Pregnancy and adolescence entail similar neuroanatomical adaptations: A comparative analysis of cerebral morphometric changes.

Mapping the impact of pregnancy on the human brain is essential for understanding the neurobiology of maternal caregiving. Recently, we found that pregnancy leads to a long-lasting reduction in cerebral gray matter volume. However, the morphometric features behind the volumetric reductions remain unexplored. Furthermore, the similarity between these reductions and those occurring during adolescence, another hormonally similar transitional period of life, still needs to be investigated. Here, we used surface-based methods to analyze the longitudinal magnetic resonance imaging data of a group of 25 first-time mothers (before and after pregnancy) and compare them to those of a group of 25 female adolescents (during 2 years of pubertal development). For both first-time mothers and adolescent girls, a monthly rate of volumetric reductions of 0.09 mm3 was observed. In both cases, these reductions were accompanied by decreases in cortical thickness, surface area, local gyrification index, sulcal depth, and sulcal length, as well as increases in sulcal width. In fact, the changes associated with pregnancy did not differ from those that characterize the transition during adolescence in any of these measures. Our findings are consistent with the notion that the brain morphometric changes associated with pregnancy and adolescence reflect similar hormonally primed biological processes.

Understanding the Role of Puberty in Structural and Functional Development of the Adolescent Brain.

Over the past two decades, there has been a tremendous increase in our understanding of structural and functional brain development in adolescence. However, understanding the role of puberty in this process has received much less attention. This review examines this relationship by summarizing recent research studies where the role of puberty was investigated in relation to brain structure, connectivity, and task-related functional magnetic resonance imaging (fMRI). The studies together suggest that puberty may contribute to adolescent neural reorganization and maturational advancement, and sex differences also emerge in puberty. The current body of work shows some mixed results regarding impact and exact direction of pubertal influence. We discuss several limitations of current studies and propose future directions on how to move the field forward.

A multisample study of longitudinal changes in brain network architecture in 4-13-year-old children.

Recent advances in human neuroimaging research have revealed that white-matter connectivity can be described in terms of an integrated network, which is the basis of the human connectome. However, the developmental changes of this connectome in childhood are not well understood. This study made use of two independent longitudinal diffusion-weighted imaging data sets to characterize developmental changes in the connectome by estimating age-related changes in fractional anisotropy (FA) for reconstructed fibers (edges) between 68 cortical regions. The first sample included 237 diffusion-weighted scans of 146 typically developing children (4-13 years old, 74 females) derived from the Pediatric Longitudinal Imaging, Neurocognition, and Genetics (PLING) study. The second sample included 141 scans of 97 individuals (8-13 years old, 62 females) derived from the BrainTime project. In both data sets, we compared edges that had the most substantial age-related change in FA to edges that showed little change in FA. This allowed us to investigate if developmental changes in white matter reorganize network topology. We observed substantial increases in edges connecting peripheral and a set of highly connected hub regions, referred to as the rich club. Together with the observed topological differences between regions connecting to edges showing the smallest and largest changes in FA, this indicates that changes in white matter affect network organization, such that highly connected regions become even more strongly imbedded in the network. These findings suggest that an important process in brain development involves organizing patterns of inter-regional interactions. Hum Brain Mapp 39:157-170, 2018. © 2017 Wiley Periodicals, Inc.

Contributions of Reward Sensitivity to Ventral Striatum Activity Across Adolescence and Early Adulthood.

It was examined how ventral striatum responses to rewards develop across adolescence and early adulthood and how individual differences in state- and trait-level reward sensitivity are related to these changes. Participants (aged 8-29 years) were tested across three waves separated by 2 years (693 functional MRI scans) in an accelerated longitudinal design. The results confirmed an adolescent peak in reward-related ventral striatum, specifically nucleus accumbens, activity. In early to mid-adolescence, increases in reward activation were related to trait-level reward drive. In mid-adolescence to early adulthood decreases in reward activation were related to decreases in state-level hedonic reward pleasure. This study demonstrates that state- and trait-level reward sensitivity account for reward-related ventral striatum activity in different phases of adolescence and early adulthood.

