Sex differences in brain and behavior in adolescence: Findings from the Philadelphia Neurodevelopmental Cohort

Sex differences in brain and behavior were investigated across the lifespan. Parameters include neurobehavioral measures linkable to neuroanatomic and neurophysiologic indicators of brain structure and function. Sexual differentiation of behavior has been related to organizational factors during sensitive periods of development, with adolescence and puberty gaining increased attention. Adolescence is a critical developmental period where transition to adulthood is impacted by multiple factors that can enhance vulnerability to brain dysfunction. Here we highlight sex differences in neurobehavioral measures in adolescence that are linked to brain function. We summarize neuroimaging studies examining brain structure, connectivity and perfusion, underscoring the relationship to sex differences in behavioral measures and commenting on hormonal findings. We focus on relevant data from the Philadelphia Neurodevelopmental Cohort (PNC), a community-based sample of nearly 10,000 clinically and neurocognitively phenotyped youths age 8-21 of whom 1600 have received multimodal neuroimaging. These data indicate early and pervasive sexual differentiation in neurocognitive measures that is linkable to brain parameters. We conclude by describing possible clinical implications.

[1]  Michael J. Brammer,et al.  Effects of age and gender on neural networks of motor response inhibition: From adolescence to mid-adulthood , 2013, NeuroImage.

[2]  L. Hedges,et al.  Sex differences in mental test scores, variability, and numbers of high-scoring individuals. , 1995, Science.

[3]  R. Gur,et al.  Normative neuropsychological test performance: effects of age, education, gender and ethnicity. , 1995, Applied neuropsychology.

[4]  D. Maurer,et al.  Developmental changes in attention: the effects of endogenous cueing and of distractors , 2001 .

[5]  Jung-Lung Hsu,et al.  Gender differences and age-related white matter changes of the human brain: A diffusion tensor imaging study , 2008, NeuroImage.

[6]  Donald S. Williams,et al.  Perfusion imaging , 1992, Magnetic resonance in medicine.

[7]  A. Beltz,et al.  Sexual differentiation of human behavior: Effects of prenatal and pubertal organizational hormones , 2011, Frontiers in Neuroendocrinology.

[8]  Timothy O. Laumann,et al.  Functional Network Organization of the Human Brain , 2011, Neuron.

[9]  Raquel E Gur,et al.  Sex differences in brain-behavior relationships between verbal episodic memory and resting regional cerebral blood flow , 2000, Neuropsychologia.

[10]  Jagath C. Rajapakse,et al.  Development of the human corpus callosum during childhood and adolescence: A longitudinal MRI study , 1999, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[11]  M. Keshavan,et al.  Sex differences in brain maturation during childhood and adolescence. , 2001, Cerebral cortex.

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

[13]  I. Deary,et al.  The neuroscience of human intelligence differences , 2010, Nature Reviews Neuroscience.

[14]  Sarah-Jayne Blakemore,et al.  The relationship between puberty and social emotion processing , 2012, Archives of Disease in Childhood.

[15]  M. Zilbovicius,et al.  Changes in regional cerebral blood flow during brain maturation in children and adolescents. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[17]  N. Makris,et al.  Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. , 2001, Cerebral cortex.

[18]  M. Hines,et al.  Sex-related variation in human behavior and the brain , 2010, Trends in Cognitive Sciences.

[19]  Tomás Paus,et al.  Development of the action observation network during early adolescence: a longitudinal study. , 2012, Social cognitive and affective neuroscience.

[20]  S. Pickering,et al.  The development of visuo-spatial working memory , 2001, Memory.

[21]  C. Sisk,et al.  Back to the future: The organizational–activational hypothesis adapted to puberty and adolescence , 2009, Hormones and Behavior.

[22]  Beatriz Luna,et al.  Developmental stages and sex differences of white matter and behavioral development through adolescence: A longitudinal diffusion tensor imaging (DTI) study , 2014, NeuroImage.

