Recommendations for a Better Understanding of Sex and Gender in the Neuroscience of Mental Health.

There are prominent sex/gender differences in the prevalence, expression, and life span course of mental health and neurodiverse conditions. However, the underlying sex- and gender-related mechanisms and their interactions are still not fully understood. This lack of knowledge has harmful consequences for those with mental health problems. Therefore, we set up a cocreation session in a 1-week workshop with a multidisciplinary team of 25 researchers, clinicians, and policy makers to identify the main barriers in sex and gender research in the neuroscience of mental health. Based on this work, here we provide recommendations for methodologies, translational research, and stakeholder involvement. These include guidelines for recording, reporting, analysis beyond binary groups, and open science. Improved understanding of sex- and gender-related mechanisms in neuroscience may benefit public health because this is an important step toward precision medicine and may function as an archetype for studying diversity.

A neurocognitive model of early onset persistent and desistant antisocial behavior in early adulthood.

It remains unclear which functional and neurobiological mechanisms are associated with persistent and desistant antisocial behavior in early adulthood. We reviewed the empirical literature and propose a neurocognitive social information processing model for early onset persistent and desistant antisocial behavior in early adulthood, focusing on how young adults evaluate, act upon, monitor, and learn about their goals and self traits. Based on the reviewed literature, we propose that persistent antisocial behavior is characterized by domain-general impairments in self-relevant and goal-related information processing, regulation, and learning, which is accompanied by altered activity in fronto-limbic brain areas. We propose that desistant antisocial development is associated with more effortful information processing, regulation and learning, that possibly balances self-relevant goals and specific situational characteristics. The proposed framework advances insights by considering individual differences such as psychopathic personality traits, and specific emotional characteristics (e.g., valence of social cues), to further illuminate functional and neural mechanisms underlying heterogenous developmental pathways. Finally, we address important open questions and offer suggestions for future research to improve scientific knowledge on general and context-specific expression and development of antisocial behavior in early adulthood.

Through the looking glass: the neural basis of self-concept in young adults with antisocial trajectories.

Self-concept is shaped by social experiences, but it is not yet well understood how the neural and behavioral development of self-concept is influenced by a history of antisocial behavior. In this pre-registered study, we examined neural responses to self-evaluations in young adults who engaged with antisocial behavior in childhood and either desisted or persisted in antisocial behavior. A self-concept task was performed by 94 young adults (age range 18-30 years). During the task, participants with a persistent or desistent antisocial trajectory (n = 54) and typically developing young adults (n = 40) rated whether positive and negative traits in different domains (prosocial and physical) described themselves. We examined both the effects of a history of antisocial behavior as well as current heterogeneity in psychopathic traits on self-concept appraisal and its neural underpinnings. Participants endorsed more positive trait statements than negative across domains, which did not differ between antisocial-history groups. However, current psychopathic traits were negatively associated with prosocial self-concept and medial prefrontal cortex activity during self-evaluation. Together, these findings suggest that antisocial tendencies might indeed be reflected in self-concept development of young adults, specifically in the prosocial domain.

Understanding the Dynamics of the Developing Adolescent Brain Through Team Science.

One of the major goals for research on adolescent development is to identify the optimal conditions for adolescents to grow up in a complex social world and to understand individual differences in these trajectories. Based on influential theoretical and empirical work in this field, achieving this goal requires a detailed understanding of the social context in which neural and behavioral development takes place, along with longitudinal measurements at multiple levels (e.g., genetic, hormonal, neural, behavioral). In this perspectives article, we highlight the promising role of team science in achieving this goal. To illustrate our point, we describe meso (peer relations) and micro (social learning) approaches to understand social development in adolescence as crucial aspects of adolescent mental health. Finally, we provide an overview of how our team has extended our collaborations beyond scientific partners to multiple societal partners for the purpose of informing and including policymakers, education and health professionals, as well as adolescents themselves when conducting and communicating research.

Resisting aggression in social contexts: The influence of life-course persistent antisocial behavior on behavioral and neural responses to social feedback.

