Estimating individual trajectories of structural and cognitive decline in mild cognitive impairment for early prediction of progression to dementia of the Alzheimer's type.

Only a third of individuals with mild cognitive impairment (MCI) progress to dementia of the Alzheimer's type (DAT). Identifying biomarkers that distinguish individuals with MCI who will progress to DAT (MCI-Converters) from those who will not (MCI-Non-Converters) remains a key challenge in the field. In our study, we evaluate whether the individual rates of loss of volumes of the Hippocampus and entorhinal cortex (EC) with age in the MCI stage can predict progression to DAT. Using data from 758 MCI patients in the Alzheimer's Disease Neuroimaging Database, we employ Linear Mixed Effects (LME) models to estimate individual trajectories of regional brain volume loss over 12 years on average. Our approach involves three key analyses: (1) mapping age-related volume loss trajectories in MCI-Converters and Non-Converters, (2) using logistic regression to predict progression to DAT based on individual rates of hippocampal and EC volume loss, and (3) examining the relationship between individual estimates of these volumetric changes and cognitive decline across different cognitive functions-episodic memory, visuospatial processing, and executive function. We find that the loss of Hippocampal volume is significantly more rapid in MCI-Converters than Non-Converters, but find no such difference in EC volumes. We also find that the rate of hippocampal volume loss in the MCI stage is a significant predictor of conversion to DAT, while the rate of volume loss in the EC and other additional regions is not. Finally, individual estimates of rates of regional volume loss in both the Hippocampus and EC, and other additional regions, correlate strongly with individual rates of cognitive decline. Across all analyses, we find significant individual variation in the initial volumes and the rates of changes in volume with age in individuals with MCI. This study highlights the importance of personalized approaches in predicting AD progression, offering insights for future research and intervention strategies.

Ovarian hormones reduce the negative association between worry and cognitive control: A combined neural and behavioral investigation.

BACKGROUND: Increased reactivity to response conflict and errors, processes governed by the dorsal anterior cingulate cortex (dACC), have both been implicated in anxiety. Anxiety is also more common in females than males. Importantly, natural changes in ovarian hormones levels are related to fluctuations in anxiety symptoms in healthy and clinical populations, and ovarian hormones likely modulate prefrontal cortex structure and function. No studies, however, have examined the role of fluctuating ovarian hormones in the association between anxiety and cognitive control across the menstrual cycle. METHODS: In this multimodal proof-of-concept study, naturally cycling females (N = 30 twins from 14 complete twin pairs and 2 participants whose co-twin was not in the final sample; age 18-29) provided saliva samples to assay for estradiol and progesterone and completed the Penn State Worry Questionnaire for 35 consecutive days. At two time points, during projected pre-ovulatory and post-ovulatory phases, they also completed the Flanker task while undergoing functional magnetic resonance imaging to probe cognitive control-related dACC activity. Multilevel modeling was used to examine within- and between-person effects of hormones and worry on cognitive-control indices. RESULTS: On days when estradiol and progesterone were low relative to a female's own average (i.e., within-subjects effect), worry was associated with greater flanker interference. In females with higher estradiol and progesterone levels compared to other females (i.e., between-subject effects), worry was associated with less error-related dACC activity, irrespective of the day that dACC activity was assessed. CONCLUSION: Findings suggest a protective effect of ovarian hormones on the link between worry and cognitive control. Associations between worry and conflict-monitoring were sensitive to daily hormonal fluctuations (within-person states), whereas associations between worry and error-monitoring were sensitive to mean hormone levels (between-person traits), suggesting that ovarian hormones are critical to consider in studies examining associations between anxiety and cognitive control in females.

Reproducible stability of verbal and spatial functions along the menstrual cycle.

Recent studies have reported brain changes in response to ovarian hormonal fluctuations along the menstrual cycle. However, it remains unclear, whether these brain changes are of an adaptive nature or whether they are linked to changes in behavior along the menstrual cycle, particularly with respect to cognitive performance. To address this knowledge gap, we report results from 3 well-powered behavioral studies with different task designs, leveraging the advantages of each design type. In all three studies we assessed whether verbal or spatial performance (i) differed between cycle phases, (ii) were related to estradiol and / or progesterone levels and (iii) were moderated by individual hormone sensitivity as estimated by premenstrual symptoms. Overall, results of all three studies point towards a null effect of menstrual cycle phase and - to a lesser extent - ovarian hormones on verbal and spatial performance and provided no evidence for a moderation of this effect by individual hormone sensitivity. We conclude that there is substantial consistency in verbal and spatial performance across the menstrual cycle, and that future studies of intra-individual variation are needed.

