Oral contraceptives in the central nervous system: Basic pharmacology, methodological considerations, and current state of the field.

Millions of women around the world use combined oral contraceptives (OCs), yet surprisingly little is known about their central nervous system (CNS) effects. This article provides a short overview of the basic pharmacology of OCs, emphasizing features that may be relevant to understanding their effects in the CNS. Historical and recent findings from studies of cognitive function, mood, and negative affect (depressive changes under OC use) are then reviewed. We also present data from an archival dataset from our own laboratory in which we explore dysphoric changes in women using four generations of contraceptive progestins. Current data in the field are consistent with a modest effect of OC use on CNS variables, but conclusions based on current findings must be made very cautiously because of multiple methodological issues in many published studies to date, and inconsistencies in the findings. Directions for future research over the next 10 years are suggested. (150 words).

Supramolecular assemblies of organo-functionalised hybrid polyoxometalates: from functional building blocks to hierarchical nanomaterials.

This review provides a comprehensive overview of recent advances in the supramolecular organisation and hierarchical self-assembly of organo-functionalised hybrid polyoxometalates (hereafter referred to as hybrid POMs), and their emerging role as multi-functional building blocks in the construction of new nanomaterials. Polyoxometalates have long been studied as a fascinating outgrowth of traditional metal-oxide chemistry, where the unusual position they occupy between individual metal oxoanions and solid-state bulk oxides imbues them with a range of attractive properties (e.g. solubility, high structural modularity and tuneable properties/reactivity). Specifically, the capacity for POMs to be covalently coupled to an effectively limitless range of organic moieties has opened exciting new avenues in their rational design, while the combination of distinct organic and inorganic components facilitates the formation of complex molecular architectures and the emergence of new, unique functionalities. Here, we present a detailed discussion of the design opportunities afforded by hybrid POMs, where fine control over their size, topology and their covalent and non-covalent interactions with a range of other species and/or substrates makes them ideal building blocks in the assembly of a broad range of supramolecular hybrid nanomaterials. We review both direct self-assembly approaches (encompassing both solution and solid-state approaches) and the non-covalent interactions of hybrid POMs with a range of suitable substrates (including cavitands, carbon nanotubes and biological systems), while giving key consideration to the underlying driving forces in each case. Ultimately, this review aims to demonstrate the enormous potential that the rational assembly of hybrid POM clusters shows for the development of next-generation nanomaterials with applications in areas as diverse as catalysis, energy-storage and molecular biology, while providing our perspective on where the next major developments in the field may emerge.

First Demonstration of Double Dissociation between COMT-Met158 and COMT-Val158 Cognitive Performance When Stressed and When Calmer.

We present here the first evidence of the much-predicted double dissociation between the effect of stress on cognitive skills [executive functions (EFs)] dependent on prefrontal cortex (PFC) by catechol-O-methyltransferase (COMT) genotype. The COMT gene polymorphism with methionine (Met) at codon 158 results in more dopamine (DA) in PFC and generally better EFs, while with valine (Val) at codon 158 the result is less PFC DA and generally poorer EFs. Many have predicted that mild stress, by raising PFC DA levels should aid EFs of COMT-Vals (bringing their PFC DA levels up, closer to optimal) and impair EFs of COMT-Mets (raising their PFC DA levels past optimal). We tested 140 men and women in a within-subject crossover design using extremely mild social evaluative stress. On trials requiring EFs (incongruent trials) of the Flanker/Reverse Flanker task, COMT-Val158 homozygotes performed better when mildly stressed than when calmer, while COMT-Met158 carriers performed worse when mildly stressed. Two other teams previously tried to obtain this, but only found stress impairing EFs of COMT-Mets, not improving EFs of COMT-Vals. Perhaps we found both because we used a much milder stressor. Evidently, the bandwidth for stress having a facilitative effect on EFs is exceedingly narrow.

Depressive affect moderates the effects of biological sex on the recognition of facial emotion.

