Sex Differences in the Adult Human Brain: Evidence from 5216 UK Biobank Participants

Abstract Sex differences in the human brain are of interest for many reasons: for example, there are sex differences in the observed prevalence of psychiatric disorders and in some psychological traits that brain differences might help to explain. We report the largest single-sample study of structural and functional sex differences in the human brain (2750 female, 2466 male participants; mean age 61.7 years, range 44–77 years). Males had higher raw volumes, raw surface areas, and white matter fractional anisotropy; females had higher raw cortical thickness and higher white matter tract complexity. There was considerable distributional overlap between the sexes. Subregional differences were not fully attributable to differences in total volume, total surface area, mean cortical thickness, or height. There was generally greater male variance across the raw structural measures. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale study provides a foundation for attempts to understand the causes and consequences of sex differences in adult brain structure and function.

[1]  Joanna M. Wardlaw,et al.  Brain cortical characteristics of lifetime cognitive ageing , 2017, Brain Structure and Function.

[2]  J. Manson,et al.  Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry , 2016, PloS one.

[3]  Martin Voracek,et al.  Meta-analysis of associations between human brain volume and intelligence differences: How strong are they and what do they mean? , 2015, Neuroscience & Biobehavioral Reviews.

[4]  Manuel Graña,et al.  Model‐based analysis of multishell diffusion MR data for tractography: How to get over fitting problems , 2012, Magnetic resonance in medicine.

[5]  A. Arnold,et al.  Sex differences in mouse cortical thickness are independent of the complement of sex chromosomes , 2003, Neuroscience.

[6]  J. Viña,et al.  Why women have more Alzheimer's disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. , 2010, Journal of Alzheimer's disease : JAD.

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

[8]  P. Costa,et al.  Gender differences in personality traits across cultures: robust and surprising findings. , 2001, Journal of personality and social psychology.

[9]  M. Jenkinson Non-linear registration aka Spatial normalisation , 2007 .

[10]  J. Rapoport,et al.  Variability of human brain structure size: ages 4–20 years , 1997, Psychiatry Research: Neuroimaging.

[11]  H. Aronen,et al.  [Functional magnetic resonance imaging of the brain]. , 1997, Duodecim; laaketieteellinen aikakauskirja.

[12]  G. J. de Vries,et al.  Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/en.2003-1504 Minireview: Sex Differences in Adult and Developing Brains: Compensation, Compensation, Compensation , 2022 .

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

[14]  Efstathios D. Gennatas,et al.  Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood , 2017, The Journal of Neuroscience.

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

[16]  Tim Olds,et al.  Worldwide variation in the performance of children and adolescents: An analysis of 109 studies of the 20-m shuttle run test in 37 countries , 2006, Journal of sports sciences.

[17]  Avshalom Caspi,et al.  Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. , 2003, Journal of child psychology and psychiatry, and allied disciplines.

[18]  Arthur W. Toga,et al.  The construction of a Chinese MRI brain atlas: A morphometric comparison study between Chinese and Caucasian cohorts , 2010, NeuroImage.

[19]  R. Haier,et al.  The Parieto-Frontal Integration Theory (P-FIT) of intelligence: Converging neuroimaging evidence , 2007, Behavioral and Brain Sciences.

[20]  Stephen M. Smith,et al.  Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm , 2001, IEEE Transactions on Medical Imaging.

[21]  Sukhwinder S. Shergill,et al.  Gender Differences in White Matter Microstructure , 2012, PloS one.

[22]  Angelica Ronald,et al.  Examining and interpreting the female protective effect against autistic behavior , 2013, Proceedings of the National Academy of Sciences.

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

[24]  Stephen Machin,et al.  Global Sex Differences in Test Score Variability , 2008, Science.

[25]  Michael Scharkow,et al.  The Relative Trustworthiness of Inferential Tests of the Indirect Effect in Statistical Mediation Analysis , 2013, Psychological science.

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

[27]  Brian A. Nosek,et al.  Power failure: why small sample size undermines the reliability of neuroscience , 2013, Nature Reviews Neuroscience.

[28]  G. J. Vries,et al.  Minireview: Sex differences in adult and developing brains: compensation, compensation, compensation. , 2004 .