The link between daily affective complexity and anxiety is altered by oral contraceptive use.

Affective complexity - the unique ways in which individuals' emotions covary and differentiate - is an important aspect of internalizing problems. For instance, daily affective complexity has been linked to anxiety increases in women and to decreases in men. The mechanisms underlying this gender difference have not been widely investigated, but a role for ovarian hormones is likely. Research on oral contraceptives (OCs) provides promising insights into such mechanisms, as OCs suppress endogenous ovarian hormone production and vary in exogenous hormone formulations. Thus, the goal of this study was to examine links between daily affective complexity and internalizing problems in OC users (n = 84), focusing on dimensionally-assessed anxiety, and to investigate whether the links varied by pill formulation. Affective complexity was operationalized as number of factors for each person, as estimated by p-technique (i.e., person-specific factor analysis) of 75-day intensive longitudinal data. There was not a relation between affective complexity and anxiety in OC users, and this did not depend on OC pill formulation (i.e., estrogenic, progestational, or androgenic activities). Thus, OC use may blunt the relation between affective complexity and anxiety, as OC users had a relation in between the established positive relation for naturally cycling women and the inverse for men (despite a similar range of factors). Findings are consistent with a growing literature showing that OC use modulates stress and anxiety-linked processes, and suggest that gendered mechanisms underlying the relation between affective complexity and anxiety may be suppressed along with ovarian hormones in OC users.

100 days of Adolescence: Elucidating Externalizing Behaviors Through the Daily Assessment of Inhibitory Control.

Inhibitory control is a transdiagnostic risk factor for externalizing behaviors, particularly during adolescence. Despite advances in understanding links between inhibitory control and externalizing behaviors across youth on average, significant questions remain about how these links play out in the day-to-day lives of individual adolescents. The goals of the current study were to: (1) validate a novel 100-occasion measure of inhibitory control; (2) assess links between day-to-day fluctuations in inhibitory control and individual differences in externalizing behaviors; and (3) illustrate the potential of intensive longitudinal studies for person-specific analyses of adolescent externalizing behaviors. Participants were 106 youth (57.5% female, Mage = 13.34 years; SDage = 1.92) who completed a virtual baseline session followed by 100 daily surveys, including an adapted Stroop Color Word task designed to assess inhibitory control. Results suggested that the novel task was generally reliable and valid, and that inhibitory control fluctuated across days in ways that were meaningfully associated with individual differences in baseline impulsive behaviors. Results of illustrative personalized analyses suggested that inhibitory control had more influence in the daily networks of adolescents who used substances during the 100 days than in a matched set of adolescents who did not. This work marks a path forward in intensive longitudinal research by validating a novel inhibitory control measure, revealing that daily fluctuations in inhibitory control may be a unique construct broadly relevant to adolescent externalizing problems, and at the same time, highlighting that links between daily inhibitory control and impulsive behaviors are adolescent-specific.

Like No Other? A Family-Specific Network Approach to Parenting Adolescents.

Numerous theories suggest that parents and adolescents influence each other in diverse ways; however, whether these influences differ between subgroups or are unique to each family remains uncertain. Therefore, this study explored whether data-driven subgroups of families emerged that exhibited a similar daily interplay between parenting and adolescent affective well-being. To do so, Subgrouping Group Iterative Multiple Model Estimation (S-GIMME) was used to estimate family-specific dynamic network models, containing same- and next-day associations among five parenting practices (i.e., warmth, autonomy support, psychological control, strictness, monitoring) and adolescent positive and negative affect. These family-specific networks were estimated for 129 adolescents (Mage = 13.3, SDage = 1.2, 64% female, 87% Dutch), who reported each day on parenting and their affect for 100 consecutive days. The findings of S-GIMME did not identify data-driven subgroups sharing similar parenting-affect associations. Instead, each family displayed a unique pattern of temporal associations between the different practices and adolescent affect. Thus, the ways in which parenting practices were related to adolescents' affect in everyday life were family specific.

