Greater male than female variability in regional brain structure across the lifespan

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Knut K. Kolskår | Lara M. Wierenga | Erick Jorge Canales-Rodríguez | Dan J Stein | B. Franke | O. Andreassen | V. Calhoun | I. Hickie | N. Jahanshad | P. Thompson | E. Crone | H. Walter | H. Völzke | R. Gur | A. Saykin | J. West | B. McDonald | P. Szeszko | A. James | R. Gur | H. Whalley | A. Simmons | Steven C. R. Williams | P. Conrod | H. H. Hulshoff Pol | D. Glahn | R. Salvador | F. Castellanos | L. Nyberg | A. Holmes | J. Smoller | N. Martin | L. Westlye | I. Agartz | B. Mazoyer | F. Crivello | J. Roffman | J. Buitelaar | A. Anticevic | S. Frangou | A. McIntosh | J. Lagopoulos | I. Gotlib | M. Sacchet | V. Clark | P. Sachdev | J. Trollor | H. Brodaty | W. Wen | P. Pauli | L. Lázaro | N. Bargalló | B. Harrison | I. Veer | D. Veltman | D. Dima | G. D. de Zubicaray | D. Boomsma | E. D. de Geus | M. Portella | B. Weber | S. Ehrlich | O. Gruber | A. Kalnin | T. Banaschewski | C. K. Tamnes | C. Mcdonald | R. Brouwer | S. Fisher | S. Hohmann | D. Brandeis | D. Wolf | C. Soriano-Mas | G. Pergola | A. Bertolino | E. Jönsson | H. Grabe | K. Mcmahon | M. Wright | K. Wittfeld | N. Hosten | T. Satterthwaite | S. Borgwardt | A. Voineskos | C. Hartman | G. Busatto | J. Raduà | C. Davey | C. Huyser | K. Sim | Lei Wang | B. Krämer | C. Ching | M. Hoogman | M. Klein | Phil H. Lee | L. Strike | D. Heslenfeld | P. Hoekstra | D. Cannon | O. A. van den Heuvel | J. Menchón | M. Zanetti | Y. Paloyelis | A. den Braber | D. van’t Ent | J. Fouche | A. Uhlmann | A. Di Giorgio | Jiyang Jiang | M. Serpa | M. Machielsen | L. Koenders | L. de Haan | K. Alpert | X. Caseras | S. Hatton | J. Oosterlaan | P. Asherson | J. Kuntsi | A. Reif | M. Aghajani | Pedro G. P. Rosa | E. Pomarol-Clotet | Geneviève Richard | D. Alnæs | P. Gruner | C. Lochner | I. Martínez-Zalacaín | D. Mataix-Cols | T. Gurholt | S. Thomopoulos | I. Sommer | Sarah Baumeister | R. Baur-Streubel | T. Chaim-Avancini | A. Conzelmann | Yuliya Yoncheva | G. Ziegler | D. van der Meer | B. Haatveit | A. Breier | A. Tomyshev | E. Dickie | P. Fuentes-Claramonte | G. Doucet | F. Howells | A. Bonvino | A. D. Giorgio | T. Akudjedu | H. Temmingh | S. Sarró | Josiane Bourque | J. Naaijen | S. Maingault | J. Joska | A. Albajes-Eizagirre | Yang Wang | D. Alnaes | I. Lebedeva | G. McPhilemy | J. Bourque

[1]  Yang Wang,et al.  Subcortical Volume Trajectories across the Lifespan: Data from 18,605 healthy individuals aged 3-90 years , 2020, bioRxiv.

[2]  Yang Wang,et al.  Cortical Thickness Trajectories across the Lifespan: Data from 17,075 healthy individuals aged 3-90 years , 2020, bioRxiv.

[3]  Athanasia M. Mowinckel,et al.  Visualisation of Brain Statistics with R-packages ggseg and ggseg3d , 2019, 1912.08200.

[4]  Christos Davatzikos,et al.  Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan , 2019, NeuroImage.

[5]  R. Shinohara,et al.  Sex differences in Variability of Brain Structure Across the Lifespan , 2019, bioRxiv.

[6]  G. Northoff,et al.  “Average is good, extremes are bad” – Non-linear inverted U-shaped relationship between neural mechanisms and functionality of mental features , 2019, Neuroscience & Biobehavioral Reviews.