Females show a small processing advantage relative to males in the ability to identify facial expressions of emotion. In laboratory studies, this is expressed as a sex difference in the accuracy of discrimination or in recognition latencies (the time required to identify an expression). Reasons for the sex difference are not well-understood. In the current pilot study, young adults (N = 62) with and without mild to moderate symptoms of depression were asked to discriminate facial images of infants and toddlers expressing six cardinal emotions. Results showed that elevated depressive affect was associated with more rapid recognition of negative emotions by females, and with potentiation of the typically observed sex difference, compared with non-depressed observers. Differences in endogenous affective status might be one proximate factor contributing to a female advantage in emotion recognition.

Endogenous variation in estradiol in women affects the weighting of metric and categorical information in spatial location memory.

Recent work has suggested that sex differences may exist in the strategies or types of cues that are utilized by men and women to remember discrete spatial locations or routes through a visual environment. The current study investigated the effects of circulating estradiol levels in women on the relative weighting of categorical versus fine-grained 'metric' information in a test of short-term memory for spatial locations, either presented within a simple geometric surround (a circular enclosure) or within more visually complex landscape scenes. Patterns of displacement error in the point location estimates made by men and women were analyzed. Results confirmed a sex difference in the weighting of metric versus categorical cues. Relative to men, women's estimates of locations were more strongly biased toward the center of the surrounding category (i.e., toward the category 'prototype'). Furthermore, objective measures of estradiol via saliva collected at the time of memory testing showed that, among naturally-cycling women, estradiol concentrations correlated in a positive, graded, fashion with the degree of emphasis that women placed on categorical information when estimating point locations. No associations were found for progesterone. These findings are consistent with a wider body of research showing that biological sex and reproductive hormone levels, including 17ß-estradiol, can subtly influence performance on certain spatial tasks. This is the first study to show that circulating estradiol levels may influence the relative emphasis placed on categorical versus metric cues when remembering simple point locations.

A brief guide to the menstrual cycle and oral contraceptive use for researchers in behavioral endocrinology.

There is increasing evidence that reproductive hormones exert regulatory effects in the central nervous system that can influence behavioral, cognitive, perceptual, affective, and motivational processes. These effects occur in adults and post-pubertal individuals, and can be demonstrated in humans as well as laboratory animals. Large changes in 17ß-estradiol and progesterone occur over the ovarian cycle (i.e., the menstrual cycle) and afford a way for researchers to explore the central nervous system (CNS) effects of these hormones under natural physiological conditions. Increasingly, oral contraceptives are also being studied, both as another route to understanding the CNS effects of reproductive hormones and also as pharmacological agents in their own right. This mini-review will summarize the basic physiology of the menstrual cycle and essential facts about oral contraceptives to help novice researchers to use both paradigms effectively.

Redox-Active Hybrid Polyoxometalate-Stabilised Gold Nanoparticles.

We report the design and preparation of multifunctional hybrid nanomaterials through the stabilization of gold nanoparticles with thiol-functionalised hybrid organic-inorganic polyoxometalates (POMs). The covalent attachment of the hybrid POM forms new nanocomposites that are stable at temperatures and pH values which destroy analogous electrostatically functionalised nanocomposites. Photoelectrochemical analysis revealed the unique photochemical and redox properties of these systems.

Asymmetric Hybrid Polyoxometalates: A Platform for Multifunctional Redox-Active Nanomaterials.

Access to asymmetrically functionalized polyoxometalates is a grand challenge as it could lead to new molecular nanomaterials with multiple or modular functionality. Now, a simple one-pot synthetic approach to the isolation of an asymmetrically functionalized organic-inorganic hybrid Wells-Dawson polyoxometalate in good yield is presented. The cluster bears two organophosphonate moieties with contrasting physical properties: a chelating metal-binding group, and a long aliphatic chain that facilitates solvent-dependent self-assembly into soft nanostructures. The orthogonal properties of the modular system are effectively demonstrated by controlled assembly of POM-based redox-active nanoparticles. This simple, high-yielding synthetic method is a promising new approach to the preparation of multi-functional hybrid metal oxide clusters, supermolecular systems, and soft-nanomaterials.