Changes in Brain Network Connections After Exposure and Response Prevention Therapy for Obsessive-Compulsive Disorder in Adolescents and Adults.

BACKGROUND: Functional alterations of tripartite neural networks during cognitive control (i.e., frontoparietal network [FPN], cingulo-opercular network, and default mode network) occur in patients with obsessive-compulsive disorder (OCD) and may contribute to illness expression. However, the degree to which changes in these networks are elicited by gold standard treatment (e.g., exposure and response prevention [EX/RP]) remains unknown. Understanding how EX/RP modulates network connectivity in adolescent versus adult patients with OCD may aid the identification of developmentally sensitive treatment targets that enhance cognitive control. METHODS: Data from a total of 169 adolescents (13-17 years) and adults (25-40 years; 57% female) were analyzed, including healthy control participants (n = 58) and patients with OCD (n = 111) who were randomized to either EX/RP or an active control therapy (stress management training). Participants performed a flanker task during functional magnetic resonance imaging pre- and posttreatment. To retain sensitivity to individual differences in connectivity, group iterative multiple model estimation was used to assess functional connectivity (i.e., density) within and between brain networks. RESULTS: Significant increases in FPN density and decreases in FPN-default mode network density were observed from pre- to posttreatment in patients who received EX/RP. The opposite patterns of change occurred in patients who received stress management training. These treatment-related changes in network density did not differ across age group. CONCLUSIONS: Results suggest EX/RP-specific changes in task-based connectivity in patients with OCD. Given baseline differences between healthy control participants and patients by age group, these treatment-related changes may indicate restoration of healthy FPN and default mode network development across patients, providing targets for improving response to EX/RP.

Determining menstrual cycle phase: An empirical examination of methodologies and recommendations for improvement in behavioral and brain sciences.

The recent decade has brought an exciting proliferation of behavioral, psychological and neuroscientific research involving the menstrual cycle. However, the reliability and validity of many popular methodologies for determining menstrual cycle phase lack empirical examination. These under-investigated methods include: (1) predicting menstrual cycle phase using self-report information only (e.g., "count" methods), (2) utilizing ovarian hormone ranges to determine menstrual cycle phase, and (3) using ovarian hormone changes from limited measurements (e.g., two time points) to determine menstrual cycle phase. In the current study, we examine the accuracy of these methods for menstrual cycle phase determination using 35-day within-person assessments of circulating ovarian hormones from 96 females across the menstrual cycle. Findings indicate that all three common methods are error-prone, resulting in phases being incorrectly determined for many participants, with Cohen's kappa estimates ranging from -0.13 to 0.53 indicating disagreement to only moderate agreement depending on the comparison. Such methodological challenges are surmountable through careful study design, more frequent hormone assays (when possible), and utilization of sophisticated statistical methods. With increased methodological rigor in behavioral, psychological and neuroscientific research, the field will be poised to detect biobehavioral correlates of ovarian hormone fluctuations for the betterment of the mental health and wellbeing of millions of females.

The direction of effects between parenting and adolescent affective well-being in everyday life is family specific.

Numerous theories and empirical studies have suggested that parents and their adolescent children reciprocally influence each other. As most studies have focused on group-level patterns, however, it remained unclear whether this was true for every family. To investigate potential heterogeneity in directionality, we applied a novel idiographic approach to examine the effects between parenting and adolescent well-being in each family separately. For 100 days, 159 Dutch adolescents (Mage = 13.31, 62% female) reported on affective well-being and four parenting dimensions. The family-specific effects of pre-registered ( https://osf.io/7n2jx/ ) dynamic structural equation models indeed revealed that a reciprocal day-to-day association between parenting and adolescent affective well-being was present only in some families, with the proportion of families displaying a reciprocal association varying across the four parenting dimensions (11-55%). In other families, either parenting predicted the adolescent's affective well-being (8-43%) or vice versa (10-27%), or no day-to-day associations were found (16-60%). Adolescents with higher trait levels of environmental sensitivity and neuroticism were more strongly affected by parenting. Thus, findings suggest that the ways in which parents and adolescents influence each other in everyday life are unique, stressing the need to move towards an idiographic parenting science.

Daily Gender and Cognition: A Person-Specific Behavioral Network Analysis.