[23]  Suzanne E. Welcome,et al.  Mapping cortical change across the human life span , 2003, Nature Neuroscience.

[24]  T. Paus Mapping brain maturation and cognitive development during adolescence , 2005, Trends in Cognitive Sciences.

[25]  Jonathan D Clayden,et al.  Normative development of white matter tracts: similarities and differences in relation to age, gender, and intelligence. , 2012, Cerebral cortex.

[26]  Michael F. Green,et al.  Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. , 2007, Archives of general psychiatry.

[27]  J. Giedd,et al.  Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging , 2006, Neuroscience & Biobehavioral Reviews.

[28]  Jay N. Giedd,et al.  The influence of puberty on subcortical brain development , 2014, NeuroImage.

[29]  Jeffrey M Spielberg,et al.  The role of testosterone and estradiol in brain volume changes across adolescence: A longitudinal structural MRI study , 2014, Human brain mapping.

[30]  Yufeng Zang,et al.  Combined structural and resting-state functional MRI analysis of sexual dimorphism in the young adult human brain: An MVPA approach , 2012, NeuroImage.

[31]  A. Addington,et al.  Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence , 2010, Proceedings of the National Academy of Sciences.

[32]  P. Kuhl Brain Mechanisms in Early Language Acquisition , 2010, Neuron.

[33]  B. Turetsky,et al.  Sex Differences in Brain Gray and White Matter in Healthy Young Adults: Correlations with Cognitive Performance , 1999, The Journal of Neuroscience.

[34]  Steven P Reise,et al.  Psychometric properties of the Penn Computerized Neurocognitive Battery. , 2015, Neuropsychology.

[35]  Todd A. Hare,et al.  Frontostriatal Maturation Predicts Cognitive Control Failure to Appetitive Cues in Adolescents , 2011, Journal of Cognitive Neuroscience.

[36]  B. Casey,et al.  Adolescence: What Do Transmission, Transition, and Translation Have to Do with It? , 2010, Neuron.

[37]  Raquel E Gur,et al.  Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients. , 2010, The American journal of psychiatry.

[38]  Ruben C. Gur,et al.  Facial emotion discrimination: I. Task construction and behavioral findings in normal subjects , 1992, Psychiatry Research.

[39]  Yong He,et al.  Hemisphere- and gender-related differences in small-world brain networks: A resting-state functional MRI study , 2011, NeuroImage.

[40]  Terry L. Jernigan,et al.  Longitudinal characterization of white matter maturation during adolescence , 2010, Brain Research.

[41]  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.

[42]  et al.,et al.  Boys do it the right way: Sex-dependent amygdala lateralization during face processing in adolescents , 2011, NeuroImage.

[43]  A. Etkin,et al.  The effects of age, sex, and hormones on emotional conflict-related brain response during adolescence , 2015, Brain and Cognition.

[44]  Rozmin Halari,et al.  Effects of age and sex on developmental neural networks of visual–spatial attention allocation , 2010, NeuroImage.

[45]  Efstathios D. Gennatas,et al.  Impact of puberty on the evolution of cerebral perfusion during adolescence , 2014, Proceedings of the National Academy of Sciences.

[46]  Catalina J. Hooper,et al.  Working memory performance in typically developing children and adolescents: behavioral evidence of protracted frontal lobe development. , 2007 .

[47]  Angela D. Friederici,et al.  Language and brain. , 2010, Wiley interdisciplinary reviews. Cognitive science.

[48]  C. Lebel,et al.  Longitudinal Development of Human Brain Wiring Continues from Childhood into Adulthood , 2011, The Journal of Neuroscience.

[49]  Dorret I. Boomsma,et al.  Longitudinal Development of Hormone Levels and Grey Matter Density in 9 and 12-Year-Old Twins , 2015, Behavior genetics.

[50]  N. Lazar,et al.  Maturation of cognitive processes from late childhood to adulthood. , 2004, Child development.

[51]  Dinggang Shen,et al.  Puberty-related influences on brain development , 2006, Molecular and Cellular Endocrinology.