Early adulthood has long been recognized as a potential turning point for the development of antisocial behavior, due to changes in social contexts and ongoing psychological and neurobiological maturation. However, it remains unclear how different developmental trajectories of antisocial behavior, their neural underpinnings, and individual differences in psychopathic traits may help explain the distinct developmental outcomes of individuals who persist in or desist from antisocial behavior in early adulthood - such as how they respond to others in social contexts. Therefore, in the current study, young adults (aged 18-30, 68% male) with a persistent or desistant antisocial trajectory (N = 54), as well as healthy controls (N = 39), completed the Social Network Aggression Task, during which they received positive, neutral, or negative feedback on a personal profile and got the opportunity to retaliate by blasting a loud noise. On a behavioral level, results indicated that in all groups, negative peer feedback evoked higher retaliatory aggression, compared to positive and neutral feedback. On a neural level, when receiving social feedback, individuals with persistent or desistent trajectories showed both similar and dissociable patterns of neural activity; desisting and persisting trajectory groups showed higher activity in the Insula, and the desisting trajectory group showed higher activity in dlPFC. Finally, when participants retaliated, they showed increased dlPFC and ACC activity following positive relative to neutral and negative feedback, where ACC activity correlated most strongly with inhibition of retaliatory responses in the desisting trajectory group. Together, these findings provide novel insights in dissociable patterns of brain activity that may increase our understanding of the mechanisms underlying different developmental trajectories of antisocial behavior.

Contextualizing adolescent structural brain development: Environmental determinants and mental health outcomes.

The spatiotemporal group-level patterns of brain macrostructural development are relatively well-documented. Current research emphasizes individual variability in brain development, including its causes and consequences. Although genetic factors and prenatal and perinatal events play critical roles, calls are now made to also study brain development in transactional interplay with the different aspects of an individual's physical and social environment. Such focus is highly relevant for research on adolescence, a period involving a multitude of contextual changes paralleled by continued refinement of complex cognitive and affective neural systems. Here, we discuss associations between selected aspects of an individual's physical and social environment and adolescent brain structural development and possible links to mental health. We also touch on methodological considerations for future research.

Mood Variability Among Early Adolescents in Times of Social Constraints: A Daily Diary Study During the COVID-19 Pandemic.

The COVID-19 pandemic and associated governmental regulations have drastically changed the daily social lives of children, adolescents, and adults. Changes in the social context may particularly affect children who are in the transition to adolescents (henceforth referred to as early adolescents) as adolescence is a crucial period for peer interactions and development of independence and autonomy. Yet, the impact of the pandemic and associated governmental regulations on early adolescents' emotional well-being has yet to be clarified. In the current study, we explored daily fluctuations in mood in 54 early adolescents (M age = 11.07) during the first few months (April 2020-June 2020) of the COVID-19 pandemic. Moreover, the role of parents and peers on adolescents' mood variability was investigated. Adolescents rated their mood (i.e., happiness, anger, sadness, anxiety) and peer interactions once a day during four separate weeks across different weeks of containment measures in the Netherlands. Moreover, adolescents reported on their experienced attachment to parents and peers and internalizing problems during baseline and the final measurement, respectively. Results showed relatively stable levels of mood during the first few months of the COVID-19 pandemic. However, individual differences in mood variability during the first assessment week were negatively associated with the experienced level of attachment to both parents and peers. Moreover, heightened levels of mood variability did not mediate the link between attachment and internalizing problems. Lastly, the quality of offline contact, but not online contact, was negatively related to adolescents' mood variability. Overall, this study suggests that mood of early adolescents did not heavily fluctuated across the first few months of the COVID-19 pandemic. Our findings add to the growing body of literature aiming to understand how adolescent's life are affected by the COVID-19 crisis and illustrates that social connectedness to parents or peers may facilitate resilience to distress and daily mood fluctuation in early adolescents.

Inter-individual variability in structural brain development from late childhood to young adulthood.

A fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined inter-individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.0-26.0 years in 269 participants (149 females) with three time points of data (807 scans), drawn from three longitudinal datasets collected in the Netherlands, Norway, and USA. We further investigated the relationship between overall brain size and developmental changes, as well as how females and males differed in change variability across development. There was considerable inter-individual variability in the magnitude of changes observed for all examined brain measures. The majority of individuals demonstrated decreases in total gray matter volume, cortex volume, mean cortical thickness, and white matter surface area in mid-adolescence, with more variability present during the transition into adolescence and the transition into early adulthood. While most individuals demonstrated increases in white matter volume in early adolescence, this shifted to a majority demonstrating stability starting in mid-to-late adolescence. We observed sex differences in these patterns, and also an association between the size of an individual's brain structure and the overall rate of change for the structure. The present study provides new insight as to the amount of individual variance in changes in structural morphometrics from late childhood to early adulthood in order to obtain a more nuanced picture of brain development. The observed individual- and sex-differences in brain changes also highlight the importance of further studying individual variation in developmental patterns in healthy, at-risk, and clinical populations.

Overlapping and distinct neural correlates of self-evaluations and self-regulation from the perspective of self and others.

Prior research has implicated the medial and lateral prefrontal cortex (PFC) in processing evaluations from the perspective of self (self-traits) and evaluations from others (peer feedback), suggesting that these areas form a neural substrate that serves an intertwined function in monitoring self in relation to others. To test this possibility, we examined neural activation overlap in medial and lateral PFC after processing self- and other-informed evaluations. Young adults (age range 18-30-yrs, n = 40) performed two fMRI tasks. The self-concept task involved rating whether positive and negative traits described themselves. The Social Network Aggression Task involved processing positive, neutral or negative feedback from others, with the possibility to retaliate by blasting a loud noise following feedback. The results show that rating positive self traits and receiving positive peer feedback was associated with increased activity in an overlapping region in medial PFC. There were no significant correlations on a behavioral level and medial PFC activity for self-versus-other evaluations. The study further replicated the finding from previous research showing that higher activity in dorsolateral PFC (dlPFC) when receiving negative social feedback was associated with reduced noise blast aggression. Finally, during retaliatory responses after receiving positive feedback, participants showed increased activity in the dlPFC. Together these findings suggest that medial PFC is more strongly involved in protecting positive self-views from both internal (self traits) and external (peer feedback) points of view, whereas dlPFC is more strongly involved in regulating retaliatory responses following social rejection, and actively inhibiting aggressive behavior after receiving positive peer feedback.

The Roles of Shame and Guilt in the Development of Aggression in Adolescents With and Without Hearing Loss.

This longitudinal study examined how shame and guilt contribute to the development of reactive and proactive aggression in adolescents with and without hearing loss. Adolescents between 9 and 16 years old (adolescents with hearing loss (n = 80; Mage = 11.91) and without hearing loss (n = 227; Mage = 11.63)) completed self-reports on three occasions with an interval of 9 months. Mixed model analyses revealed that both reactive aggression and proactive aggression decreased with age, whereas shame and guilt peaked in early adolescence. Adolescents with hearing loss reported higher levels of proactive aggression, lower levels of shame and guilt, and showed protracted development for guilt compared to their hearing peers. In both groups, shame contributed to an increase in reactive aggression, whereas guilt contributed to a decrease in proactive aggression. These longitudinal associations highlight the unique role that shame and guilt play in the development of adolescent aggression.

ADHD, financial distress, and suicide in adulthood: A population study.

Attention-deficit/hyperactivity disorder (ADHD) exerts lifelong impairment, including difficulty sustaining employment, poor credit, and suicide risk. To date, however, studies have assessed selected samples, often via self-report. Using mental health data from the entire Swedish population (N = 11.55 million) and a random sample of credit data (N = 189,267), we provide the first study of objective financial outcomes among adults with ADHD, including associations with suicide. Controlling for psychiatric comorbidities, substance use, education, and income, those with ADHD start adulthood with normal credit demand and default rates. However, in middle age, their default rates grow exponentially, yielding poor credit scores and diminished credit access despite high demand. Sympathomimetic prescriptions are unassociated with improved financial behaviors. Last, financial distress is associated with fourfold higher risk of suicide among those with ADHD. For men but not women with ADHD who suicide, outstanding debt increases in the 3 years prior. No such pattern exists for others who suicide.