Gender is person-specific, and it influences and is influenced by a breadth of multidimensional psychological factors, including cognition. Directionality is important for research on gender and cognition, as debate surrounds, for instance, whether masculine self-concepts precede spatial skills, or whether the reverse is true. In order to provide novel insights into the individualized nature of these relations, a person-specific network approach devised by Peter Molenaar and the first author - group iterative multiple model estimation for multiple solutions (GIMME-MS) - was applied to 75-day intensive longitudinal data on gender self-concept (i.e., femininity-masculinity, instrumentality, and expressivity) and cognition (i.e., mental rotations and verbal recall) from 103 young adults. GIMME-MS estimates individualized networks that contain same-day and next-day directed relations, prioritizing relations common across participants. It is ideal for analyzing behavioral time series with unclear directionality, as it generates multiple solutions from which an optimal one is selected. GIMME-MS revealed notable heterogeneity in the presence, direction, and nature of relations from gender self-concept to cognition (∼26% of participants) and vice versa (∼21% of participants). Findings are wholly novel in revealing the person-specific nature of gender and its cognitive dynamics, yet somehow, unsurprising given the revolutionary corpus of Peter Molenaar.

The daily association between affect and alcohol use: A meta-analysis of individual participant data.

Influential psychological theories hypothesize that people consume alcohol in response to the experience of both negative and positive emotions. Despite two decades of daily diary and ecological momentary assessment research, it remains unclear whether people consume more alcohol on days they experience higher negative and positive affect in everyday life. In this preregistered meta-analysis, we synthesized the evidence for these daily associations between affect and alcohol use. We included individual participant data from 69 studies (N = 12,394), which used daily and momentary surveys to assess affect and the number of alcoholic drinks consumed. Results indicate that people are not more likely to drink on days they experience high negative affect, but are more likely to drink and drink heavily on days high in positive affect. People self-reporting a motivational tendency to drink-to-cope and drink-to-enhance consumed more alcohol, but not on days they experienced higher negative and positive affect. Results were robust across different operationalizations of affect, study designs, study populations, and individual characteristics. These findings challenge the long-held belief that people drink more alcohol following increases in negative affect. Integrating these findings under different theoretical models and limitations of this field of research, we collectively propose an agenda for future research to explore open questions surrounding affect and alcohol use.

Risk Factors for the Development of Multisite Pain in Children.

OBJECTIVE: Chronic pain has economic costs on par with cardiovascular disease, diabetes, and cancer. Despite this impact on the health care system and increasing awareness of the relationship between pain and mortality, efforts to identify simple symptom-based risk factors for the development of pain, particularly in children, have fallen short. This is critically important as pain that manifests during childhood often persists into adulthood. To date, no longitudinal studies have examined symptoms in pain-free children that presage a new, multisite manifestation of pain in the future. We hypothesized that female sex, sleep problems, and heightened somatic symptoms complaints at baseline would be associated with the risk of developing new multisite pain 1 year later. METHODS: Symptom assessments were completed by parents of youth (ages 9 to 10) enrolled in the Adolescent Brain Cognitive Development study. Multivariate logistic regression models focused on children who developed multisite pain 1 year later (n=331) and children who remained pain free (n=3335). RESULTS: Female sex (odds ratio [OR]=1.35; 95% CI, 1.07, 1.71; P =0.01), elevated nonpainful somatic symptoms (OR=1.17; 95% CI, 1.06, 1.29; P <0.01), total sleep problems (OR=1.20; 95% CI, 1.07, 1.34; P <0.01), and attentional issues (OR=1.22; 95% CI, 1.10, 1.35; P <0.001) at baseline were associated with new multisite pain 1 year later. Baseline negative affect was not associated with new multisite pain. DISCUSSION: Identifying symptom-based risk factors for multisite pain in children is critical for early prevention. Somatic awareness, sleep and attention problems represent actionable targets for early detection, treatment, and possible prevention of multisite pain in youth.

Sources of Heterogeneity in Functional Connectivity During English Word Processing in Bilingual and Monolingual Children.