Estrogens, Aging, and Working Memory.

PURPOSE OF REVIEW: Working memory (WM) is a key process that is integral to many complex cognitive tasks, and it declines significantly with advancing age. This review will survey recent evidence supporting the idea that the functioning of the WM system in women is modulated by circulating estrogens. RECENT FINDINGS: In postmenopausal women, increased estrogen concentrations may be associated with improved WM function, which is evident on WM tasks that have a high cognitive load or significant manipulation demands. Experimental studies in rhesus monkeys and human neuroimaging studies support a prefrontal locus for these effects. Defining the basic neurochemical or cellular mechanisms that underlie the ability of estrogens to regulate WM is a topic of current research in both human and animal investigations. An emerging body of work suggests that frontal executive elements of the WM system are influenced by the circulating estrogen concentrations currently available to the CNS and that the effects are region-specific within the frontal cortex. These findings have implications for women's brain health and cognitive aging.

The differential effects of a focus on symptoms versus recovery in reducing stigma of schizophrenia.

PURPOSE: We extend investigations of the impact of the content of video contact with an individual with schizophrenia on stigma reduction. We examine whether differential impacts persist over a 2-week period and the extent to which they are mediated by perceived similarity and feelings of empathy and/or sympathy. METHOD: We used a randomized control trial wherein participants were exposed to a video in which an individual described his recovery from schizophrenia, or the same person described acute symptoms of schizophrenia, or a no-video control condition. Outcomes included impressions of and preferred social distance to the person in the video and people in general with schizophrenia and well as perceptions of similarity and feelings of sympathy and empathy. We also measured an overt behaviour, seating distance, at 2-week follow-up. RESULTS: The recovery-focused material was generally more effective in improving impressions and reducing preferred level of social distance. Although the symptom-focused video resulted in great sympathy for the person, this did not translate into positive impressions or reduced social distance. Mediational analyses yielded findings consistent with the benefits of the recovery video being mediated by increased perceptions of similarity and lower feelings of sympathy. Exposure to the recovery-focused video resulted in less anxiety in anticipation of meeting the person in the video relative to the control condition. CONCLUSIONS: Video contact emphasizing potential for recovery from schizophrenia was more effective in reducing stigmatizing responses than contact highlighting acute symptoms. Increased sympathy does not necessarily translate into reductions in stigma.

The development of hand preference and dichotic language lateralization in males and females with congenital adrenal hyperplasia.

People with congenital adrenal hyperplasia (CAH) are exposed to elevated levels of androgens in utero due to overproduction by the adrenal cortex. In order to test whether high levels of prenatal androgens influence the development of handedness preferences and left-hemisphere language representation, we studied 39 patients with CAH (28 females, 11 males) and 25 unaffected sibling controls (17 females, 8 males). Hand preference for 15 unimanual activities was evaluated via questionnaire and pantomime, and a consonant-vowel dichotic listening test was administered. Contemporary theories disagree as to whether high testosterone is said to increase or decrease the probability of developing a typical right-hand preference. Results showed no significant differences on the handedness inventory. Relative to controls, however, patients with CAH showed a significantly larger right-ear advantage on the dichotic syllables task, indicating stronger left-hemisphere lateralization of language. These results support an emerging body of evidence suggesting that high testosterone may bias lateralized development toward the population norm, but run counter to the Geschwind-Behan-Galaburda model which associates high prenatal testosterone with a greater prevalence of left-handedness.

Oral contraceptives and cognition: A role for ethinyl estradiol.

