Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

Corticostriatal Connectivity during Prosocial Decision-making Relates to Giving Behavior during Adolescence.

Prosocial behavior during adolescence becomes more differentiated based on the recipient of the action as well as the perceived value or benefit, relative to the cost to self, for the recipients. The current study investigated how functional connectivity of corticostriatal networks tracked the value of prosocial decisions as a function of target recipient (caregiver, friend, stranger) and age of the giver, and how they related to giving behavior. Two hundred sixty-one adolescents (9-15 and 19-20 years of age) completed a decision-making task in which they could give money to caregivers, friends, and strangers while undergoing fMRI. Results indicated that adolescents were more likely to give to others as the value of the prosocial decision (i.e., the difference between the benefit to other relative to the cost to self) increased; this effect was stronger for known (caregiver and friends) than unknown targets, and increased with age. Functional connectivity between the nucleus accumbens (NAcc) and OFC increased as the value of the prosocial decisions decreased for strangers, but not for known others, irrespective of choice. This differentiated NAcc-OFC functional connectivity during decision-making as a function of value and target also increased with age. Furthermore, regardless of age, individuals who evinced greater value-related NAcc-OFC functional connectivity when considering giving to strangers relative to known others showed smaller differentiated rates of giving between targets. These findings highlight the role of corticostriatal development in supporting the increasing complexity of prosocial development across adolescence.

Neural Mechanisms Underlying Trust to Friends, Community Members, and Unknown Peers in Adolescence.

Trust plays an important role during adolescence for developing social relations. Although prior developmental studies give us insight into adolescents' development of differentiation between close (e.g., friends) and unknown (e.g., unknown peers) targets in trust choices, less is known about the development of trust to societal targets (e.g., members of a community organization) and its underlying neural mechanisms. Using a modified version of the Trust Game, our preregistered fMRI study examined the underlying neural mechanisms of trust to close (friend), societal (community member), and unknown others (unknown peer) during adolescence in 106 participants (aged 12-23 years). Adolescents showed most trust to friends, less trust to community members, and the least trust to unknown peers. Neural results show that target differentiation in adolescents' trust behavior is associated with activity in social brain regions implicated during mentalizing, reward processing, and cognitive control. Recruitment of the medial prefrontal cortex (mPFC) and OFC was higher for closer targets (i.e., friend and community member). For the mPFC, this effect was most pronounced during no trust choices. Trust to friends was additionally associated with increased activity in the precuneus and bilateral temporal parietal junction. In contrast, bilateral dorsolateral prefrontal cortex and anterior cingulate cortex were most active for trust to unknown peers. The mPFC showed increased activity with age and consistent relations with individual differences in feeling needed/useful.

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.

Longitudinal changes in DLPFC activation during childhood are related to decreased aggression following social rejection.

Regulating aggression after social feedback is an important prerequisite for developing and maintaining social relations, especially in the current times with larger emphasis on online social evaluation. Studies in adults highlighted the role of the dorsolateral prefrontal cortex (DLPFC) in regulating aggression. Little is known about the development of aggression regulation following social feedback during childhood, while this is an important period for both brain maturation and social relations. The current study used a longitudinal design, with 456 twins undergoing two functional MRI sessions across the transition from middle (7 to 9 y) to late (9 to 11 y) childhood. Aggression regulation was studied using the Social Network Aggression Task. Behavioral aggression after social evaluation decreased over time, whereas activation in the insula, dorsomedial PFC and DLPFC increased over time. Brain-behavior analyses showed that increased DLPFC activation after negative feedback was associated with decreased aggression. Change analyses further revealed that children with larger increases in DLPFC activity from middle to late childhood showed stronger decreases in aggression over time. These findings provide insights into the development of social evaluation sensitivity and aggression control in childhood.

Longitudinal neural and behavioral trajectories of charity contributions across adolescence.

This study examined the development of prosocial charity donations and neural activity in the ventral striatum when gaining rewards for self and for charity. Participants 10-22 years (95% European heritage) participated in three annual behavioral-fMRI waves (T1: n = 160, T2: n = 167, T3: n = 175). Behaviorally, donations to charity as measured with an economic Dictator Game increased with age. Perspective taking also increased with age. In contrast, self-gain and charity-gain enjoyment decreased with age. Ventral striatum activity was higher for rewards for self than for charity, but this difference decreased during adolescence. Latent growth curve models revealed that higher donations were associated with a smaller difference between ventral striatum activation for self and charity. These findings show longitudinal brain-donations associations in adolescence.

Variability and change in adolescents' prosocial behavior across multiple time scales.

We examined variability and change in adolescents' prosocial behaviors directed to peers and friends across four time scales: two-years, one-year, two-monthly, and daily. Data from three longitudinal datasets with a total of 569 adolescents (55.7% girl, Mage  = 15.23, SD = 3.90) were included. The overall time-related stability of prosocial behavior across time scales was moderate to excellent. Variability did not differ between early (age 10-15) and late (age 16-21) adolescence, but late adolescence was associated with higher mean levels of prosociality. Finally, results indicated that prosocial behaviors measured over longer periods (i.e., two-years and one-year) were positively associated with cognitive processes (perspective taking), whereas prosocial behaviors measured over shorter periods (i.e., two-monthly) were positively associated with affective processes (empathy).