Emotional functioning and the development of internalizing and externalizing problems in young boys with and without autism spectrum disorder.

Children with autism spectrum disorder are at risk of developing internalizing and externalizing problems. However, information on early development of behavior problems and the contributing role of emotional functioning in preschool children with autism spectrum disorder is scarce. This study collected data of boys with and without autism spectrum disorder (N = 156; age: 2-6 years) over three consecutive years (three waves), about their internalizing and externalizing symptoms and emotional functioning (i.e. emotion control, recognition, and vocabulary), using parent-report questionnaires. No age effect was found on internalizing or externalizing problems for boys with and without autism spectrum disorder. Boys with autism spectrum disorder displayed more behavior problems than their typically developing peers and showed lower levels of emotional functioning. Better emotion control and improved emotion recognition were associated with a decrease in problem behaviors for boys with and without autism spectrum disorder, whereas improved emotion vocabulary was uniquely related to a decrease in externalizing problems in boys with autism spectrum disorder. Our findings suggest that boys with and without autism spectrum disorder showed similar developmental courses of internalizing and externalizing problems. However, lower levels of emotional functioning were already more pronounced in boys with autism spectrum disorder at a young age. This contributes to higher levels of behavior problems.

Age and Gender Effects in Sensitivity to Social Rewards in Adolescents and Young Adults.

Adolescence is a sensitive period for socio-cultural processing and a vast literature has established that adolescents are exceptionally attuned to the social context. Theoretical accounts posit that the social reward of social interactions plays a large role in adolescent sensitivity to the social context. Yet, to date it is unclear how sensitivity to social reward develops across adolescence and young adulthood and whether there are gender differences. The present cross-sectional study (N = 271 participants, age 11-28 years) examined age and gender effects in self-reported sensitivity to different types of social rewards. In order to achieve this aim, the Dutch Social Reward Questionnaire for Adolescents was validated. Findings revealed that each type of social reward was characterized by distinct age and gender effects. Feeling rewarded by gaining positive attention from others showed a peak in late adolescence, while enjoying positive reciprocal relationships with others showed a linear increase with age. Enjoying cruel behavior toward others decreased with age for girls, while boys showed no changes with age and reported higher levels across ages. Reward from giving others control showed a mid-adolescent dip, while enjoying group interactions did not show any changes with age. Taken together, the results imply that the social reward of social interactions is a nuanced and complex construct, which encompasses multiple components that show unique effects with age and gender. These findings enable us to gain further traction on the ubiquitous effects of the social context on decision-making in adolescent's lives.

Sex Effects on Development of Brain Structure and Executive Functions: Greater Variance than Mean Effects.

Although male brains have consistently reported to be 8-10% larger than female brains, it remains not well understood whether there are differences between sexes (average or variance) in developmental trajectories. Furthermore, if sex differences in average brain growth or variance are observed, it is unknown whether these sex differences have behavioral relevance. The present longitudinal study aimed to unravel sex effects in cortical brain structure, development, and variance, in relation to the development of educationally relevant cognitive domains and executive functions (EFs). This was assessed with three experimental tasks including working memory, reading comprehension, and fluency. In addition, real-life aspects of EF were assessed with self- and parent-reported Behavior Rating Inventory of Executive Function scores. The full data set included 271 participants (54% female) aged between 8 and 29 years of which three waves were collected at 2-year intervals, resulting in 680 T1-weighted MRI scans and behavioral measures. Analyses of average trajectories confirmed general age-related patterns of brain development but did not support the hypothesis of sex differences in brain development trajectories, except for left banks STS where boys had a steeper decline in surface area than girls. Also, our brain age prediction model (including 270 brain measures) did not indicate delayed maturation in boys compared with girls. Interestingly, support was found for greater variance in male brains than female brains in both structure and development, consistent with prior cross-sectional studies. Behaviorally, boys performed on average better on a working memory task with a spatial aspect and girls performed better on a reading comprehension task, but there was no relation between brain development and cognitive performance, neither for average brain measures, brain age, or variance measures. Taken together, we confirmed the hypothesis of greater males within-group variance in brain structures compared with females, but these were not related to EF. The sex differences observed in EF were not related to brain development, possibly suggesting that these are related to experiences and strategies rather than biological development.