[7]  S. Djurovic,et al.  Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk. , 2019, JAMA psychiatry.

[8]  Margaret D. King,et al.  Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process? , 2019, Biological Psychiatry.

[9]  Lara M. Wierenga,et al.  Sex Effects on Development of Brain Structure and Executive Functions: Greater Variance than Mean Effects , 2019, Journal of Cognitive Neuroscience.

[10]  S. Bölte,et al.  Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models , 2018, bioRxiv.

[11]  Petter Laake,et al.  A Key Characteristic of Sex Differences in the Developing Brain: Greater Variability in Brain Structure of Boys than Girls , 2018, Cerebral cortex.

[12]  Mark E Bastin,et al.  Sex Differences in the Adult Human Brain: Evidence from 5216 UK Biobank Participants , 2017, bioRxiv.

[13]  Lara M. Wierenga,et al.  Unraveling age, puberty and testosterone effects on subcortical brain development across adolescence , 2018, Psychoneuroendocrinology.

[14]  Chang Liu,et al.  Development of subcortical volumes across adolescence in males and females: A multisample study of longitudinal changes , 2017, NeuroImage.

[15]  Cyril R Pernet,et al.  Beyond differences in means: robust graphical methods to compare two groups in neuroscience , 2017, bioRxiv.

[16]  S. Blakemore,et al.  Development of the Cerebral Cortex across Adolescence: A Multisample Study of Inter-Related Longitudinal Changes in Cortical Volume, Surface Area, and Thickness , 2017, The Journal of Neuroscience.

[17]  Dhruv Marwha,et al.  Meta-analysis reveals a lack of sexual dimorphism in human amygdala volume , 2017, NeuroImage.

[18]  N. Jahanshad,et al.  Multimodal neuroimaging of male and female brain structure in health and disease across the life span , 2016, Journal of neuroscience research.

[19]  Heath R. Pardoe,et al.  Motion and morphometry in clinical and nonclinical populations , 2016, NeuroImage.

[20]  Richard A. Lippa,et al.  Joel et al.'s method systematically fails to detect large, consistent sex differences , 2016, Proceedings of the National Academy of Sciences.

[21]  Anne Fausto-Sterling,et al.  Beyond sex differences: new approaches for thinking about variation in brain structure and function , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[22]  Christian Monseur,et al.  Gender differences in variability and extreme scores in an international context , 2016, Large-scale Assessments in Education.

[23]  Wenli Ma,et al.  The human hippocampus is not sexually-dimorphic: Meta-analysis of structural MRI volumes , 2016, NeuroImage.

[24]  Daniel S. Margulies,et al.  Sex beyond the genitalia: The human brain mosaic , 2015, Proceedings of the National Academy of Sciences.

[25]  M. Dylan Tisdall,et al.  Head motion during MRI acquisition reduces gray matter volume and thickness estimates , 2015, NeuroImage.

[26]  Kosha Ruparel,et al.  Within-individual variability in neurocognitive performance: age- and sex-related differences in children and youths from ages 8 to 21. , 2014, Neuropsychology.

[27]  S. Baron-Cohen,et al.  Neuroscience and Biobehavioral Reviews a Meta-analysis of Sex Differences in Human Brain Structure , 2022 .

[28]  J. Nathans,et al.  Cellular Resolution Maps of X Chromosome Inactivation: Implications for Neural Development, Function, and Disease , 2014, Neuron.

[29]  Janet Shibley Hyde,et al.  Gender similarities and differences. , 2014, Annual review of psychology.

[30]  L. Engqvist,et al.  THE VARIABILITY IS IN THE SEX CHROMOSOMES , 2013, Evolution; international journal of organic evolution.

[31]  N. Logothetis,et al.  Scaling Brain Size, Keeping Timing: Evolutionary Preservation of Brain Rhythms , 2013, Neuron.

[32]  Chi-Hua Chen,et al.  Genetics of brain structure: Contributions from the vietnam era twin study of aging , 2013, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[33]  E. Crone,et al.  Sex differences and structural brain maturation from childhood to early adulthood , 2013, Developmental Cognitive Neuroscience.

[34]  R. McCrae,et al.  Do Men Vary More than Women in Personality? A Study in 51 Cultures. , 2013, Journal of research in personality.

