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Sexually dimorphic development of depression-related brain networks during healthy human adolescence

L. Dorfschmidt, R.A.I. Bethlehem, J. Seidlitz, F. Váša, S.R. White, R. Romero-García, M.G. Kitzbichler, A. Aruldass, I.M. Goodyer, P. Fonagy, P.B. Jones, R.J. Dolan, the NSPN consortium, N.A. Harrison, P.E. Vértes, E.T. Bullmore
doi: https://doi.org/10.1101/2020.07.06.184473
L. Dorfschmidt
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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  • For correspondence: ld548@cam.ac.uk
R.A.I. Bethlehem
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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J. Seidlitz
2Department X, University of Pennsylvania, Philadelphia 000 000, USA
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F. Váša
3Department of Neuroimaging, King’s College London, SE5 8AF, UK
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S.R. White
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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R. Romero-García
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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M.G. Kitzbichler
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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A. Aruldass
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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I.M. Goodyer
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
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P. Fonagy
7Research Department of Clinical, Educational and Health Psychology, University College London, London WC1E 6BT, United Kingdom
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P.B. Jones
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
6Cambridgeshire and Peterborough NHS Foundation Trust, Huntingdon, PE29 3RJ, UK
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R.J. Dolan
4Wellcome Trust Centre for Neuroimaging, University College London Institute of Neurology, University College London, London WC1N 3BG, UK
5Max Planck University College London Centre for Computational Psychiatry and Ageing Research, University College London, London WC1B 5EH, UK
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N.A. Harrison
8Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton, BN1 9RY, UK
9Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, CF94 4HQ, UK
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P.E. Vértes
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
10School of Mathematical Sciences, Queen Mary University of London, London E1 4NS, UK
11The Alan Turing Institute, London NW1 2DB, UK
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E.T. Bullmore
1Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, UK
6Cambridgeshire and Peterborough NHS Foundation Trust, Huntingdon, PE29 3RJ, UK
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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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Sexually dimorphic development of depression-related brain networks during healthy human adolescence
L. Dorfschmidt, R.A.I. Bethlehem, J. Seidlitz, F. Váša, S.R. White, R. Romero-García, M.G. Kitzbichler, A. Aruldass, I.M. Goodyer, P. Fonagy, P.B. Jones, R.J. Dolan, the NSPN consortium, N.A. Harrison, P.E. Vértes, E.T. Bullmore
bioRxiv 2020.07.06.184473; doi: https://doi.org/10.1101/2020.07.06.184473
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Sexually dimorphic development of depression-related brain networks during healthy human adolescence
L. Dorfschmidt, R.A.I. Bethlehem, J. Seidlitz, F. Váša, S.R. White, R. Romero-García, M.G. Kitzbichler, A. Aruldass, I.M. Goodyer, P. Fonagy, P.B. Jones, R.J. Dolan, the NSPN consortium, N.A. Harrison, P.E. Vértes, E.T. Bullmore
bioRxiv 2020.07.06.184473; doi: https://doi.org/10.1101/2020.07.06.184473

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