Longitudinal structural brain development and externalizing behavior in adolescence.

BACKGROUND: Cross-sectional studies report relations between externalizing behavior and structural abnormalities in cortical thickness of prefrontal regions and volume reductions in subcortical regions. To understand how these associations emerge and develop, longitudinal designs are pivotal. METHOD: In the current longitudinal study, a community sample of children, adolescents and young adults (N = 271) underwent magnetic resonance imaging (MRI) in three biennial waves (680 scans). At each wave, aspects of externalizing behavior were assessed with parent-reported aggression and rule-breaking scores (Child Behavior Checklist), and self-reported aggression scores (Buss-Perry Aggression Questionnaire). Regions of interest (ROIs) were selected based on prior research: dorsolateral prefrontal (dlPFC), orbitofrontal (OFC), anterior cingulate cortex (ACC), insula, and parahippocampal cortex, as well as subcortical regions. Linear mixed models were used to assess the longitudinal relation between externalizing behavior and structural brain development. Structural covariance analyses were employed to identify whether longitudinal relations between ROIs (maturational coupling) were associated with externalizing behavior. RESULTS: Linear mixed model analyses showed a negative relation between parent-reported aggression and right hippocampal volume. Moreover, this longitudinal relation was driven by change in hippocampal volume and not initial volume of hippocampus at time point 1. Exploratory analyses showed that stronger maturational coupling between prefrontal regions, the limbic system, and striatum was associated with both low and high externalizing behavior. CONCLUSIONS: Together, these findings reinforce the hypothesis that altered structural brain development coincides with development of more externalizing behavior. These findings may guide future research on normative and deviant development of externalizing behavior.

Adolescents' responses to online peer conflict: How self-evaluation and ethnicity matter.

For parents, online platforms where their children interact with others often feel like a "black box" in terms of what exactly is happening. In this study, we developed an ecologically valid online computer game in which a (computer-generated) peer teammate tried to provoke frustration, in order to examine (a) adolescents' responses and (b) how indices of self-evaluation (i.e., sense of coherence and self-esteem) and demographic variables (i.e., gender and ethnicity) matter to these responses. Like gender, being a member of a minority or majority group may influence how provocations by peers are interpreted, influencing how one responds. Fifteen-year-old Dutch and Moroccan-Dutch adolescents (N = 167) completed self-reports and played the online computer game. The game indeed elicited frustration, with increased self-reported anger. Moreover, expressions of displeasure were much more common during and after provocation than before provocation. Crucially, perceived self-evaluation mattered; higher levels of sense of coherence but lower levels of self-esteem (only in Moroccan-Dutch group) contributed to fewer expressions of displeasure. Gender did not play a moderating role. Our findings provide initial insights into individual differences in adolescents' responses in an online peer-conflict situation. HIGHLIGHTS: We studied Dutch and Moroccan-Dutch adolescents' responses during online peer provocation and how self-evaluation and demographic variables matter.Provocation by the (computer-generated) peer teammate increased expressions of displeasure.More sense of coherence but less self-esteem was associated with fewer expressions of displeasure, but ethnicity moderated the effect with self-esteem.

Development of Multifaceted Risk Taking and the Relations to Sex Steroid Hormones: A Longitudinal Study.

Risk taking is a multidimensional construct. It is currently unclear which aspects of risk-taking change most during adolescence and if/how sex hormones contribute to risk-taking tendencies. This study applied a longitudinal design with three time-points, separated by 2 years, in participants aged 8-29 years (670 observations). The Balloon Analogue Risk Task, a delay discounting task, and various self-report questionnaires were administered, to measure aspects of risk taking. Longitudinal analyses demonstrated mostly nonlinear age-related patterns in risk-taking behavior and approach-related personality characteristics (peaking in late adolescence). Increased testosterone and estradiol were found to increase risk-taking behavior and impulsive personality, but decrease avoidance-like personality. This study demonstrates that risk taking is most pronounced in mid-to-late adolescence and suggests that sex hormones accelerate this maturational process.