[29]  Steve D. M. Brown,et al.  Prevalence of sexual dimorphism in mammalian phenotypic traits , 2017, Nature Communications.

[30]  J. Archer Sex Differences in Aggression in Real-World Settings: A Meta-Analytic Review , 2004 .

[31]  C. Mazure,et al.  Sex differences in Alzheimer's disease and other dementias , 2016, The Lancet Neurology.

[32]  D. Madden,et al.  Disconnected aging: Cerebral white matter integrity and age-related differences in cognition , 2014, Neuroscience.

[33]  R. Gur,et al.  Complementarity of sex differences in brain and behavior: From laterality to multimodal neuroimaging , 2017, Journal of neuroscience research.

[34]  Margaret M McCarthy,et al.  Reframing sexual differentiation of the brain , 2011, Nature Neuroscience.

[35]  Richard D. Morey,et al.  Baysefactor: Computation of Bayes Factors for Common Designs , 2018 .

[36]  Joanna M Wardlaw,et al.  What are White Matter Hyperintensities Made of? , 2015, Journal of the American Heart Association.

[37]  Mark E Bastin,et al.  Ageing and brain white matter structure in 3,513 UK Biobank participants , 2016, Nature Communications.

[38]  W. Revelle psych: Procedures for Personality and Psychological Research , 2017 .

[39]  Stephen M. Smith,et al.  A Bayesian model of shape and appearance for subcortical brain segmentation , 2011, NeuroImage.

[40]  M. V. D. Heuvel,et al.  Exploring the brain network: A review on resting-state fMRI functional connectivity , 2010, European Neuropsychopharmacology.

[41]  R. Woods,et al.  Sex differences in cortical thickness mapped in 176 healthy individuals between 7 and 87 years of age. , 2007, Cerebral cortex.

[42]  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.

[43]  Stephen M. Smith,et al.  Probabilistic independent component analysis for functional magnetic resonance imaging , 2004, IEEE Transactions on Medical Imaging.

[44]  Richard K. Olson,et al.  Explaining the sex difference in dyslexia , 2017, Journal of child psychology and psychiatry, and allied disciplines.

[45]  I. Zucker,et al.  Sex bias in neuroscience and biomedical research , 2011, Neuroscience & Biobehavioral Reviews.

[46]  Ian J. Deary,et al.  Brother–sister differences in the g factor in intelligence: analysis of full, opposite-sex siblings from the NLSY1979 , 2007 .

[47]  Evert F. S. van Velsen,et al.  Brain cortical thickness in the general elderly population: The Rotterdam Scan Study , 2013, Neuroscience Letters.

[48]  I. Deary,et al.  Intelligence and educational achievement , 2007 .

[49]  F. Collins,et al.  A new initiative on precision medicine. , 2015, The New England journal of medicine.

[50]  Jean-Philippe Thiran,et al.  Accelerated Microstructure Imaging via Convex Optimization (AMICO) from diffusion MRI data , 2015, NeuroImage.

[51]  Alan C. Evans,et al.  Changes in thickness and surface area of the human cortex and their relationship with intelligence. , 2015, Cerebral cortex.

[52]  P. Matthews,et al.  Multimodal population brain imaging in the UK Biobank prospective epidemiological study , 2016, Nature Neuroscience.

[53]  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.

[54]  Jonathan J. Evans,et al.  Cognitive Test Scores in UK Biobank: Data Reduction in 480,416 Participants and Longitudinal Stability in 20,346 Participants , 2016, PloS one.

[55]  L Penke,et al.  Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age , 2013, Molecular Psychiatry.

[56]  B. McEwen,et al.  Understanding the broad influence of sex hormones and sex differences in the brain , 2017, Journal of neuroscience research.

[57]  Warren D. Taylor,et al.  Variability in Frontotemporal Brain Structure: The Importance of Recruitment of African Americans in Neuroscience Research , 2010, PloS one.

[58]  L. Cahill Why sex matters for neuroscience , 2006, Nature Reviews Neuroscience.

[59]  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.

[60]  Stephen M. Smith,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

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

[62]  Christian Windischberger,et al.  Toward discovery science of human brain function , 2010, Proceedings of the National Academy of Sciences.

[63]  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.

