The human brain undergoes various phases of active development during the lifespan. While these neurodevelopmental processes are fundamental to the emergence of new cognitive and social capacities, they also coincide with a period of increased risk of neuropsychiatric disorders, which generally have their highest rates of clinical incidence in the first two decades. Since many neuropsychiatric disorders display sex differences in both prevalence or clinical presentation, this raises the question of whether there are underlying sex differences in processes of adolescent brain development. In this thesis, functional and structural magnetic resonance imaging (MRI) is used to map normative brain development, in adolescence and later life, which might differentially predispose men and women to different levels of risk for adolescent and adult mental illness.

First, Chapter 1 reviews relevant research on understanding developmental changes in the brain during adolescence, focusing on prior studies of normative sexual differentiation of neurodevelopmental trajectories, and vulnerabilities associated with developmental changes.

Chapter 2 investigates whether there are sex differences in normative adolescent development of functional connectivity networks, using an accelerated longitudinal cohort of healthy adolescents aged 14-25 years (N=298), comprising 2 or 3 repeated scans on most participants. Sexually divergent development of functional connectivity was identified in the default mode network, limbic cortex, and subcortical structures. In these regions, females were shown to have a more “disruptive” pattern of development, whereby weak functional connectivity at age 14 became stronger during adolescence, specifically in a cortico-subcortical system including many areas of the default mode network. Using open data on whole genome transcription at multiple sites in adult post mortem brains (provided by the Allen Brain Institute), this fMRI-derived map of sexually divergent brain network development was found to be spatially co-located with brain regions where transcription was enriched for genes on the X chromosome and neurodevelopmentally relevant genes.

Chapter 3 starts from the hypothesis that the known sex difference in the prevalence of major depressive disorder (MDD), with increased rates of diagnosis in adolescent females compared to males, could be the psychological or clinical representation of underlying sex differences in adolescent brain network development. To test this hypothesis, the sexually differentiated fMRI network identified in the previous chapter was further contextualized. The fMRI-derived map of sexually divergent brain network development was found to be co- located with prior loci of reward-related brain activation; a map of functional dysconnectivity in major depressive disorder derived from a prior, independent case-control study of adult MDD; and an adult brain gene transcriptional profile enriched for MDD risk genes, as defined by prior genome-wide association studies of MDD. These results collectively suggested that normative sexual divergence in adolescent development of a cortico-subcortical brain functional network was psychologically, anatomically and genetically relevant to depression.

Chapter 4 reviews literature on similarity-based structural brain networks. Subsequently, Chapter 5 investigates adolescent changes in structural brain network development using morphometric similarity networks derived from the same accelerated longitudinal cohort of healthy adolescents previously used for analysis of functional network development. Morphometric similarity was found to increase during adolescence in insula and limbic regions and to decrease elsewhere in the brain. This profile of decreasing morphometric similarity, or increasing dissimilarity, was associated with the well-known adolescent process of cortical shrinkage, i.e., reduced macro-structural measures of cortical thickness, and with increased magnetization transfer, a micro-structural measure of intra-cortical myelination. Regional nodes of the morphometric similarity networks that became more dissimilar, putatively more differentiated in terms of their cyto- and myelo-architectonics during adolescence, were also found to de-couple from brain functional connectivity, suggesting that increasing morphometric dissimilarity may reflect adolescent development of functional independence.

In an effort to move from group level to subject-specific analyses, and acknowledging that brain development is not restricted to adolescence but is a continuous process throughout life, in Chapter 6 a total of 41 prior studies, including a total of 90,000 structural MRI scans, were aggregated to estimate lifespan trajectories of normative subcortical development from 180 days post conception to 100 years of age. This analysis identified novel milestones of subcortical volume development; in particular a set of subcortical regions was defined that reached peak grey matter volume during adolescence. Furthermore, subject-specific deviations from normative, non-linear neurodevelopmental trajectories? were derived and used to estimate case-control differences in subcortical volume across the lifespan in multiple neuropsychiatric disorders, demonstrating the potential clinical applications of these normative subcortical growth charts.

In Chapter 7, these new experimental results on adolescent and life-span development of functional and structural brain networks, and subcortical grey matter volume were summarised and drawn together, highlighting how these insights are aligned with each other and with the existing scientific literature on brain development, sexual differentiation and risk of psychiatric disorders.