Unraveling age, puberty and testosterone effects on subcortical brain development across adolescence.

The onset of adolescence in humans is marked by hormonal changes that give rise to secondary sexual characteristics, noted as puberty. It has, however, proven challenging to unravel to what extent pubertal changes may have organizing effects on the brain beyond chronological age, as reported in animal studies. The present longitudinal study aimed to characterize the unique effects of age and puberty on subcortical brain volumes and included three waves of data collection at two-year intervals and 680 T1-weighted MRI scans of 271 participants (54% females) aged between 8 and 29 years old. Generalized additive mixed model procedures were used to assess the effects of age, self-report pubertal status and testosterone level on basal ganglia, thalamus, hippocampus, amygdala and cerebellum gray matter volumes. We observed age-related increases in putamen and pallidum volumes, and decreases in accumbens and thalamus volumes, all show larger volumes in boys than girls. Only the cerebellum showed an interaction effect of age by sex, such that males showed prolonged increases in cerebellar volume than females. Next, we showed that changes in self-report puberty status better described developmental change than chronological age for most structures in males, and for caudate, pallidum and hippocampal volumes in females. Furthermore, changes in testosterone level were related to development of pallidum, accumbens, hippocampus and amygdala volumes in males and caudate and hippocampal volumes in females. The modeling approach of the present study allowed us to characterize the complex interactions between chronological age and pubertal maturational changes, and the findings indicate puberty unique changes in brain structure that are sex specific.

Emotion Control Predicts Internalizing and Externalizing Behavior Problems in Boys With and Without an Autism Spectrum Disorder.

Children and adolescents with Autism Spectrum Disorder (ASD) often show comorbid emotional and behavior problems. The aim of this longitudinal study is to examine the relation between emotion control (i.e., negative emotionality, emotion awareness, and worry/rumination) and the development of internalizing and externalizing problems. Boys with and without ASD (N = 157; age 9-15) were followed over a period of 1.5 years (3 waves). We found that baseline levels of worry/rumination was a specific predictor of later externalizing problems for boys with ASD. Furthermore, the developmental trajectory of worry/rumination predicted the development of internalizing and externalizing problems in both groups. Our findings suggest that worry/rumination may constitute a transdiagnostic factor underlying both internalizing and externalizing problems in boys with and without ASD.

Emerging depression in adolescence coincides with accelerated frontal cortical thinning.

BACKGROUND: Adolescence is a transition period characterized by heightened emotional reactivity, which for some sets the stage for emerging depressive symptoms. Prior studies suggest that adolescent depression is associated with deviant cortical and subcortical brain structure. Longitudinal studies are, however, currently scarce, but critical to detect which adolescents are at risk for developing depressive symptoms. METHODS: In this longitudinal study, a community sample of 205 participants underwent magnetic resonance imaging (MRI) in three biennial waves (522 scans) spanning 5 years across ages 8-25 years. Depressive symptomatology was assessed using self-report at the third time point. Mixed models were used to examine the relations between structural brain development, specifically regional change in cortical thickness, surface area and subcortical volumes (hippocampus and amygdala), and depressive symptoms. RESULTS: Accelerated frontal lobe cortical thinning was observed in adolescents who developed depressive symptoms at the third time point. This effect remained after controlling for parent-reported affective problems at the first time point. Moreover, the effect was driven by specific lateral orbitofrontal and precentral regions. In addition, differential developmental trajectories of parietal cortical thickness and surface area in several regions were found for participants reporting higher depressive symptomatology, but these results did not survive correction for multiple comparisons. Volumes or developmental volume changes in hippocampus or amygdala were not related to depressive symptoms. CONCLUSIONS: This study showed that emerging depression is associated with cortical thinning in frontal regions within individuals. These findings move beyond detecting cross-sectional correlations and set the stage for early detection, which may inform future intervention.