[64]  L. Jäncke,et al.  Brain size, sex, and the aging brain , 2015, Human brain mapping.

[65]  A. Dale,et al.  Thinning of the cerebral cortex in aging. , 2004, Cerebral cortex.

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

[67]  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.

[68]  S. Sala,et al.  Handbook of Frontal Lobe Assessment (DRAFT) , 2015 .

[69]  F. Schmidt,et al.  Linking "big" personality traits to anxiety, depressive, and substance use disorders: a meta-analysis. , 2010, Psychological bulletin.

[70]  R. Kahn,et al.  Sex differences in the risk of schizophrenia: evidence from meta-analysis. , 2003, Archives of general psychiatry.

[71]  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.

[72]  Alex R. Smith,et al.  Sex differences in the structural connectome of the human brain , 2013, Proceedings of the National Academy of Sciences.

[73]  Mathias Benedek,et al.  Sex differences in the IQ-white matter microstructure relationship: A DTI study , 2014, Brain and Cognition.

[74]  Meng Li,et al.  Gender consistency and difference in healthy adults revealed by cortical thickness , 2010, NeuroImage.

[75]  Alan C. Evans,et al.  Patterns of cortical degeneration in an elderly cohort with cerebral small vessel disease , 2010, Human brain mapping.

[76]  M. Voracek,et al.  Why can't a man be more like a woman? Sex differences in Big Five personality traits across 55 cultures. , 2008, Journal of personality and social psychology.

[77]  Timothy Edward John Behrens,et al.  Characterization and propagation of uncertainty in diffusion‐weighted MR imaging , 2003, Magnetic resonance in medicine.

[78]  Angela R. Laird,et al.  Definition and characterization of an extended social-affective default network , 2014, Brain Structure and Function.

[79]  J. Gross,et al.  The cognitive control of emotion , 2005, Trends in Cognitive Sciences.

[80]  Karen F. Berman,et al.  Regional Variations in Brain Gyrification Are Associated with General Cognitive Ability in Humans , 2016, Current Biology.

[81]  Zlatan Krizan,et al.  Evaluating gender similarities and differences using metasynthesis. , 2015, The American psychologist.

[82]  Daniel C. Alexander,et al.  NODDI: Practical in vivo neurite orientation dispersion and density imaging of the human brain , 2012, NeuroImage.

[83]  Bruce Fischl,et al.  Geometrically Accurate Topology-Correction of Cortical Surfaces Using Nonseparating Loops , 2007, IEEE Transactions on Medical Imaging.

[84]  P. Pye-Smith The Descent of Man, and Selection in Relation to Sex , 1871, Nature.

[85]  C. Sudlow,et al.  Enlarged perivascular spaces and cerebral small vessel disease , 2013, International journal of stroke : official journal of the International Stroke Society.

[86]  Emma Ashwin,et al.  Fetal Testosterone Influences Sexually Dimorphic Gray Matter in the Human Brain , 2012, The Journal of Neuroscience.

[87]  A. Craig,et al.  How do you feel — now? The anterior insula and human awareness , 2009, Nature Reviews Neuroscience.

[88]  A M Dale,et al.  Measuring the thickness of the human cerebral cortex from magnetic resonance images. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[89]  P. Elliott,et al.  UK Biobank: Current status and what it means for epidemiology , 2012 .

[90]  C. Sudlow,et al.  Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia , 2015, Molecular Psychiatry.

[91]  Brent L. Hughes,et al.  Prefrontal-Subcortical Pathways Mediating Successful Emotion Regulation , 2008, Neuron.

[92]  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.

[93]  Stefan Klein,et al.  Improving alignment in Tract-based spatial statistics: Evaluation and optimization of image registration , 2013, NeuroImage.

[94]  So Yoon Yoon,et al.  A Meta-Analysis on Gender Differences in Mental Rotation Ability Measured by the Purdue Spatial Visualization Tests: Visualization of Rotations (PSVT:R) , 2013 .

[95]  P. Sundgren,et al.  Diffusion tensor imaging of the brain: review of clinical applications , 2004, Neuroradiology.

[96]  Gina Rippon,et al.  Recommendations for sex/gender neuroimaging research: key principles and implications for research design, analysis, and interpretation , 2014, Front. Hum. Neurosci..

