The transition from childhood to adolescence is a period of opportunities (as young people physically and sexually mature, and peer and familial relationships change), challenges (as responsibilities and exposure to a range of risks, such as substance use and sexual activity, increase), and vulnerabilities (with half of all lifetime cases of mental illness starting by age 14 years) [
1]. The transition coincides with the biological processes of puberty and changes in brain structure and function [
2,
3]. Indeed, it is increasingly being recognised that pubertal maturation may influence brain development, and in turn, psychosocial maturation. In this regard, the
timing of pubertal stage relative to peers is relevant. Early pubertal timing predicts adolescent onset mental illness and other poor outcomes during adolescence, and in some cases better accounts for sex differences in the onset of psychopathology than age [
4,
5]. Specifically, early pubertal timing has been consistently associated with depressive symptoms in girls [
6,
7], while findings for boys are mixed [
8]. Further, advancing pubertal stage increases risk for both the onset and persistence of depressive symptoms in girls [
9] and violent and anti-social behaviours in both sexes [
10].
The current literature on puberty and brain development has many general methodological limitations [see [
11], and specifically has not addressed the differential effects of adrenarche (the earlier phase of pubertal development driven by the hypothalamic-pituitary-adrenal [HPA] axis) and gonadarche (the later phase driven by the hypothalamic-pituitary-gonadal [HPG] axis). Despite the fact that the timing of both phases of pubertal development have been associated with behavioural and mental health problems [
6,
7,
12], most research has focused on gonadarche and little is known about the earlier adrenal phase of pubertal development. This emphasis has likely been a product of the relative difficulty in assessing adrenarcheal development due to the paucity of early physical signs, and that adrenarche has only been detected in humans and some higher primates [
13], limiting experimental animal work.
This paper is a methodological description of the
Imaging brain development in the Childhood to Adolescence Transition Study (iCATS), which was embedded in a larger
Childhood to Adolescence Transition Study (CATS) [
14]. Both of these studies aim to address existing gaps in knowledge. However, iCATS will specifically, and uniquely, examine the influence of adrenarcheal timing on brain development and function, and on mental health.
Puberty and adolescent brain development
The principal focus in studies of adolescent brain development was traditionally on age-related changes [e.g., [
15]. Based on findings (e.g., peaks in grey matter density that appear to coincide with timing of puberty onset, [
16]) researchers have more recently suggested that brain development patterns align better with pubertal changes rather than with age. It is well established that steroid hormones play critical roles in development [
17]. However, the extant literature remains sparse, and predominantly focuses on gonadarcheal indices. Importantly, although there is informative animal work regarding the links between gonadarcheal hormones and brain structure and function, relatively little is known about this relationship in humans [
16] and particularly in relation to adrenarcheal hormones [
18].
Recently, a small number of adolescent MRI studies have investigated, in more detail, the relationships among brain structure and function, gender, and hormones that change at puberty. A structural MRI study by Peper and colleagues [
19] with 10–15 year olds showed an association between testosterone levels and global grey matter density in males (and not in females). Neufang and colleagues [
20] examined 46 participants aged 8–15 years and found a positive relationship between Tanner stage and testosterone levels and grey matter volume in the amygdala, and a negative relationship between these measures and hippocampal volume, regardless of gender. In addition, males showed a negative relationship between testosterone and parietal cortex grey matter. In a more recent study specifically examining adrenarcheal hormones, Nguyen et al. [
21] explored associations between androgens and cortical thickness and found that DHEA levels were positively associated with cortical thickness in various frontal, parietal, and temporal cortical regions from various ages between 4–13 years. For instance, DHEA was positively associated with cortical thickness of the left dorsolateral prefrontal cortex from ages 4 to 8 for males and females. Conversely, sex-specific changes were observed in the association between testosterone and cortical thickness. Specifically, pre-pubertal males (defined as Tanner Stage 1 or 2) typically demonstrated negative associations between testosterone and cortical thickness, whereas pre-pubertal females demonstrated positive associations. Trajectories of white matter development have also been found to differ as a function of pubertal hormones. Peper and colleagues (2009) reported a positive association between gonadotropic hormones and white matter density at age nine. A study by Perrin and colleagues [
22] found that trajectories of white matter development in males were related to expression levels of a gene encoding a testosterone receptor, suggesting that effects of testosterone may be responsible for the sexually dimorphic relationship between age and white matter volume. These studies demonstrate promising evidence that pubertal hormones influence structural brain development in humans.
Few studies have investigated the effects of puberty on brain function in normal samples. Forbes and colleagues [
23] found that those with more advanced pubertal maturation (measured by Tanner stage) exhibited less striatal and more medial prefrontal reactivity to reward, and that testosterone was positively correlated with striatal reactivity in boys during reward anticipation and negatively correlated with striatal reactivity in girls and boys during reward outcome.
Importantly, these published studies have not investigated possible effects of the timing of pubertal events on brain development, highlighted as a critical area for future investigation [
16]. We have recently completed the first study of the relationship between pubertal timing, brain structure and depressive symptoms during early adolescence [
24]. We found that larger volume of the pituitary gland, a key component of the HPG and HPA axes, mediated the relationship between early pubertal timing and depressive symptoms in 155 adolescents (72 females). Relatedly, we also found that pituitary volume in early adolescence predicts HPA activity in mid-adolescence in the same cohort [
25]. These findings are consistent with neurobiological mechanisms being responsible for the link between early pubertal timing and depressive symptoms in adolescents.
However, as these studies only used self- and parent-report measures of pubertal development and did not differentiate adrenarche and gonadarche, they cannot differentiate the relationship between specific adrenarcheal hormones, brain development and function. Furthermore, the focus on one brain region (the pituitary gland), although important, did not allow investigation of the role of brain development more broadly in these processes.
Aims
The broad aim of iCATS is to elucidate which children are most at risk for adverse outcomes as they pass through puberty. The specific aim of iCATS is to identify the neurobiological mechanisms that mediate this risk. The primary objective of this study is to explore the hypothesis that patterns of structural and functional brain development will mediate the relationship between pubertal timing and the indices of affect, self-regulation, and mental health symptoms collected across waves (and therefore years of development).
Current understanding of the relationship between puberty and brain development is rudimentary, with few studies looking specifically at the effects of pubertal timing [
24]. We hypothesise, based on extant literature, that earlier exposure to adrenarche will be associated with neurodevelopmental and behavioral outcomes that have been previously associated with greater risk for mental health problems. Our specific aims are to:
1.
Investigate the relationship between adrenarcheal timing and brain structure in both sexes, by examining associations between advanced adrenarcheal development, measured by DHEA, DHEA-S and testosterone, and (i) cortical grey matter, (ii) white matter, (iii) limbic, and (iv) striatal volumes.
2.
Investigate the relationship between adrenarcheal timing and brain function (both at rest and in the context of affective processing) in both sexes, by examining associations between advanced adrenarcheal development and both function and connectivity in (i) limbic, (ii) prefrontal, and (iii) parietal regions.
3.
Investigate if (i) stressful life events, (ii) long-term cortisol levels and (iii) immune system function moderate the associations between adrenarche and brain structure and function described in Aims 1 and 2.
4.
Investigate the relationship between Aims 1 – 3, health and risk, by examining whether the patterns of structural and functional brain changes identified above mediate the relationship between pubertal development and indices of affect, self-regulation, and mental health symptoms.