRI and completed the Questionnaire of Self-Representation (QSR), which evaluates self-assertion and self-esteem. Resting-state functional connectivity (RSFC) was calculated for regions implicated in self-referential processes (dorsomedial prefrontal cortex [dmPFC], posterior cingulate cortex [PCC], and dorsal anterior cingulate cortex [dACC]) and correlated with QSR scores. QSR scores were on average larger in patients compared with HC and did not vary over time. RSFC between the dACC and regions supporting body awareness (precentral/postcentral and supramarginal gyri, superior parietal lobule) decreased more between T1 and T2 in BC patients than in HC. BC patients had lower RSFC than HC between the dmPFC and the PCC, and regions supporting mental imagery (precuneus, lingual gyrus), at each time point, and a greater decrease from T1 and T2. QSR scores negatively correlated with RSFC. Patients described themselves as having greater self-awareness and positive self-image, reflecting a fighting spirit. In parallel, patients presented a decrease in cortical activity related to body awareness and mental imagery of self-representations over time that may be related to the positive self-image patients have and could reflect a temporary adaptive strategy.

Sex Differences and Exogenous Estrogen Influence Learning and Brain Responses to Prediction Errors.

Animal studies show marked sex differences as well as effects of estrogen (E2) in the mesocorticolimbic dopaminergic (DA) pathways, which play a critical role in reward processing and reinforcement learning and are also implicated in drug addiction. In this computational pharmacological fMRI study, we investigate the effects of both factors, sex and estrogen, on reinforcement learning and the dopaminergic system in humans; 67 male and 64 naturally cycling female volunteers, the latter in their low-hormone phase, were randomly assigned, double-blind, to take E2 or placebo. They completed a reinforcement learning task in the MRI scanner for which we have previously shown reward prediction error (RPE)-related activity to be dopaminergic. We found RPE-related brain activity to be enhanced in women compared with men and to a greater extent when E2 levels were elevated in both sexes. However, both factors, female sex and E2, slowed adaptation to RPEs (smaller learning rate). This discrepancy of larger RPE-related activity yet smaller learning rates can be explained by organizational sex differences and activational effects of circulating E2, which both affect DA release differently to DA receptor binding capacities.

Metaphor processing is supramodal semantic processing: The role of the bilateral lateral temporal regions in multimodal communication.

This paper presents an fMRI study on healthy adult understanding of metaphors in multimodal communication. We investigated metaphors expressed either only in coverbal gestures ("monomodal metaphors") or in speech with accompanying gestures ("multimodal metaphors"). Monomodal metaphoric gestures convey metaphoric information not expressed in the accompanying speech (e.g. saying the non-metaphoric utterance, "She felt bad" while dropping down the hand with palm facing up; here, the gesture alone indicates metaphoricity), whereas coverbal gestures in multimodal metaphors indicate metaphoricity redundant to the speech (e.g. saying the metaphoric utterance, "Her spirits fell" while dropping the hand with palm facing up). In other words, in monomodal metaphors, gestures add information not spoken, whereas the gestures in multimodal metaphors can be redundant to the spoken content. Understanding and integrating the information in each modality, here spoken and visual, is important in multimodal communication, but most prior studies have only considered multimodal metaphors where the gesture is redundant to what is spoken. Our participants watched audiovisual clips of an actor speaking while gesturing. We found that abstract metaphor comprehension recruited the lateral superior/middle temporal cortices, regardless of the modality in which the conceptual metaphor is expressed. These results suggest that abstract metaphors, regardless of modality, involve resources implicated in general semantic processing and are consistent with the role of these areas in supramodal semantic processing as well as the theory of embodied cognition.

Test-retest reliability of the emotional enhancement of memory.

Emotionally arousing stimuli are usually better remembered than neutral ones. This effect can be observed immediately after encoding and becomes more robust after a period of consolidation. The magnitude of this effect in an individual has been treated in various research contexts implicitly as reliable and temporally stable. However, we recently observed in 69 participants that an individual's memory advantage for negative over neutral stimuli, whether immediate or delayed, was very weakly correlated with the advantage measured after 3.5 years, albeit with slightly different memory paradigms. In the current study, we tested whether the test-retest reliability of these emotional memory effects might be larger if the temporal lapse between tests was shorter (10 weeks) and more similar memory tests were used. We observed that the better memory for emotional stimuli is highly replicable on the group level. However, the retest reliability on the individual level was very low. We replicated these findings by re-analysing data from a previous study where female participants took emotional memory tests at two different points of their menstrual cycle. We conclude, therefore, that the individual emotional enhancement of memory is not stable or that it cannot be measured reliably with the standard emotional memory paradigm.

Handling or being the concept: An fMRI study on metonymy representations in coverbal gestures.

In "Two heads are better than one," "head" stands for people and focuses the message on the intelligence of people. This is an example of figurative language through metonymy, where substituting a whole entity by one of its parts focuses attention on a specific aspect of the entity. Whereas metaphors, another figurative language device, are substitutions based on similarity, metonymy involves substitutions based on associations. Both are figures of speech but are also expressed in coverbal gestures during multimodal communication. The closest neuropsychological studies of metonymy in gestures have been nonlinguistic tool-use, illustrated by the classic apraxic problem of body-part-as-object (BPO, equivalent to an internal metonymy representation of the tool) vs. pantomimed action (external metonymy representation of the absent object/tool). Combining these research domains with concepts in cognitive linguistic research on gestures, we conducted an fMRI study to investigate metonymy resolution in coverbal gestures. Given the greater difficulty in developmental and apraxia studies, perhaps explained by the more complex semantic inferencing involved for external metonymy than for internal metonymy representations, we hypothesized that external metonymy resolution requires greater processing demands and that the neural resources supporting metonymy resolution would modulate regions involved in semantic processing. We found that there are indeed greater activations for external than for internal metonymy resolution in the temporoparietal junction (TPJ). This area is posterior to the lateral temporal regions recruited by metaphor processing. Effective connectivity analysis confirmed our hypothesis that metonymy resolution modulates areas implicated in semantic processing. We interpret our results in an interdisciplinary view of what metonymy in action can reveal about abstract cognition.