Introduction

There is a dramatic increase in publications about the adolescent brain, but there has been less attention given to the role of puberty in the process of brain development in adolescents. Puberty is about the neuroendocrinological development of the adrenal glands, gonads and the growth that leads to reproductive competence. There are also a lot of physical, psychological and social changes. Earlier there was the hypothesis that pubertal development lead to the changes in the brain that occur during adolescence. There was a lack of empirical data to support this hypothesis. Since then there have been studies conducted. This article evaluates the evidence that is found about changes in brain structure, function and connectivity that coincide with pubertal development.

Measuring pubertal development

Puberty comes with adrenarche (activation of the hypothalamic-pituitary-adrenal axis) and gonadarche (reactivation of hypothalamic-pituitary-gonadal axis which leads to gonadal activation) which leads to an increase in sex hormones. Age is often used as a determination for pubertal development in animals, but humans show variability in onset (range of 5 years) and tempo of puberty. Therefore it is important to have specific measures. In humans there are two ways of measuring the pubertal development: assessing levels of sex steroid hormones or by assessing objective physical development (like body hair, gonadal development, breast development, menarche).

With the help of phenotypic pubertal assessment scales, the length of exposure to hormones, the levels of exposure and the sensitivity to hormones can be determined. Examples of questionnaires are the Pubertal Development Scale (PDS) and the Tanner Scale. Participants (or parents, teachers, clinicians) answer questions about (their own) pubertal development. When using these questionnaires, the influence of the physical changes during puberty on how adolescents or others perceive themselves, can also be measured. There are also limitations to this kind of assessments, because when there are multiple assessors, there is variability in the answers. Also, the perception people have about their pubertal development is highly influenced by their (social) culture.     

There can also be hormonal measures using serum, saliva or urine to measure the extent of pubertal development. These are useful, because of their objectivity it can help to compare between individuals. There are again, limitations, such as that hormonal concentrations vary from day to day (diurnal variation) and that there are cyclical patterns. They are also influenced by environmental and internal stressors. There is also a lack of understanding of these variations.

Animal evidence for role of puberty and pubertal hormones in the development of the brain

It seems as if puberty is a second sensitive period for sex steroid hormone effects on the brain (the first period being the perinatal period). It could also be that the first sensitive period is until the end of puberty. Research shows that males who are deprived of testosterone during puberty exhibit less developed social and sexual behaviors. Estradiol during adolescence leads to female reproductive behavior in mice and it seems essential for female play behavior in adulthood. These results provide evidence for sex steroid-dependent organizational development and shows that puberty and pubertal hormones play a role in this.

Sex steroid hormone exposure leads to new cell formation and proliferation. Also it seems that these hormones have an influence on cell death: for example, female rats experience greater cell death than male rats during early puberty. So it seems that ovarian hormones may promote cell death in the medial prefrontal cortex (mPFC). A third way in which hormones during puberty influence brain structure and organization is that they influence the complexity and organization of neural dendrites in the brain.

Sex hormones also influence functional brain development. For instance, there have been androgen receptors (AR) and estrogen receptors (ER) found in the brain. These ARs and ERs are found in multiple regions in the brain where they vary in their concentration.

Human studies on the role of puberty and pubertal hormones in the development of the brain

There have been no sex differences found in timing of gray matter development during puberty between men and women, even though this was thought to be true for a long time. Improvements in research methods (specific measures of puberty and longitudinal designs from different cohorts) lead to more reliable findings.

Cortical development

The only published longitudinal study about cortical development indices that pubertal development was related to decreases in gray matter volume. Cortical gray matter contains cortical thickness and surface area.

Subcortical development

It seems that the relationship between puberty and structural brain development is complex and non-linear. It also interacts with the effects of age.

Sex differences in brain structure

The biggest sex difference regarding the brain is in overall volume. This specifically means that boys and men have on average larger brains than girls and women. This could be partially explained by differences in body size. This finding can have implications for research! Also, it seems that boys show greater variability in brain volumes than girls do.

Puberty and Functional Changes in Humans

It seems that during mid-adolescence there is heightened neural activity in the subcortical brain regions that are associated with processing emotions such as rewards, happiness and fear. Some researchers have suggested that this increase is because of heightened sex hormones. These sex hormones may increase the sensitivity in the brain regions. Researchers have also suggested that pubertal development advance social-cognitive processes which rely on social brain network areas. There is some evidence for these hypotheses, but the results are mixed.

