Abstract
Adolescence is a period of critical development of the brain, that coincides with a sexually dimorphic increase in risk of depression for females. We hypothesized that there might be sexual dimorphisms in human brain network development underlying the dimorphism in depression. First, we tested for sex differences in parameters of brain network development (baseline connectivity at age 14, FC14, adolescent change in connectivity FC14–26, and maturational index, MI), measured repeatedly in resting state functional MRI scans from N=298 healthy young people aged 14-26 years, scanned a total of 520 times. We measured the maturational index (−1 < MI < 1) at each of 346 regions for each sex separately. Regions with negative MI were located in the cortical default mode network (DMN), the limbic system and subcortical nuclei. This cortico-subcortical system shared a disruptive pattern of development, e.g., weak functional connectivity with these regions at age 14 became stronger over the course of adolescence. This developmentally disruptive system was sexually dimorphic, i.e., the sex difference in MI was significantly less than zero at 83 regions. We then investigated the biological plausibility, and relevance to depression, of this fMRI-derived map of dimorphic brain development. It was significantly co-located with the cortical expression map of a weighted function of whole genome transcription, by partial least squares regression on prior adult post mortem data. Genes that were most strongly expressed in disruptively developing brain regions were enriched for X chromosome genes; genes specialized for perinatal and adolescent phases of cortical and subcortical development, respectively; and risk genes for major depressive disorder (MDD), defined by genome-wide significant association. The dimorphic development map was also significantly co-located with (i) brain regions activated by prior task-activated fMRI studies of reward and emotional processing and (ii) a map of adult MDD-related differences in functional connectivity from an independent case-control fMRI study (N=96). We conclude that sex differences in adolescent development of cortico-subcortical functional network connectivity were biologically validated by anatomical co-location with brain tissue expression of sex-, development- and MDD-related genes. Dimorphically disruptive development of DMN, limbic and subcortical connectivity could be relevant to the increased risk of depressive symptoms in adolescent females.
Competing Interest Statement
E.T.B. serves on the Scientific Advisory Board of Sosei Heptares.
Footnotes
↵** A complete list of the NSPN Consortium can be found in the SI Appendix.