Adolescents' trust and reciprocity toward friends, unknown peers, and community members.

Using a newly developed version of the Trust Game among 196 adolescents aged 11-20 years, this study examined whether adolescents distinguish between trust and reciprocity to unknown peers, friends, and community members. We also tested for effects of age, gender, and individual differences in attending to others' emotions, emotional support to friends, societal contributions, and institutional and interpersonal trust beliefs. Results indicated that adolescents showed the least trust and reciprocity to unknown peers, more to a community member, and most to friends. Reciprocity increased with age, and individual differences in societal contributions and interpersonal trust were positively related to trust and reciprocity. This study was the first to show that community members are a specific target in adolescents' social world.

Longitudinal Change in Adolescent Depression and Anxiety Symptoms from before to during the COVID-19 Pandemic.

This study aimed to examine changes in depression and anxiety symptoms from before to during the first 6 months of the COVID-19 pandemic in a sample of 1,339 adolescents (9-18 years old, 59% female) from three countries. We also examined if age, race/ethnicity, disease burden, or strictness of government restrictions moderated change in symptoms. Data from 12 longitudinal studies (10 U.S., 1 Netherlands, 1 Peru) were combined. Linear mixed effect models showed that depression, but not anxiety, symptoms increased significantly (median increase = 28%). The most negative mental health impacts were reported by multiracial adolescents and those under 'lockdown' restrictions. Policy makers need to consider these impacts by investing in ways to support adolescents' mental health during the pandemic.

Moral Beauty During the COVID-19 Pandemic: Prosocial Behavior Among Adolescents and the Inspiring Role of the Media.

In this study, we examined whether adolescents helped others during the COVID-19 pandemic and how stories in the media inspired them in doing so. Using an online daily diary design, 481 younger adolescents (M = 15.29, SD = 1.76) and 404 older adolescents (M = 21.48, SD = 1.91) were followed for 2 weeks. Findings from linear mixed effects models demonstrated that feelings of being moved by stories in the media were related to giving emotional support to family and friends, and to helping others, including strangers. Exposure to COVID-19 news and information was found to spark efforts to support and help as well and keeping physical distance in line with the advised protective behaviors against COVID-19. Moreover, helping others was related to increased happiness. Overall, the findings of this study highlight the potential role of the media in connecting people in times of crisis.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Longitudinal network re-organization across learning and development.

While it is well understood that the brain experiences changes across short-term experience/learning and long-term development, it is unclear how these two mechanisms interact to produce developmental outcomes. Here we test an interactive model of learning and development where certain learning-related changes are constrained by developmental changes in the brain against an alternative development-as-practice model where outcomes are determined primarily by the accumulation of experience regardless of age. Participants (8-29 years) participated in a three-wave, accelerated longitudinal study during which they completed a feedback learning task during an fMRI scan. Adopting a novel longitudinal modeling approach, we probed the unique and moderated effects of learning, experience, and development simultaneously on behavioral performance and network modularity during the task. We found nonlinear patterns of development for both behavior and brain, and that greater experience supported increased learning and network modularity relative to naïve subjects. We also found changing brain-behavior relationships across adolescent development, where heightened network modularity predicted improved learning, but only following the transition from adolescence to young adulthood. These results present compelling support for an interactive view of experience and development, where changes in the brain impact behavior in context-specific fashion based on developmental goals.

Alcohol use and brain morphology in adolescence: A longitudinal study in three different cohorts.

Alcohol consumption is commonly initiated during adolescence, but the effects on human brain development remain unknown. In this multisite study, we investigated the longitudinal associations of adolescent alcohol use and brain morphology. Three longitudinal cohorts in the Netherlands (BrainScale n = 200, BrainTime n = 239 and a subsample of the Generation R study n = 318) of typically developing participants aged between 8 and 29 years were included. Adolescent alcohol use was self-reported. Longitudinal neuroimaging data were collected for at least two time points. Processing pipelines and statistical analyses were harmonized across cohorts. Main outcomes were global and regional brain volumes, which were a priori selected. Linear mixed effect models were used to test main effects of alcohol use and interaction effects of alcohol use with age in each cohort separately. Alcohol use was associated with adolescent's brain morphology showing accelerated decrease in grey matter volumes, in particular in the frontal and cingulate cortex volumes, and decelerated increase in white matter volumes. No dose-response association was observed. The findings were most prominent and consistent in the older cohorts (BrainScale and BrainTime). In summary, this longitudinal study demonstrated differences in neurodevelopmental trajectories of grey and white matter volume in adolescents who consume alcohol compared with non-users. These findings highlight the importance to further understand underlying neurobiological mechanisms when adolescents initiate alcohol consumption. Therefore, further studies need to determine to what extent this reflects the causal nature of this association, as this longitudinal observational study does not allow for causal inference.

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.

Self and Others in Adolescence.