[35]  Bruce Fischl,et al.  A Comparison of Heritability Maps of Cortical Surface Area and Thickness and the Influence of Adjustment for Whole Brain Measures: A Magnetic Resonance Imaging Twin Study , 2012, Twin Research and Human Genetics.

[36]  A. Arnold The end of gonad-centric sex determination in mammals. , 2012, Trends in genetics : TIG.

[37]  Bruce Fischl,et al.  Genetic and environmental contributions to regional cortical surface area in humans: a magnetic resonance imaging twin study. , 2011, Cerebral cortex.

[38]  Dick F Swaab,et al.  Sex Differences in the Brain, Behavior, and Neuropsychiatric Disorders , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[39]  I. Craig,et al.  Commentary on “A Role for the X Chromosome in Sex Differences in Variability in General Intelligence?” (Johnson et al., 2009) , 2009, Perspectives on psychological science : a journal of the Association for Psychological Science.

[40]  I. Deary,et al.  A Role for the X Chromosome in Sex Differences in Variability in General Intelligence? , 2009, Perspectives on psychological science : a journal of the Association for Psychological Science.

[41]  P. Laake,et al.  Greater intrasex phenotype variability in males than in females is a fundamental aspect of the gender differences in humans. , 2009, Developmental psychobiology.

[42]  S. Kvaløy,et al.  [Use of radiotherapy in South-Eastern Norway Regional Health Authority]. , 2009, Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke.

[43]  I. Deary,et al.  Sex Differences in Variability in General Intelligence: A New Look at the Old Question , 2008, Perspectives on psychological science : a journal of the Association for Psychological Science.

[44]  A. Arnold,et al.  Sex difference in neural tube defects in p53‐null mice is caused by differences in the complement of X not Y genes , 2008, Developmental neurobiology.

[45]  Nicolai Meinshausen,et al.  Quantile Regression Forests , 2006, J. Mach. Learn. Res..

[46]  Robert Plomin,et al.  Sex differences in variance of intelligence across childhood. , 2006 .

[47]  Anders M. Dale,et al.  An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest , 2006, NeuroImage.

[48]  Alan C. Evans,et al.  Mapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI , 2006, NeuroImage.

[49]  S. Grillner,et al.  Mechanisms for selection of basic motor programs – roles for the striatum and pallidum , 2005, Trends in Neurosciences.

[50]  T. Robbins,et al.  Inhibition and the right inferior frontal cortex , 2004, Trends in Cognitive Sciences.

[51]  Edith V. Sullivan,et al.  Morphological changes in aging brain structures are differentially affected by time-linked environmental influences despite strong genetic stability , 2004, Neurobiology of Aging.

[52]  Leo Breiman,et al.  Random Forests , 2001, Machine Learning.

[53]  Sarah A. Mustillo,et al.  Prevalence and development of psychiatric disorders in childhood and adolescence. , 2003, Archives of general psychiatry.

[54]  E. Maguire,et al.  The Human Hippocampus and Spatial and Episodic Memory , 2002, Neuron.

[55]  N. Makris,et al.  Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. , 2002, Archives of general psychiatry.

[56]  A. Dale,et al.  Whole Brain Segmentation Automated Labeling of Neuroanatomical Structures in the Human Brain , 2002, Neuron.

[57]  R. Kahn,et al.  Quantitative genetic modeling of variation in human brain morphology. , 2001, Cerebral cortex.

[58]  G. Dawson,et al.  The role of early experience in shaping behavioral and brain development and its implications for social policy , 2000, Development and Psychopathology.

[59]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[60]  A. Dale,et al.  High‐resolution intersubject averaging and a coordinate system for the cortical surface , 1999, Human brain mapping.

[61]  Nancy B. Spinner,et al.  Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing , 1997, Nature Genetics.

[62]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[63]  G. Alliger,et al.  Averaging Untransformed Variance Ratios Can Be Misleading: A Comment on Feingold , 1992 .

[64]  Charles F. Stevens,et al.  How Cortical Interconnectedness Varies with Network Size , 1989, Neural Computation.

[65]  W. D. Smith,et al.  Perspective , 1974 .

[66]  W. C. Spackman Correspondence , 1921, The Indian medical gazette.