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.

Frontostriatal White Matter Integrity Predicts Development of Delay of Gratification: A Longitudinal Study.

The ability to delay gratification increases considerably across development. Here, we test the hypothesis that this impulse control capacity is driven by increased maturation of frontostriatal circuitry using a fiber-tracking approach combined with longitudinal imaging. In total, 192 healthy volunteers between 8 and 26 years underwent diffusion tensor imaging scanning and completed a delay-discounting task twice, separated by a 2-year interval. We investigated dynamic associations between frontostriatal white matter (WM) integrity and delay of gratification skills. Moreover, we examined the predictive value of frontostriatal WM integrity for future delay of gratification skills. Results showed that delay discounting increases with age in a quadratic fashion, with greatest patience during late adolescence. Data also indicated nonlinear development of frontostriatal WM, with relative fast development during childhood and early adulthood and--on average--little change during mid-adolescence. Furthermore, the positive association between age and delay discounting was further increased in individuals with higher WM integrity of the frontostriatal tracts. Predictive analysis showed that frontostriatal WM development explained unique variance in current and future delay of gratification skills. This study adds to a descriptive relation between WM integrity and delay of gratification by showing that maturation of frontostriatal connectivity predicts changes in delay of gratification skills. These findings have implications for studies examining deviances in impulse control by showing that the developmental path between striatum and prefrontal cortex may be an important predictor for when development goes astray. SIGNIFICANCE STATEMENT: During the transition from childhood to adulthood, individuals generally show increased patience and become better in delaying gratification. The exact neural correlates of delay of gratification, however, remain poorly understood. By measuring both frontostriatal white matter (WM) integrity and delay of gratification skills at two time points, we were able to provide links for our understanding of the neural mechanisms underlying this type of impulse regulation capacity. We demonstrate that the ability to delay gratification improves between childhood and young adulthood and this improvement is predicted by the integrity of frontostriatal WM connections. This study adds to a descriptive relation between WM quality and delay of gratification by showing that maturation of frontostriatal connectivity predicts improvements in delay of gratification skills.

Neural Mechanisms Underlying Risk and Ambiguity Attitudes.

Individual differences in attitudes to risk (a taste for risk, known probabilities) and ambiguity (a tolerance for uncertainty, unknown probabilities) differentially influence risky decision-making. However, it is not well understood whether risk and ambiguity are coded differently within individuals. Here, we tested whether individual differences in risk and ambiguity attitudes were reflected in distinct neural correlates during choice and outcome processing of risky and ambiguous gambles. To these ends, we developed a neuroimaging task in which participants ( n = 50) chose between a sure gain and a gamble, which was either risky or ambiguous, and presented decision outcomes (gains, no gains). From a separate task in which the amount, probability, and ambiguity level were varied, we estimated individuals' risk and ambiguity attitudes. Although there was pronounced neural overlap between risky and ambiguous gambling in a network typically related to decision-making under uncertainty, relatively more risk-seeking attitudes were associated with increased activation in valuation regions of the brain (medial and lateral OFC), whereas relatively more ambiguity-seeking attitudes were related to temporal cortex activation. In addition, although striatum activation was observed during reward processing irrespective of a prior risky or ambiguous gamble, reward processing after an ambiguous gamble resulted in enhanced dorsomedial PFC activation, possibly functioning as a general signal of uncertainty coding. These findings suggest that different neural mechanisms reflect individual differences in risk and ambiguity attitudes and that risk and ambiguity may impact overt risk-taking behavior in different ways.

Amygdala-orbitofrontal connectivity predicts alcohol use two years later: a longitudinal neuroimaging study on alcohol use in adolescence.

