The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n= 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.

During evolution, the mammalian cerebral cortex has expanded disproportionately to brain volume. As a consequence, most mammals with large brains have profusely convoluted cortices. The human cortex is a good example of this trend, however, given the large variability in human brain size, it is not clear how cortical folding varies from the smallest to the largest brains. We analyzed cortical folding in a large cohort of human subjects exhibiting a 1.7-fold variation in brain volume. We show that the same disproportionate increase of cortical surface relative to brain volume observed across species can be also observed across human brains: the largest brains can have up to 20% more surface than a scaled-up small brain. We introduce next a novel local measure of cortical folding, and we show that the correlation between cortical folding and size varies along a rostro-caudal gradient, being especially significant in the prefrontal cortex. The expansion of the cerebral cortex, and in particular that of its prefrontal region, is a major evolutionary landmark in the emergence of human cognition. Our results suggest that this may be, at least in part, a natural outcome of increasing brain size.

Neurobiological underpinnings of cortical thickness in the human brain are largely unknown. Here we use cell-type-specific gene markers to evaluate the contribution of 9 neural cell-types in explaining inter-regional variations in cortical thickness and age-related cortical thinning in the adolescent brain. Gene-expression data were derived from the Allen Human Brain Atlas (and validated using the BrainSpan Atlas). Values of cortical thickness/thinning were obtained with magnetic resonance imaging in a sample of 987 adolescents. We show that inter-regional profiles in cortical thickness relate to those in the expression of genes marking CA1 pyramidal cells, astrocytes, and microglia; taken together, the 3 cell types explain 70% of regional variation in cortical thickness. We also show that inter-regional profiles in cortical thinning relate to those in the expression of genes marking CA1 and S1 pyramidal cells, astrocytes and microglia. Using Gene Ontology analysis, we demonstrate that the difference in the contribution of CA1 and S1 pyramidal cells may relate to biological processes such as neuronal plasticity and potassium channel activity, respectively. This "virtual histology" approach (scripts provided) can be used to examine neurobiological underpinnings of cortical profiles associated with development, aging, and various disorders.