[97]  L Penke,et al.  Brain white matter tract integrity as a neural foundation for general intelligence , 2012, Molecular Psychiatry.

[98]  Elizabeth Jefferies,et al.  Situating the default-mode network along a principal gradient of macroscale cortical organization , 2016, Proceedings of the National Academy of Sciences.

[99]  R. Woods,et al.  Gender effects on cortical thickness and the influence of scaling , 2006, Human brain mapping.

[100]  Mark W. Woolrich,et al.  Probabilistic diffusion tractography with multiple fibre orientations: What can we gain? , 2007, NeuroImage.

[101]  R. Collins What makes UK Biobank special? , 2012, The Lancet.

[102]  Ivan Toni,et al.  On the relationship between the “default mode network” and the “social brain” , 2012, Front. Hum. Neurosci..

[103]  J. Gilmore,et al.  Impact of sex and gonadal steroids on neonatal brain structure. , 2014, Cerebral cortex.

[104]  Dustin Scheinost,et al.  Sex differences in normal age trajectories of functional brain networks , 2015, Human brain mapping.

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

[106]  N. Gemmell,et al.  Mother's curse: the effect of mtDNA on individual fitness and population viability. , 2004, Trends in ecology & evolution.

[107]  L. Cahill An issue whose time has come , 2017, Journal of neuroscience research.

[108]  I. Deary,et al.  Are Apparent Sex Differences in Mean IQ Scores Created in Part by Sample Restriction and Increased Male Variance , 2009 .

[109]  Sven Bergmann,et al.  A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. , 2014, American journal of human genetics.

[110]  J. Fish,et al.  Handbook of Frontal Lobe Assessment , 2016, Neuropsychological rehabilitation.

[111]  Camilla L. Nord,et al.  Power-up: A Reanalysis of 'Power Failure' in Neuroscience Using Mixture Modeling , 2017, The Journal of Neuroscience.

[112]  Ruben C. Gur,et al.  Sex differences in brain and behavior in adolescence: Findings from the Philadelphia Neurodevelopmental Cohort , 2016, Neuroscience & Biobehavioral Reviews.

[113]  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.

[114]  Christopher Rorden,et al.  Image Processing and Quality Control for the first 10,000 Brain Imaging Datasets from UK Biobank , 2017 .

[115]  P. Laake,et al.  Gender and the 2003 Quality Reform in higher education in Norway , 2009 .

[116]  Richard J. Haier,et al.  Sex Differences in Brain Volume Are Related to Specific Skills, Not to General Intelligence. , 2012 .

[117]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[118]  Daniel P. Kennedy,et al.  The social brain in psychiatric and neurological disorders , 2012, Trends in Cognitive Sciences.

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

[120]  Stuart J. Ritchie,et al.  Sex Differences in the Adult Human Brain: Evidence from 5216 UK Biobank Participants , 2017, bioRxiv.

[121]  C. Dulac,et al.  Genomic Imprinting in the Adult and Developing Brain , 2013 .

[122]  J. Lakin Sex differences in reasoning abilities: Surprising evidence that male–female ratios in the tails of the quantitative reasoning distribution have increased , 2013 .

[123]  Elena Choleris,et al.  Sex, hormones, and genotype interact to influence psychiatric disease, treatment, and behavioral research , 2017, Journal of neuroscience research.

[124]  Aurel Ion Clinciu,et al.  Sex differences in intelligence: A multi-measure approach using nationally representative samples from Romania , 2016 .

[125]  Raquel E Gur,et al.  Age group and sex differences in performance on a computerized neurocognitive battery in children age 8-21. , 2012, Neuropsychology.

[126]  Patrick Ian Armstrong,et al.  Men and things, women and people: a meta-analysis of sex differences in interests. , 2009, Psychological bulletin.

[127]  Rebecca C. Knickmeyer,et al.  Why Are Autism Spectrum Conditions More Prevalent in Males? , 2011, PLoS biology.

[128]  Thomas E. Nichols,et al.  A positive-negative mode of population covariation links brain connectivity, demographics and behavior , 2015, Nature Neuroscience.

[129]  Nikos Makris,et al.  Automatically parcellating the human cerebral cortex. , 2004, Cerebral cortex.