This study tested the relation between cortical-subcortical functional connectivity and alcohol consumption in adolescents using an accelerated longitudinal design, as well as normative developmental patterns for these measures. Participants between ages 8 and 27 completed resting-state neuroimaging scans at two time points separated by two years (N = 274 at T1, N = 231 at T2). In addition, participants between ages 12 and 27 reported on recent and lifetime alcohol use (N = 193 at T1, N = 244 at T2). Resting-state connectivity analyses focused on amygdala-orbitofrontal connectivity given prior research linking reduced coupling between these regions to alcohol use. Mixed model analyses revealed that age had a cubic relationship with alcohol use, with little to no use in childhood, steep increases in adolescence and leveling off in adulthood. No age effects were found for amygdala-OFC connectivity. Prediction analyses showed that left amygdala-orbitofrontal connectivity at the first time point predicted recent and lifetime alcohol use two years later. There was no evidence for the reversed relation, suggesting that brain connectivity measures precede explorative risk-taking behavior in adolescence, possibly because decreased subcortical-frontal connectivity biases towards more explorative or risky behavior.

Longitudinal changes in adolescent risk-taking: a comprehensive study of neural responses to rewards, pubertal development, and risk-taking behavior.

Prior studies have highlighted adolescence as a period of increased risk-taking, which is postulated to result from an overactive reward system in the brain. Longitudinal studies are pivotal for testing these brain-behavior relations because individual slopes are more sensitive for detecting change. The aim of the current study was twofold: (1) to test patterns of age-related change (i.e., linear, quadratic, and cubic) in activity in the nucleus accumbens, a key reward region in the brain, in relation to change in puberty (self-report and testosterone levels), laboratory risk-taking and self-reported risk-taking tendency; and (2) to test whether individual differences in pubertal development and risk-taking behavior were contributors to longitudinal change in nucleus accumbens activity. We included 299 human participants at the first time point and 254 participants at the second time point, ranging between ages 8-27 years, time points were separated by a 2 year interval. Neural responses to rewards, pubertal development (self-report and testosterone levels), laboratory risk-taking (balloon analog risk task; BART), and self-reported risk-taking tendency (Behavior Inhibition System/Behavior Activation System questionnaire) were collected at both time points. The longitudinal analyses confirmed the quadratic age pattern for nucleus accumbens activity to rewards (peaking in adolescence), and the same quadratic pattern was found for laboratory risk-taking (BART). Nucleus accumbens activity change was further related to change in testosterone and self-reported reward-sensitivity (BAS Drive). Thus, this longitudinal analysis provides new insight in risk-taking and reward sensitivity in adolescence: (1) confirming an adolescent peak in nucleus accumbens activity, and (2) underlining a critical role for pubertal hormones and individual differences in risk-taking tendency.

Annual Research Review: Neural contributions to risk-taking in adolescence--developmental changes and individual differences.

BACKGROUND: Risk-taking, which involves voluntary choices for behaviors where outcomes remain uncertain, undergoes considerable developmental changes during childhood, adolescence, and early adulthood. In addition, risk-taking is thought to be a key element of many externalizing disorders, such as ADHD, delinquency, conduct disorder, and substance abuse. In this review, we will discuss the potential adaptive and nonadaptive properties of risk-taking in childhood and adolescence. FINDINGS: We propose that the changes in brain architecture and function are a crucial element underlying these developmental trajectories. We first identify how subcortical and cortical interactions are important for understanding risk-taking behavior in adults. Next, we show how developmental changes in this network underlie changes in risk-taking behavior. Finally, we explore how these differences can be important for understanding externalizing behavioral disorders in childhood and adolescence. CONCLUSIONS: We conclude that longitudinal studies are of crucial importance for understanding these developmental trajectories, and many of these studies are currently underway.

Short fused? associations between white matter connections, sex steroids, and aggression across adolescence.