Diversity and variation in language experiences, such as bilingualism, contribute to heterogeneity in children's neural organization for language and brain development. To uncover sources of such heterogeneity in children's neural language networks, the present study examined the effects of bilingual proficiency on children's neural organization for language function. To do so, we took an innovative person-specific analytical approach to investigate young Chinese-English and Spanish-English bilingual learners of structurally distinct languages. Bilingual and English monolingual children (N = 152, M(SD)age = 7.71(1.32)) completed an English word recognition task during functional near-infrared spectroscopy neuroimaging, along with language and literacy tasks in each of their languages. Two key findings emerged. First, bilinguals' heritage language proficiency (Chinese or Spanish) made a unique contribution to children's language network density. Second, the findings reveal common and unique patterns in children's patterns of task-related functional connectivity. Common across all participants were short-distance neural connections within left hemisphere regions associated with semantic processes (within middle temporal and frontal regions). Unique to more proficient language users were additional long-distance connections between frontal, temporal, and bilateral regions within the broader language network. The study informs neurodevelopmental theories of language by revealing the effects of heterogeneity in language proficiency and experiences on the structure and quality of emerging language neural networks in linguistically diverse learners.

The influence of autoregressive relation strength and search strategy on directionality recovery in group iterative multiple model estimation.

Unified structural equation modeling (uSEM) implemented in the group iterative multiple model estimation (GIMME) framework has recently been widely used for characterizing within-person network dynamics of behavioral and functional neuroimaging variables. Previous studies have established that GIMME accurately recovers the presence of relations between variables. However, recovery of relation directionality is less consistent, which is concerning given the importance of directionality estimates for many research questions. There is evidence that strong autoregressive relations may aid directionality recovery and indirect evidence that a novel version of GIMME allowing for multiple solutions could improve recovery when such relations are weak, but it remains unclear how these strategies perform under a range of study conditions. Using comprehensive simulations that varied the strength of autoregressive relations among other factors, this study evaluated the directionality recovery of two GIMME search strategies: (a) estimating autoregressive relations by default in the null model (GIMME-AR) and (b) generating multiple solution paths (GIMME-MS). Both strategies recovered directionality best-and were roughly equivalent in performance-when autoregressive relations were strong (e.g., ß = .60). When they were weak (ß ≤ .10), GIMME-MS displayed an advantage, although overall directionality recovery was modest. Analyses of empirical data in which autoregressive relations were characteristically strong (resting state functional MRI) versus weak (daily diary) mirrored simulation results and confirmed that these strategies can disagree on directionality when autoregressive relations are weak. Findings have important implications for psychological and neuroimaging applications of uSEM/GIMME and suggest specific scenarios in which researchers might or might not be confident in directionality results. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Estimating both directed and undirected contemporaneous relations in time series data using hybrid-group iterative multiple model estimation.

Researchers across varied fields increasingly are collecting and analyzing intensive longitudinal data (ILD) to examine processes across time at the individual level. Two types of relations are typically examined: lagged and contemporaneous. Lagged relations capture how variables at a prior time point can be used to explain variance in variables at a later time point. These are always modeled using auto- and cross-regressions by means of vector autoregression (VAR). By contrast, there are two types of relations commonly used to model the contemporaneous relations, which model how variables relate instantaneously. Until now, researchers must opt to either model contemporaneous relations as undirected relations among residuals (e.g., partial or full correlations) or as directed relations among the variables (e.g., paths or regressions). The choice for how to model contemporaneous relations has implications for inferences as well as the potential to introduce bias in the VAR lagged relations if the wrong type of relation is used. This article introduces a novel data-driven method, hybrid-group iterative multiple model estimation (GIMME), that provides a solution to the problem of having to choose one or the other type of contemporaneous relation to model. The modeling framework utilized in hybrid-GIMME allows for both types of contemporaneous relations in addition to the standard VAR relations. Both simulated and empirical data were used to test the performance of hybrid-GIMME. Results suggest this is a robust method for recovering contemporaneous relations in an exploratory manner, particularly with an ample number of time points per person. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Personalized Neural Networks Underlie Individual Differences in Ethnic Identity Exploration and Resolution.

This study examined how ethnic identity relates to large-scale brain networks implicated in social interactions, social cognition, self-definition, and cognitive control. Group Iterative Multiple Model Estimation (GIMME) was used to create sparse, person-specific networks among the default mode and frontoparietal resting-state networks in a diverse sample of 104 youths aged 17-21. Links between neural density (i.e., number of connections within and between these networks) and ethnic identity exploration and resolution were evaluated in the full sample. Ethnic identity resolution was positively related to frontoparietal network density, suggesting that having clarity about one's ethnic group membership is associated with brain network organization reflecting cognitive control. These findings help fill a critical knowledge gap about the neural underpinnings of ethnic identity.