This article is part of a Special Issue "Estradiol and cognition". Estrogens have been seen to play a role in human cognitive abilities, but questions remain about the cognitive impact of ethinyl estradiol, which is contained in many oral contraceptives (OCs). Inconsistencies in past studies likely reflect small samples and heterogeneous groups of OC users. The aims of the present work were to examine OC effects on sex-typed spatial and verbal abilities by (a) comparing mental rotations and expressional fluency in normally-cycling (NC) women and men to OC users considered as a heterogeneous group and then to homogeneous groups of OC users created by classifying pills according to their active constituents, and (b) determining the relation between synthetic hormone doses in OCs and mental rotations and expressional fluency. Participants were 136 men, 93 NC women, and 148 OC users, including homogeneous monophasic (n = 55) and triphasic (n = 43) OC groups, aged 18 to 30 years. Significant effects of OC use were seen in homogeneous group comparisons but not when OC users were considered as a heterogeneous group. On mental rotations, men outperformed women, and monophasic OC users outperformed NC women. The latter difference may be attributable to estradiol, as ethinyl estradiol was inversely related to spatial ability among OC users and was lower in monophasic than in triphasic users. On expressional fluency, NC women and monophasic OC users outperformed men, and monophasic users outperformed triphasic users. Thus, results show the importance of ethinyl estradiol and of considering pill constituents when studying the cognitive effects of OCs.

Working memory in pregnant women: Relation to estrogen and antepartum depression.

This article is part of a Special Issue "Estradiol and cognition". Subjective changes in concentration and memory are commonly reported by women during the second or third trimesters of pregnancy, but the nature of the problem is poorly understood. We hypothesized that these self-reports might reflect difficulties in working memory (WM). It was further hypothesized that antepartum depression (depression arising during pregnancy) may play an etiological role, either on its own or due to secondary changes in endocrine function or sleep. Using WM tasks that emphasized executive control processes mediated by the prefrontal cortex (PFC) we compared pregnant women tested at 34-36 weeks of gestation (n = 28) with age- and education-matched non-pregnant controls (n = 26). All pregnant women were screened for depression. Evidence of a WM disturbance was found, and was evident only among pregnant women showing depressive symptoms. In contrast, pregnant women who were not depressed showed WM performance that equalled, or even significantly exceeded, non-pregnant controls. No significant differences were observed on control tests of other cognitive functions. Multiple regression revealed that serum estradiol concentrations, along with severity of depressive affect but not sleep disruption, significantly predicted variation in the WM scores. In agreement with studies of estradiol and WM in other contexts, higher estradiol was associated with better WM, while higher levels of depressive symptoms predicted poorer WM. We conclude that memory disturbance during gestation might not be as widespread as commonly believed, but can be seen among women experiencing antepartum depression. The high level of WM performance found in healthy, non-depressed, pregnant women is discussed from an adaptationist perspective.

Sex differences on prefrontally-dependent cognitive tasks.

There is preliminary evidence to suggest that the prefrontal cortex (PFC) is modulated by sex steroids in humans and other primates. The current study examined whether sex differences in performance could be discerned on two working memory tasks that emphasize monitoring and updating processes, and on two tasks that engage the ventromedial PFC/orbitofrontal cortex (VMPFC/OFC). Healthy young adults (48 females; 45 males) completed the n-back, Self-Ordered Pointing (SOP), Iowa Gambling Task (IGT), and a probabilistic reversal learning task. On the IGT, males selected more cards from the advantageous decks than females. On the reversal learning task, there was no significant sex difference in acquisition of the reinforcement contingencies, but males made fewer errors than females during the reversal phase. The sexes did not differ significantly on the n-back or SOP tasks. These findings provide tentative support for the hypothesis that functions carried out by the VMPFC/OFC are sexually differentiated in humans.

Sex differences in the weighting of metric and categorical information in spatial location memory.