Functional neuroimaging studies in adults show that aggression involves reduced brain communication between subcortical and cortical areas dedicated to motivation and control, respectively. Prior research indicates that sex steroid hormone production during adolescence negatively influences the rapid development of white matter connectivity between subcortical and cortical areas during adolescence and may potentiate aggression. Here, we tested this hypothesis in 258 participants between 8 and 25 years of age by using Diffusion Weighted Imaging to examine the microstructure of white matter connections within the fronto-temporal-subcortical network. Trait aggression was measured using the Buss Perry Aggression Questionnaire and testosterone and estradiol levels were measured in saliva. Results indicated that higher levels of testosterone were associated with less white matter integrity within the fronto-temporal-subcortical network (i.e., higher mean diffusivity [MD] longitudinal [LD], and radial diffusivity [RD]). Furthermore, lower fractional anisotropy and higher MD, LD, and RD values within this network increased expressive forms of aggression and reduced inhibited forms of aggression (hostility). Our study indicates higher levels of testosterone relating to lower quality of structural cortical-subcortical connectivity, arguably resulting in a shift from inhibited towards expressive forms of aggression. Our data adds evidence to the idea that aggressive tendencies are subcortically driven, but individuals with relatively high testosterone might have lower structural connectivity within cortical control areas, resulting in a stronger tendency to act on these aggressive tendencies.

Gambling for self, friends, and antagonists: differential contributions of affective and social brain regions on adolescent reward processing.

Adolescence is a time of increasing emotional arousal, sensation-seeking and risk-taking, especially in the context of peers. Recent neuroscientific studies have pinpointed to the role of the ventral striatum as a brain region which is particularly sensitive to reward, and to 'social brain' regions, such as the medial prefrontal cortex (mPFC), the precuneus, and the temporal parietal junction, as being particularly responsive to social contexts. However, no study to date has examined adolescents' sensitivity to reward across different social contexts. In this study we examined 249 participants between the ages 8 and 25, on a monetary reward-processing task. Participants could win or lose money for themselves, their best friend and a disliked peer. Winning for self resulted in a mid- to late adolescent specific peak in neural activation in the ventral striatum, whereas winning for a disliked peer resulted in a mid- to late adolescent specific peak in the mPFC. Our findings reveal that ventral striatum and mPFC hypersensitivity in adolescence is dependent on social context. Taken together, these results suggest that increased risk-taking and sensation seeking observed in adolescence might not be purely related to hyperactivity of the ventral striatum, but that these behaviors are probably strongly related to the social context in which they occur.

Delay discounting and frontostriatal fiber tracts: a combined DTI and MTR study on impulsive choices in healthy young adults.

Delay discounting, a measure of impulsive choice, has been associated with decreased control of the prefrontal cortex over striatum responses. The anatomical connectivity between both brain regions in delaying gratification remains unknown. Here, we investigate whether the quality of frontostriatal (FS) white matter tracts can predict individual differences in delay-discounting behavior. We use tract-based diffusion tensor imaging and magnetization transfer imaging to measure the microstructural properties of FS fiber tracts in 40 healthy young adults (from 18 to 25 years). We additionally explored whether internal sex hormone levels affect the integrity of FS tracts, based on the hypothesis that sex hormones modulate axonal density within prefrontal dopaminergic circuits. We calculated fractional anisotropy (FA), mean diffusivity (MD), longitudinal diffusivity, radial diffusivity (RD), and magnetization transfer ratio (MTR), a putative measure of myelination, for the FS tract. Results showed that lower integrity within the FS tract (higher MD and RD and lower FA), predicts faster discounting in both sexes. MTR was unrelated to delay-discounting performance. In addition, testosterone levels in males were associated with a lower integrity (higher RD) within the FS tract. Our study provides support for the hypothesis that enhanced structural integrity of white matter fiber bundles between prefrontal and striatal brain areas is associated with better impulse control.

Development of risk taking: contributions from adolescent testosterone and the orbito-frontal cortex.