Research has demonstrated that adolescence is an important time for self- and other-oriented development that underlies many skills vital for becoming a contributing member of society with healthy intergroup relations. It is often assumed that these two processes, thinking about self and thinking about others, are pitted against each other when adolescents engage in social decision making such as giving or sharing. Recent evidence from social neuroscience, however, does not support this notion of conflicting motives, suggesting instead that thinking about self and others relies on a common network of social-affective brain regions, with the medial prefrontal cortex playing a central role in the integration of perspectives related to self and others. Here, we argue that self- and other-oriented thinking are intertwined processes that rely on an overlapping neural network. Adolescents' motivation to contribute to society can be fostered most when self- and other-oriented motives align.

On Imbalance of Impulse Control and Sensation Seeking and Adolescent Risk: An Intra-individual Developmental Test of the Dual Systems and Maturational Imbalance Models.

Heterogeneity in development of imbalance between impulse control and sensation seeking has not been studied until now. The present study scrutinized this heterogeneity and the link between imbalance and adolescent risk. Seven-wave data of 7,558 youth (50.71% males; age range from 12/13 until 24/25) were used. Three developmental trajectories were identified. The first trajectory, "sensation seeking to balanced sensation seeking", included participants with a higher level of sensation seeking than impulse control across all ages. The second trajectory, "moderate dominant control", included participants showing moderate and increasing impulse control relative to sensation seeking across all ages. The third trajectory, "strong late dominant control", included participants showing the highest level of impulse control which was about as strong as sensation seeking from early to middle adolescence and became substantially stronger from late adolescence to early adulthood. Although the systematic increase of impulse control in all subgroups is in line with both models, neither of these combined trajectories of control and sensation seeking was predicted by the Dual Systems Model or the Maturational Imbalance Model. Consistent with both models the "sensation seeking to balanced sensation seeking" trajectory showed the highest level of substance use. It can be concluded that, even though both theories adequately predict the link between imbalance and risk, neither the Dual Systems Model nor the Maturational Imbalance Model correctly predict the heterogeneity in development of imbalance between impulse control and sensation seeking.

Familiarity and Audience Effects on Giving: A Functional Magnetic Resonance Imaging Study.

Giving is often characterized by the conflicting decision to give up something of value to benefit others. Recent evidence indicated that giving is highly context-dependent. To unravel the neural correlates of social context, in this study, young adults (n = 32) performed a novel giving fMRI paradigm, in which they divided coins between self and known (friends) or unknown (unfamiliar) others. A second manipulation included presence of others; giving decisions were made with an audience or anonymously. Results showed that participants gave more coins to a friend than to an unfamiliar other and generally gave more in the presence of an audience. On a neural level, medial prefrontal cortex and the right insula were most active for relatively generous decisions. These findings possibly reflect that aversion of norm deviation or fairness concerns drive differences in the frequency of giving. Next, activation in separate subregions of the TPJ-IPL (i.e., a region that comprises the TPJ and inferior parietal lobule) was found for target and audience contexts. Overall, our findings suggest that donation size and social contextual information are processed in separable brain regions and that TPJ-IPL plays an important role in balancing self- and other-oriented motives related to the social context.

I am happy for us: Neural processing of vicarious joy when winning for parents versus strangers.

This study investigated the neural processes underlying vicarious joy and their dependence on emotional closeness. Prior studies revealed that the nucleus accumbens (NAcc) is a target brain region for processing rewards for self, but the neural mechanisms of processing rewards for others are not yet well understood. A functional magnetic resonance imaging (fMRI) paradigm was employed in young adults (N = 30), in combination with a self-report questionnaire on the perceived emotional closeness to the target. We examined the neural correlates of vicarious rewards when winning money for oneself or one of three other targets. To examine family relationships, two of the targets were the mother and father of the participants, and the third target was an unknown stranger. We found an increase in activation in the NAcc when playing for family members compared with a stranger. We further observed a difference in neural activation when winning for the father compared with the mother in an extended network involving the medial prefrontal cortex and precuneus, brain regions involved in mentalizing. These findings were not related to reports of emotional closeness. This new paradigm has considerable value for future research into the fundamental neural processes underlying empathy and vicarious joy.

Behavioral and Neural Pathways Supporting the Development of Prosocial and Risk-Taking Behavior Across Adolescence.

This study tested the pathways supporting adolescent development of prosocial and rebellious behavior. Self-report and structural brain development data were obtained in a three-wave, longitudinal neuroimaging study (8-29 years, N = 210 at Wave 3). First, prosocial and rebellious behavior assessed at Wave 3 were positively correlated. Perspective taking and intention to comfort uniquely predicted prosocial behavior, whereas fun seeking (current levels and longitudinal changes) predicted both prosocial and rebellious behaviors. These changes were accompanied by developmental declines in nucleus accumbens and medial prefrontal cortex (MPFC) volumes, but only faster decline of MPFC (faster maturity) related to less rebellious behavior. These findings point toward a possible differential susceptibility marker, fun seeking, as a predictor of both prosocial and rebellious developmental outcomes.