Reward processing

When participants won during a gambling task, they showed heightened activity in their ventral striatum and ventral medial prefrontal cortex (VMPFC). These regions are often implicated to be the core of the reward network in the brain. Also, higher levels of testosterone (for both boys and girls) lead to more activity in the ventral striatum. For girls, higher levels of estradiol was correlated with stronger activity in the VMPFC. The latter finding could not be replicated, though the effect of testosterone has been established well over multiple studies. Testosterone also seems to lead to more risk-taking behavior. Estradiol does not seem to significantly relate to risk taking. It even seems as if estradiol leads to less risk-taking!

Processing faces that express emotion

It seems that the amygdala is active when processing emotion on faces, especially when these faces express fear. This neural response in the amygdala when viewing fearful faces peaks during mid-adolescence. But, there has also been found more amygdala activity when viewing happy faces and the results depend on sex. Results have shown that the higher the testosterone levels, the larger the increases in activity in the amygdala and in the ventral striatum when observing fearful faces. This was found for boys as well as for girls. Also, the individuals who showed an increase in ventral striatum activity also showed an increase in activity in the amygdala. This suggests that feelings of fear and of reward are both involved during processing facial expressions.

One study examined how males and females solved incongruent information. This would tell the researchers something about how emotional faces have an impact on thoughts and actions. The study was like this: participants were instructed to approach happy and avoid angry faces, this was the congruent condition. The incongruent condition was to avoid the happy faces and approach the angry faces. It seems that adolescents who had higher testosterone levels, regardless of their sex, showed more activity in the anterior prefrontal cortex for the incongruent condition. Adolescents who had lower levels of testosterone showed stronger activity in the amygdala for incongruent trials. These results show that during pubertal maturation activity from the limbic system (amygdala) shift to more prefrontal control activity (anterior prefrontal cortex).

Processing social cognitive emotions

It seems that pubertal development leads to neural-cognitive development in regions in the brain that are important for the processing of social-cognitive emotions. It is important to note that the literature on neural activity and pubertal changes is mixed: some studies do show that there are neural changes during puberty and others show that this is the other way around. There have not been many studies conducted that link neural development with behavior or that statistically compare sexes. This leads to less directions for future research. But, some directions for further research are to control for menstrual cycle, to include reports from the individual self as from others and to include hormone levels. Also, it is recommended to include boys as well as girls in the studies.

Sex-differences in puberty related neural activity

Reward processing develops in adolescence and there have been sex differences reported. For example, men showed more activation in brain regions for rewards when they could get monetary rewards and women showed greater activation in social-related rewards. During adulthood there were not always sex differences found. This could be because of the nature of the reward or sample sizes. It seems that emotional processing develops in adolescence. There also seems to be evidence for sex differences in adulthood: there seems to be greater activity in the amygdala and gray matter for women than for men and there seems to be greater activity in the insula and prefrontal cortex for men than for women.

In spatial tasks, there is a significant parietal activation for men and women, but women show more frontal lobe activation than men. This could be a compensation for their, on average poorer performance compared to men on spatial tasks. Also, when processing language, men and women use regions in their left hemisphere, but women show some activation in the right hemisphere too.

The role of puberty in brain connectivity

Connectivity in the brain is very important, because deficits lead to neuropsychiatric illnesses (depression, schizophrenia) which often start during puberty. Since sex hormones influence the connectivity, it is important to investigate the relation between the increase of sex hormones during puberty and brain connectivity.

Structural connectivity

The communication between brain regions occurs through axonal pathways that are the base of the structural white matter in the brain. The process of myelination of these pathways continue up to adolescence. The studies that investigate the white matter connections and the pubertal hormones are limited. There is, however, evidence for that estradiol and testosterone are related to the microstructure of white matter. Also, it seems that pubertal development may be related to the maturation of the white matter connectivity.

Functional connectivity

Adults show a more focal pattern in functional connectivity and long-distance connections than children and adolescents do. Children and adolescents show a more diffuse pattern of their functional connections. They also seem to have short-range connectivity. It also seems that during adolescence there is a fine-tuning of the connections between the subcortical and cortical prefrontal and limbic circuits.

It seems that for adults, injecting testosterone leads to disruption in the functional connectivity in their subcortical-cortical functions.

There also seems to be more connectivity in the default mode network (DMN) in women than in men. The DMN involves the posterior cingulate cortex, the medial prefrontal cortex, the angular cortex hippocampus, and precunes. These are the areas that are involved in mentalizing and memory. Men seem to have more connectivity in their visual and dorsal attention networks than women do.

Summary

So, there have not been many studies conducted that study the relation between pubertal hormones and brain connectivity. Recommendations for future research are to focus on the whole brain so that the effects of hormones on the brain can be better understood. This is because all the connections in the brain contribute to a network. Even small changes in parts of this network can have a large effect on the network as a whole. Connectomics is the study of all the connections in the brain.