The role of puberty in the development of risk taking remains poorly understood. Here, in a normative sample of 268 participants between 8 and 25 years old, we applied a psycho-endocrine neuroimaging approach to investigate the contribution of testosterone levels and OFC morphology to individual differences in risk taking. Risk taking was measured with the balloon analogue risk-taking task. We found that, corrected for age, higher endogenous testosterone level was related to increased risk taking in boys (more explosions) and girls (more money earned). In addition, a smaller medial OFC volume in boys and larger OFC surface area in girls related to more risk taking. A mediation analysis indicated that OFC morphology partly mediates the association between testosterone level and risk taking, independent of age. Mediation was found in such a way that a smaller medial OFC in boys potentiates the association between testosterone and risk taking but suppresses the association in girls. This study provides insights into endocrinological and neural underpinnings of normative development of risk taking, by indicating that OFC morphology, at least partly, mediates the association between testosterone and risk-taking behavior.

Heritability of volumetric brain changes and height in children entering puberty.

The human brain undergoes structural changes in children entering puberty, while simultaneously children increase in height. It is not known if brain changes are under genetic control, and whether they are related to genetic factors influencing the amount of overall increase in height. Twins underwent magnetic resonance imaging brain scans at age 9 (N = 190) and 12 (N = 125). High heritability estimates were found at both ages for height and brain volumes (49-96%), and high genetic correlation between ages were observed (r(g) > 0.89). With increasing age, whole brain (+1.1%), cerebellum (+4.2%), cerebral white matter (+5.1%), and lateral ventricle (+9.4%) volumes increased, and third ventricle (-4.0%) and cerebral gray matter (-1.6%) volumes decreased. Children increased on average 13.8 cm in height (9.9%). Genetic influences on individual difference in volumetric brain and height changes were estimated, both within and across traits. The same genetic factors influenced both cerebral (20% heritable) and cerebellar volumetric changes (45%). Thus, the extent to which changes in cerebral and cerebellar volumes are heritable in children entering puberty are due to the same genes that influence change in both structures. The increase in height was heritable (73%), and not associated with cerebral volumetric change, but positively associated with cerebellar volume change (r(p) = 0.24). This association was explained by a genetic correlation (r(g) = 0.48) between height and cerebellar change. Brain and body each expand at their own pace and through separate genetic pathways. There are distinct genetic processes acting on structural brain development, which cannot be explained by genetic increase in height.

Pubertal maturation and sex steroids are related to alcohol use in adolescents.

Adolescents often show risk-taking behavior, including experimentation with alcohol. Previous studies have shown that advanced pubertal maturation is related to increased alcohol use in adolescents, even when controlling for age. Little is known about the underlying mechanisms of this relation between pubertal maturation and alcohol use. The goal of the present study was twofold. In Experiment 1, we investigated whether advanced pubertal maturation is associated with higher levels of alcohol use, when controlling for age. To this end, questionnaires on pubertal development and alcohol use were administered to a large sample of 797 Dutch adolescents (405 boys) aged 11-16 years. In Experiment 2, we explored whether sex steroids contribute to this relation between pubertal maturation and alcohol use by examining the association between salivary sex steroid levels and alcohol use in 168 adolescents (86 boys). It was found that, when controlling for age, advanced pubertal maturation is related to increased alcohol use in adolescent boys and girls. Controlling for age, higher testosterone and estradiol levels correlated with the onset of alcohol use in boys. In addition, higher estradiol levels were associated with a larger quantity of alcohol use in boys. Correlations between sex steroids and alcohol use were not significant in girls. These findings show that advanced pubertal maturation is related to advanced alcohol use, and that higher sex steroid levels could be one of the underlying mechanisms of this relation in boys. Sex steroids might promote alcohol use by stimulating brain regions implicated in reward processing.

Brain SCALE: brain structure and cognition: an adolescent longitudinal twin study into the genetic etiology of individual differences.

