The early puberal brain: Work in progress. A study on genetic and hormonal influences

The timing and speed of developmental processes during healthy puberty might be of critical importance to optimal adult functioning. Indeed, diseases that affect the brain at a young age, such as schizophrenia, are likely to have their origin in this period. The general aim of this thesis was to explore possible mechanisms contributing to individual variation in brain structure at the brink of puberty. Two lines of research were conducted: (1) The relative importance of genetic and environmental influences on global and regional brain volume (2) The association between hypothalamus-pituitary-gonadal (HPG)-axis hormones and brain structure. Research was based on a sample of 107 twin-families consisting of 9-year-old healthy twin pairs (45 monozygotic (MZ) and 62 dizygotic (DZ) pairs) and one of their full siblings (N=85) between 10 and 15 years of age. Results showed that in 9-year-olds, global brain volumes are already remarkably heritable, with estimates ranging from 77% (i.e., gray matter) to 94% (i.e., total brain volume). Regionally, white matter density in posterior parts of the fronto-occipital and superior longitudinal fascicles, cingulum and corpus callosum were found to be significantly heritable with estimates ranging up to 93%. Interestingly, the areas within gray matter density that were significantly heritable were substantially smaller, and included the amygdala and temporal lobes. The onset of secondary sexual characteristics (SSC) of puberty was associated with decreased frontal and parietal gray matter densities and was mainly found in girls. Nocturnal rises in luteinizing hormone (LH) levels from the pituitary mark the beginning of puberty in both boys and girls, even before SSC of puberty are visible. An increased production of LH was associated with larger global and focal white matter. This association was driven by a common genetic factor. LH-levels were however not related to global or regional gray matter. The pubertal brain might respond differentially to changing hormone levels over time, therefore the possible association between sex steroids testosterone and estradiol and brain structure was studied in a more advanced stage of puberty. Indeed in girls, a higher level of estradiol was mainly associated with decreased gray matter within the prefrontal, parietal and temporal cortices (not with white matter). At this age, testosterone levels were not associated with gray or white matter. Sex differences in brain structure were not related to sex steroid levels. The last study of this thesis describes the possible influence of the intrauterine presence of a male co-twin on masculinization of brain volume, possibly mediated by higher prenatal testosterone exposure. Results showed that, corrected for larger global brain volumes in boys, children with a male-co twin showed a larger total brain and cerebellar volume versus children with a female-co-twin. It might be suggested that prenatal testosterone plays a role in development of sex differences in the human brain. This thesis contains the first series of studies that has provided important new leads into the complex interplay between genetic and environmental factors, hormones and brain structure in this critical period of life.