According to the Category Adjustment model, remembering a spatial location involves the Bayesian combination of fine-grained and categorical information about that location, with each cue weighted by its relative certainty. However, individuals may differ in terms of their certainty about each cue, resulting in estimates that rely more or less on metric or categorical representations. To date, though, very little research has examined individual differences in the relative weighting of these cues in spatial location memory. Here, we address this gap in the literature. Participants were asked to recall point locations in uniform geometric shapes and in photographs of complex, natural scenes. Error patterns were analyzed for evidence of a sex difference in the relative use of metric and categorical information. As predicted, women placed relatively more emphasis on categorical cues, while men relied more heavily on metric information. Location reproduction tasks showed a similar effect, implying that the sex difference arises early in spatial processing, possibly during encoding.

Estradiol and mental rotation: relation to dimensionality, difficulty, or angular disparity?

Several studies have reported that performance on spatial rotation tests is better at menses than at high estradiol phases of the menstrual cycle in women. These effects are debated because nearly all reports of menstrual cycle variability have relied on a single test, the Mental Rotations Test (MRT, Vandenberg and Kuse, 1978). In the present study, we investigated key features of the MRT that might be responsible for its association with estradiol levels. We hypothesized that associations could be demonstrated for other tasks that share the same characteristics. Forty-four women ages 20-38 years, matched on education and general ability, were assessed at low (n=24) or high (n=20) estradiol stages of the menstrual cycle on a set of spatial tests that varied in dimensionality, plane of rotation, angular disparity, and effortfulness. Saliva was used to quantify estradiol and progesterone. Low estradiol was found to be associated with significantly better accuracy on the MRT and also on a mental rotation task that required large angles of rotation but employed only two-dimensional object representations and rotations limited to the picture plane. In contrast, a task using identical stimuli that required only small angles of rotation did not show an estradiol effect. A group difference also was seen on a test of perceptual closure. The results confirm that the estradiol effect is not limited to the MRT, and identify the rotational element, but also aspects of figural perception, as possible processes that may be responsive to estrogens. These findings advance our understanding by showing an association between estradiol and discrete spatial processes. Implications for understanding the origins of the robust sex difference commonly observed on the MRT are discussed.

A prospective study of diagnostic conversion of major depressive disorder to bipolar disorder in pregnancy and postpartum.

OBJECTIVES: The aim of the present study was to determine the rate of, and risk factors for, a change in diagnosis from major depressive disorder to bipolar disorder, and from bipolar II disorder to bipolar I disorder in pregnancy and postpartum. METHODS: Patients with a prior history of major depressive disorder or bipolar II disorder were recruited between 24 and 28 weeks' gestation and followed through to one year postpartum. Diagnostic interviews were conducted using the Structured Clinical Interview for DSM-IV at study intake and repeated using the Mini-International Psychiatric Interview at one, three, six, and 12 months after childbirth. Fisher's exact test was used to assess the association between various risk factors and diagnostic switch. RESULTS: A total of 146 participants completed the intake interview and at least one follow-up interview postpartum. Of these, 92 were diagnosed with major depressive disorder and 54 with bipolar II disorder at intake. Six women (6.52%) experienced a diagnostic change from major depressive disorder to bipolar II disorder during the first six months after childbirth. There were no cases of switching to bipolar I disorder, but in one participant the diagnosis changed from bipolar II disorder to bipolar I disorder during the three months after childbirth. Bipolar switch was associated with a family history of bipolar disorder. CONCLUSIONS: The postpartum period appears to be a time of high risk for a new onset of hypomania in women with major depressive disorder. Our rate of diagnostic switching to bipolar II disorder (6.52%) is at least 11- to 18-fold higher than the rates of switching in similar studies conducted in both men and women.

Association study of the estrogen receptor gene ESR1 with postpartum depression--a pilot study.

