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.

Transitioning from childhood into adolescence: A comprehensive longitudinal behavioral and neuroimaging study on prosocial behavior and social inclusion.

Acting prosocially and feeling socially included are important factors for developing social relations. However, little is known about the development of neural trajectories of prosocial behavior and social inclusion in the transition from middle childhood to early adolescence. In this pre-registered study, we investigated the development of prosocial behavior, social inclusion, and their neural mechanisms in a three-wave longitudinal design (ages 7-13 years; NT1 = 512; NT2 = 456; NT3 = 336). We used the Prosocial Cyberball Game, a ball tossing game in which one player is excluded, to measure prosocial compensating behavior. Prosocial compensating behavior showed a linear developmental increase, similar to parent-reported prosocial behavior, whereas parent-reported empathy showed a quadratic trajectory with highest levels in late childhood. On a neural level we found a peak in ventral striatum activity during prosocial compensating behavior. Neural activity during social inclusion showed quadratic age effects in anterior cingulate cortex, insula, striatum, and precuneus, and a linear increase in temporo-parietal junction. Finally, changes in prosocial compensating behavior were negatively associated with changes in ventral striatum and mPFC activity during social inclusion, indicating an important co-occurrence between development in brain and social behavior. Together these findings shed a light on the mechanisms underlying social development from childhood into adolescence.

Development of social feedback processing and responses in childhood: an fMRI test-replication design in two age cohorts.

This study investigated behavioral and neural correlates underlying social feedback processing and subsequent aggressive behaviors in childhood in two age cohorts (test sample: n = 509/n = 385 and replication sample: n = 354/n = 195, 7-9 years old). Using a previously validated Social Network Aggression Task, we showed that negative social feedback resulted in most behavioral aggression, followed by less aggression after neutral and least aggression after positive feedback. Receiving positive and negative social feedback was associated with increased activity in the insula, medial prefrontal cortex and ventrolateral prefrontal cortex. Responding to feedback was associated with additional activation in the dorsolateral prefrontal cortex (DLPFC) following positive feedback. This DLPFC activation correlated negatively with aggression. Furthermore, age analyses showed that older children showed larger reductions in aggression following positive feedback and more neural activation in the DLPFC when responding to positive feedback compared to younger children. To assess the robustness of our results, we examined these processes in two independent behavioral/functional magnetic resonance imaging samples using equivalence testing, thereby contributing to replicable reports. Together, these findings demonstrate an important role of social saliency and regulatory processes where regulation of aggression rapidly develops between the ages of 7 and 9 years.

The nature of the self: Neural analyses and heritability estimates of self-evaluations in middle childhood.

How neural correlates of self-concept are influenced by environmental versus genetic factors is currently not fully understood. We investigated heritability estimates of behavioral and neural correlates of self-concept in middle childhood since this phase is an important time window for taking on new social roles in academic and social contexts. To do so, a validated self-concept fMRI task was applied in a twin sample of 345 participants aged between 7 and 9 years. In the self-concept condition, participants were asked to indicate whether academic and social traits applied to them whereas the control condition required trait categorization. The self-processing activation analyses (n = 234) revealed stronger medial prefrontal cortex (mPFC) activation for self than for control conditions. This effect was more pronounced for social-self than academic self-traits, whereas stronger dorsolateral prefrontal cortex (DLPFC) activation was observed for academic versus social self-evaluations. Behavioral genetic modeling (166 complete twin pairs) revealed that 25-52% of the variation in academic self-evaluations was explained by genetic factors, whereas 16-49% of the variation in social self-evaluations was explained by shared environmental factors. Neural genetic modeling (91 complete twin pairs) for variation in mPFC and anterior prefrontal cortex (PFC) activation for academic self-evaluations confirmed genetic and unique environmental influences, whereas anterior PFC activation for social self-evaluations was additionally influenced by shared environmental influences. This indicates that environmental context possibly has a larger impact on the behavioral and neural correlates of social self-concept at a young age. This is the first study demonstrating in a young twin sample that self-concept depends on both genetic and environmental factors, depending on the specific domain.

Neural and behavioral signatures of social evaluation and adaptation in childhood and adolescence: The Leiden consortium on individual development (L-CID).

The transition period between early childhood and late adolescence is characterized by pronounced changes in social competence, or the capacity for flexible social adaptation. Here, we propose that two processes, self-control and prosociality, are crucial for social adaptation following social evaluation. We present a neurobehavioral model showing commonalities in neural responses to experiences of social acceptance and rejection, and multiple pathways for responding to social context. The Leiden Consortium on Individual Development (L-CID) provides a comprehensive approach towards understanding the longitudinal developmental pathways of, and social enrichment effects on, social competence, taking into account potential differential effects of such enrichment. Using Neurosynth based brain maps we point towards the medial prefrontal cortex as an important region integrating social cognition, self-referential processing and self-control for learning to respond flexibly to changing social contexts. Based on their role in social evaluation processing, we suggest to examine medial prefrontal cortex connections with lateral prefrontal cortex and the ventral striatum as potential neural differential susceptibility markers, in addition to previously established markers of differential susceptibility.