Prenatal androgen influences on the brain: A review, critique, and illustration of research on congenital adrenal hyperplasia.

Sex hormones, especially androgens, contribute to sex and gender differences in the brain and behavior. Organizational effects are particularly important because they are thought to be permanent, reflecting hormone exposure during sensitive periods of development. In human beings, they are often studied with natural experiments in which sex hormones are dissociated from other biopsychosocial aspects of development, such as genes and experiences. Indeed, the greatest evidence for organizational effects on sex differences in human behavior comes from studies of females with congenital adrenal hyperplasia (CAH), who have heightened prenatal androgen exposure, female-typical rearing, and masculinized toy play, activity and career interests, spatial skills, and some personal characteristics. Interestingly, however, neuroimaging studies of females with CAH have revealed few neural mechanisms underlying these hormone-behavior links, with the exception of emotion processing; studies have instead shown reduced gray matter volumes and reduced white matter integrity most consistent with other disease-related processes. The goals of this narrative review are to: (a) describe methods for studying prenatal androgen influences, while offering a brief overview of behavioral outcomes; (b) provide a critical methodological review of neuroimaging research on females with CAH; (c) present an illustrative analysis that overcomes methodological limitations of previous work, focusing on person-specific neural reward networks (and their associations with sensation seeking) in women with CAH and their unaffected sisters in order to inform future research questions and approaches that are most likely to reveal organizational hormone effects on brain structure and function.

Adolescent functional network connectivity prospectively predicts adult anxiety symptoms related to perceived COVID-19 economic adversity.

BACKGROUND: Stressful events, such as the COVID-19 pandemic, are major contributors to anxiety and depression, but only a subset of individuals develop psychopathology. In a population-based sample (N = 174) with a high representation of marginalized individuals, this study examined adolescent functional network connectivity as a marker of susceptibility to anxiety and depression in the context of adverse experiences. METHODS: Data-driven network-based subgroups were identified using an unsupervised community detection algorithm within functional neural connectivity. Neuroimaging data collected during emotion processing (age 15) were extracted from a priori regions of interest linked to anxiety and depression. Symptoms were self-reported at ages 15, 17, and 21 (during COVID-19). During COVID-19, participants reported on pandemic-related economic adversity. Differences across subgroup networks were first examined, then subgroup membership and subgroup-adversity interaction were tested to predict change in symptoms over time. RESULTS: Two subgroups were identified: Subgroup A, characterized by relatively greater neural network variation (i.e., heterogeneity) and density with more connections involving the amygdala, subgenual cingulate, and ventral striatum; and the more homogenous Subgroup B, with more connections involving the insula and dorsal anterior cingulate. Accounting for initial symptoms, subgroup A individuals had greater increases in symptoms across time (ß = .138, p = .042), and this result remained after adjusting for additional covariates (ß = .194, p = .023). Furthermore, there was a subgroup-adversity interaction: compared with Subgroup B, Subgroup A reported greater anxiety during the pandemic in response to reported economic adversity (ß = .307, p = .006), and this remained after accounting for initial symptoms and many covariates (ß = .237, p = .021). CONCLUSIONS: A subgrouping algorithm identified young adults who were susceptible to adversity using their personalized functional network profiles derived from a priori brain regions. These results highlight potential prospective neural signatures involving heterogeneous emotion networks that predict individuals at the greatest risk for anxiety when experiencing adverse events.

Hormonal contraceptive influences on cognition and psychopathology: Past methods, present inferences, and future directions.

In the last decade, there has been a remarkable surge in research on the neural and behavioral correlates of hormonal contraceptive use, particularly oral contraceptive use. Questions have evolved swiftly and notably, with studies no longer revealing if hormonal contraceptives matter for the brain and behavior, but rather how, when, and for whom they matter most. Paralleling this shift, the goal of this review is to move beyond an average synthesis of hormonal contraceptive influences on human cognition and psychopathology (and their neural substrates) in order to consider the nature and specificity of effects. Accompanied by an evaluation of study methods and informed by findings from animal models, this consideration uncovers promising areas of research in the next ten years, including potential activational and organizational effects of hormonal contraceptive use, individual differences in effects that matter for the wellbeing of unique individuals, and correlates of intrauterine device use.