Perinatal mood disorders, such as postpartum depression (PPD), are costly for society, with potentially serious consequences for mother and child. While multiple genes appear to play a role in PPD susceptibility, the contributions of specific genetic variations remain unclear. Previously implicated as a candidate gene, the estrogen receptor alpha gene (ESR1) is a key player in mediating hormonal differences during pregnancy and the postpartum period. This study addresses genetic factors in perinatal mood disorders, testing nine polymorphisms in ESR1. Two hundred fifty-seven postpartum women were screened for mood disorders, including 52 women with PPD and 32 without any symptoms of mood disorders. We detected a significant association for the upstream TA microsatellite repeat with Edinburgh Postnatal Depression Scale scores (p = 0.007). The same variant was also associated with the occurrence of PPD. Separately, 11 candidate functional polymorphisms in 7 additional genes were genotyped to investigate gene-gene interaction with the ESR1 TA repeat, identifying a potential interaction with the serotonin transporter. Our results support a role for ESR1 in the etiology of PPD, possibly through the modulation of serotonin signaling. Our findings for ESR1 could have broad implications for other disorders and therapies that involve estrogens.

The GPCR adaptor protein Norbin regulates S1PR1 trafficking and the morphology, cell cycle and survival of PC12 cells.

Norbin is an adaptor protein that binds numerous G protein-coupled receptors (GPCRs), is highly expressed in neurons, and is essential for a functioning nervous system in rodent models. Yet, beyond its control of neurite outgrowth and synaptic plasticity, few cellular roles of Norbin have been investigated to date. Furthermore, while Norbin is known to regulate the steady-state cell surface levels of several GPCRs, only in one case has the protein been shown to control the agonist-induced receptor internalisation which serves to attenuate GPCR signalling. Here, we generated a Norbin-deficient PC12 cell line which enabled us to study both the cellular functions of Norbin and its roles in GPCR trafficking and signalling. We show that Norbin limits cell size and spreading, and is required for the growth, viability and cell cycle progression of PC12 cells. We also found that Norbin regulates both the steady-state surface level and agonist-induced internalisation of the GPCR sphingosine-1-phosphate receptor 1 (S1PR1) in these cells, suggesting that its role in agonist-dependent GPCR trafficking is more widespread than previously appreciated. Finally, we show that Norbin limits the S1P-stimulated activation of Akt and p38 Mapk, and is required for the activation of Erk in PC12 cells. Together, our findings provide a better understanding of the cellular functions of Norbin and its control of GPCR trafficking.

Effects of oral contraceptives on spatial cognition depend on pharmacological properties and phase of the contraceptive cycle.

The central nervous system effects of oral contraceptives (OCs) are not well-documented. In a set of 3 studies, we investigated a specific cognitive function, mental rotation, in healthy women currently using OCs for contraceptive purposes (n = 201) and in medication-free controls not using OCs (n = 44). Mental rotation was measured using a well-standardized and extensively validated psychometric test, the Vandenberg Mental Rotations Test (MRT). In an initial study (Study 1), current OC users (n = 63) were tested during the active or inactive phases of the contraceptive cycle in a parallel-groups design. Studies 2 and 3 were based on an archival dataset (n = 201 current OC users) that consisted of data on the MRT collected in real-time over a 30-year period and compiled for purposes of the present work. The OCs were combined formulations containing ethinyl estradiol (10-35 ug/day) plus a synthetic progestin. All 4 families of synthetic progestins historically used in OCs were represented in the dataset. Cognitive performance was evaluated during either active OC use ('active phase') or during the washout week of the contraceptive cycle ('inactive phase') when OC steroids are not used. The results showed a significant phase-of-cycle (POC) effect. Accuracy on the MRT was mildly diminished during the active phase of OC use, while scores on verbal fluency and speeded motor tasks were modestly improved. The POC effect was most evident in women using OCs that contained first- or second-generation progestins (the estrane family of progestins or OCs containing levonorgestrel), but not in women using OCs containing recently developed progestins and lower doses of ethinyl estradiol. Using independently established ratings of the estrogenic, androgenic, and progestogenic intensities of the different OC formulations, each brand of OC was classified according to its distinct endocrine profile. Multiple regression revealed that the effects of OC use on the MRT could be predicted based on the estrogenic strength of the contraceptives used. Estrogenic potency, not androgenic or anti-androgenic effects of the OC pill, may underlie the effects of OC usage on spatial cognition.