As hypothesized, we found interactions between sex and the effect of pubertal status on the development of the hippocampus, amygdala, and cortical gray matter. In these structures, we show that the effects of sex are not significant in pre/early puberty but are significant in mid/late pubertal children. Significant interactions of sex with physical sexual maturity for the right hippocampus were driven by nonsignificant volume increases with increased sexual maturity in boys, and significant volume decreases with increased sexual maturity in girls, independent of age. Significant sex by puberty interactions in the cerebral cortex were driven by volume reductions in girls at more advanced pubertal stages, but no effect of sexual maturity on cortical volumes in boys was seen. All these effects were significant even when age was used as an additional predictor, suggesting that sexual dimorphisms in MTL and cortical gray matter are driven more by pubertal influences, and less so by other factors co-occurring with increased age during adolescence.
In boys, sexual maturity, measured using TS, predicted volume increases in the MTL, significantly so in the left amygdala. However, we were unable to dissociate these from concomitant age effects in our population.
In girls, larger TS measurements were associated with a more mature pattern of cortical gray matter. Girls in earlier stages of puberty had larger gray matter volumes in the right and left cortex than girls of the same age in later stages of puberty. However, effects of sexual maturity on MTL volume were in an unpredicted direction. MTL volume was smaller in more than in less sexually mature girls. When we used multiple regression analysis, modeling effects of both advancing pubertal status and age, we found that girls in earlier stages of puberty had significantly larger gray matter volumes in the right amygdala than girls in later stages, independent of age. Consistent with our findings using TS, adolescent girls with higher levels of TES had smaller bilateral cortical gray matter than adolescent girls of the same age with lower levels. Furthermore, circulating TES predicted right MTL volume, but as with TS results, it was in an unpredicted direction. Girls with higher levels had smaller right amygdala and hippocampal volumes than girls with lower levels of circulating TES, though these effects did not remain significant when age was used as an additional predictor.
Mean volume increases in MTL volume in boys but statistically significant decreases in girls with the progression of puberty may be related to sex differences in the number of new cells added to the amygdala during puberty. In rats, it has been found that more new cells are added to the amygdala in males than in females during puberty and that reducing endogenous levels of pubertal hormones via gonadectomy reduces the number of new cells created (Ahmed et al. 2008
). Another potential cellular mechanism of the observed sex differences is that boys and girls differ in the soma sizes of neurons with gonadal steroid hormone receptors within the amygdala. This sexual dimorphism has been observed in the amygdala of rodents and has also been found to depend on TES levels (Romeo and Sisk 2001
We found sex differences in the right and left thalamus, similar to previous reports (Neufang et al. 2008
; Peper et al. 2009
). However, we found no evidence that pubertal influences are significantly associated with sex differences in this region. We did find that circulating TES significantly predicted thalamic volume when boys and girls were pooled. However, TES did not significantly predict thalamic volume in either boys or girls alone or independent of concomitant age effects. Previous human brain imaging studies have also been unable to link sex differences in basal ganglia or thalamic volumes (Neufang et al. 2008
; Peper et al. 2009
) to pubertal influences (Neufang et al. 2008
; Peper et al. 2009
), further supporting the hypothesis that any true sexual dimorphisms in these structures are likely unrelated to puberty-driven brain maturation.
The functional relevance of these structural findings in understanding puberty-related changes in adolescent boys and girls could be numerous. Interactions between the amygdala, critical for processing emotional information, and thinning cortical regions, important for controlling impulses and evaluation of risk (i.e., the frontal lobes), should be considered in interpretation of sex differences in puberty-related brain development (for review, see McGaugh 2004
). Thinner cortex in frontal and parietal cortices has been linked to more mature brain activation patterns in children and adolescents (Lu et al. 2007
). If thinner cortex is associated with improved executive control over the emotional processing centers of the amygdala, then one might expect differences in emotional processing between boys and girls, depending on pubertal status and the state of brain regions involved. Indeed, the incidence of depression and anxiety symptoms are much higher in girls than in boys starting in late childhood (Bailey et al. 2007
; Van Oort et al. 2009
), and perhaps earlier development of frontal lobes and frontolimbic connections in the right than in left hemisphere explains why clinically relevant anxiety and depression occurs in girls during adolescence. Higher left-sided and lower right-sided connectivity between the amygdala and frontal lobes, more right-lateralized frontal lobe activity, and lower rates of left-sided prefrontal cortical activity measured using fMRI and electroencephalography have all been associated with anxiety and depression in adults (Davidson et al. 1999
; Davidson and Irwin 1999
). Previous studies have shown that right frontal cortical thinning occurs prior to left frontal cortical thinning in children 5–11 years of age (Sowell et al. 2001
). Perhaps there is a greater lag between right and left hemisphere frontolimbic system maturation in girls than in boys, a hypothesis that warrants further study.
While risk and reward processing and decision-making skills develop in both boys and girls during adolescence, boys tend to be less risk averse than girls during adolescence (Van Leijenhorst et al. 2008
). Our findings of trophic changes in medial temporal limbic regions without the presumed increased efficiency and cognitive control that accompany cortical thinning in the frontal lobes may explain why boys are more likely to take risks than girls, whose cortical development occurs so much earlier. Conversely, the relatively early cortical maturation in girls, while possibly related to increased anxiety and depression symptoms, may also reduce their propensity to take unnecessary risks.
Our findings both agree and differ from previous reports, and may help shed light on discrepancies in the literature regarding MTL maturation. We show that MTL volumes rise in boys, and decline in girls, when evaluated as a function of sexual maturity. Both may be due to pubertal hormones causing an increase in MTL size when adolescents are young and a decrease in size when adolescents are older. Perhaps when girls are younger than age 10, gonadal steroid hormones initiate cellular mechanisms, like cellular proliferation or synaptogenesis, which could cause significant volume increases. But after age 10 or 11, the same hormones could facilitate cellular mechanisms like synaptic pruning, causing a decrease in size of the MTL. The results presented here, and those of prior studies (Neufang et al. 2008
), further support the notion that the impact of rising pubertal hormones on brain structure may vary depending on the sex of the individual and the state of brain maturation at the time the hormones are introduced. Also, as we state above, the offsets between maturation of cortical and limbic structures, or right and left hemispheres, may differ by gender, even in puberty-matched populations. The age range of male and female participants, which varies across studies, undoubtedly affects conclusions that can be drawn by comparing findings. Future longitudinal studies will be ideal in parsing hormonal or other age-related influences on changes in the trajectories of gray matter volumes.
Finally, note that this study is framed in a larger context of identifying puberty-specific, as opposed to other age-related, effects on adolescent brain maturation. Puberty-related changes in specific neural systems and structures are a critical component for building more complete accounts of both typical development and pathology. For example, rates of depression in females increase sharply during adolescence, with evidence that pubertal hormones are stronger predictors than age (Angold et al. 1999
). As noted by several researchers (Dahl 2004, 2008
; Nelson et al. 2005
; Blakemore and Choudhury 2006
; Dahl and Gunnar 2009
; see Steinberg and Cauffman 2006
), the clinical and social policy implications of understanding adolescent brain development require a deeper understanding of the interactions among the various neural systems that must integrate cognitive, affective, and social information processing, not just the individual systems for each of these functions. Future research designed to specifically disentangle pubertal effects on brain development, including longitudinal studies, can advance these goals and better inform clinical and social policy impacting the health of youth.