From childhood into adolescence, the child's brain undergoes considerable changes in both structure and function. Twin studies are of great value to explore to what extent genetic and environmental factors explain individual differences in brain development and cognition. In The Netherlands, we initiated a longitudinal study in which twins, their siblings and their parents are assessed at three year intervals. The participants were recruited from The Netherlands Twin Register (NTR) and at baseline consisted of 112 families, with 9-year-old twins and an older sibling. Three years later, 89 families returned for follow-up assessment. Data collection included psychometric IQ tests, a comprehensive neuropsychological testing protocol, and parental and self-ratings of behavioral and emotional problems. Physical maturation was measured through assessment of Tanner stages. Hormonal levels (cortisol, luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogens) were assessed in urine and saliva. Brain scans were acquired using 1.5 Tesla Magnetic Resonance Imaging (MRI), which provided volumetric measures and measures of cortical thickness. Buccal swabs were collected for DNA isolation for future candidate gene and genome-wide analysis studies. This article gives an overview of the study and the main findings. Participants will return for a third assessment when the twins are around 16 years old. Longitudinal twin-sibling studies that map brain development and cognitive function at well-defined ages aid in the understanding of genetic influences on normative brain development.

Heritability of DTI and MTR in nine-year-old children.

Overall brain size is strikingly heritable throughout life. The influence of genes on variation in focal gray and white matter density is less pronounced and may vary with age. This paper describes the relative influences of genes and environment on variation in white matter microstructure, measured along fiber tracts with diffusion tensor imaging and magnetization transfer imaging, in a sample of 185 nine-year old children from monozygotic and dizygotic twin pairs. Fractional anisotropy, a measure of microstructural directionality, was not significantly influenced by genetic factors. In contrast, studying longitudinal and radial diffusivity separately, we found significant genetic effects for both radial and longitudinal diffusivity in the genu and splenium of the corpus callosum and the right superior longitudinal fasciculus. Moreover, genetic factors influencing the magnetization transfer ratio (MTR), putatively representing myelination, were most pronounced in the splenium of the corpus callosum and the superior longitudinal fasciculi, located posterior in the brain. The differences in the extent to which genetic and environmental factors influence the various diffusion parameters and MTR, suggest that different physiological mechanisms (either genetic or environmental) underlie these traits at nine years of age.

Effects of gestational age and birth weight on brain volumes in healthy 9 year-old children.

OBJECTIVE: To assess the effects of gestational age and birth weight on brain volumes in a population-based sample of normal developing children at the age of 9 years. STUDY DESIGN: A total of 192 children from twin births were included in the analyses. Data on gestational age and birth weight were reported shortly after birth. Total brain, cerebellum, cerebrum, gray and white matter, and lateral ventricle volumes were assessed with structural magnetic resonance imaging. The Wechsler Intelligence Scale for Children-III was administered to assess general cognitive abilities. Structural equation modeling was used to analyze the effects of gestational age and birth weight on brain volumes. RESULTS: Shorter gestational age was associated with a relatively smaller cerebellar volume (P = .002). This effect was independent of IQ scores. Lower birth weight was associated with lower IQ score (P = .03). Birth weight was not associated with brain volumes. CONCLUSION: The effect of gestational age on cerebellar volume is not limited to children with very premature birth or very low birth weight, but is also present in children born >32 weeks of gestation and with birth weight >1500 g.

Sex differences and brain development during puberty and adolescence.

Sex differences in behavior, and whether these behavioral differences are related to sex differences in brain development, has been a longstanding topic of debate. Presumably, sex differences can provide critically important leads for explaining the etiology of various illnesses that show (i) large sex differences in prevalence and (ii) have an origin before or during adolescence. The general aim of this chapter is to provide an overview of scientific studies on sex differences in normative brain and behavioral development across puberty and adolescence, including the (sex) hormone-driven transition phase of puberty. Moreover, we describe the literature on brain and behavioral development in gender dysphoria, a severe and persistent incongruence between the self-identified gender and the assigned sex at birth. From the literature it becomes clear there is evidence for a specific link between pubertal maturation and developmental changes in arousal, motivation, and emotion. However, this link is rather similar between boys and girls. Moreover, although there is substantial evidence for sex differences in mean brain structure, these have not always been linked to sex differences in behavior, cognition, or psychopathology. Furthermore, there is little evidence for sex differences in brain development and thus, studies so far have been unable to explain sex differences in cognition. Suggestions for future research and methodologic considerations are provided.