[52]  Susan D. Voyer,et al.  Magnitude of sex differences in spatial abilities: a meta-analysis and consideration of critical variables. , 1995, Psychological bulletin.

[53]  Christos Davatzikos,et al.  Neuroimaging of the Philadelphia Neurodevelopmental Cohort , 2014, NeuroImage.

[54]  Tomáš Paus,et al.  Growth of white matter in the adolescent brain: Myelin or axon? , 2010, Brain and Cognition.

[55]  B. Turetsky,et al.  A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia , 2004, Biological Psychiatry.

[56]  D. Fair,et al.  Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone , 2014, Brain Research.

[57]  B. Biswal,et al.  Simultaneous assessment of flow and BOLD signals in resting‐state functional connectivity maps , 1997, NMR in biomedicine.

[58]  Alan C. Evans,et al.  Testosterone-related cortical maturation across childhood and adolescence. , 2012, Cerebral cortex.

[59]  R. Gur,et al.  Age-related volumetric changes of brain gray and white matter in healthy infants and children. , 2001, Cerebral cortex.

[60]  Donna M. Palmer,et al.  Explicit identification and implicit recognition of facial emotions: I. Age effects in males and females across 10 decades , 2009, Journal of clinical and experimental neuropsychology.

[61]  Alan C. Evans,et al.  Topological Organization of Functional Brain Networks in Healthy Children: Differences in Relation to Age, Sex, and Intelligence , 2013, PloS one.

[62]  A. Alavi,et al.  Sex differences in regional cerebral glucose metabolism during a resting state , 1995, Science.

[63]  R. Gur,et al.  Establishing a link between sex-related differences in the structural connectome and behaviour , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[64]  Neal D Ryan,et al.  Neural Systems of Threat Processing in Adolescents: Role of Pubertal Maturation and Relation to Measures of Negative Affect , 2011, Developmental neuropsychology.

[65]  Paul van Geert,et al.  Focus on variability: New tools to study intra-individual variability in developmental data , 2002 .

[66]  Kathrin Cohen Kadosh,et al.  The social brain in adolescence: Evidence from functional magnetic resonance imaging and behavioural studies , 2011, Neuroscience & Biobehavioral Reviews.

[67]  J. R. Thomas,et al.  Gender differences across age in motor performance a meta-analysis. , 1985, Psychological bulletin.

[68]  G. Chrousos,et al.  Developmental processes in early adolescence. Relations among chronologic age, pubertal stage, height, weight, and serum levels of gonadotropins, sex steroids, and adrenal androgens. , 1987, Journal of adolescent health care : official publication of the Society for Adolescent Medicine.

[69]  R. Gur,et al.  White matter organization and neurocognitive performance variability in schizophrenia , 2013, Schizophrenia Research.

[70]  D. Geary,et al.  PSYCHOLOGICAL SCIENCE IN THE PUBLIC INTEREST The Science of Sex Differences in Science and Mathematics , 2022 .

[71]  Christos Davatzikos,et al.  Comparative Evaluation of Registration Algorithms in Different Brain Databases With Varying Difficulty: Results and Insights , 2014, IEEE Transactions on Medical Imaging.

[72]  R. Gur,et al.  A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: Standardization and initial construct validation , 2010, Journal of Neuroscience Methods.

[73]  John A. Detre,et al.  The development and future of perfusion fMRI for dynamic imaging of human brain activity , 2012, NeuroImage.

[74]  Joanna Jacobus,et al.  Sex differences in adolescent white matter architecture , 2011, Brain Research.

[75]  Kerry Lee,et al.  Exploring developmental differences in visual short-term memory and working memory. , 2010, Developmental psychology.

[76]  T. Salthouse Localizing age-related individual differences in a hierarchical structure. , 2004, Intelligence.

[77]  R. Gur,et al.  Neuropsychological laterality indices of schizophrenia: interactions with gender. , 1999, Schizophrenia bulletin.

[78]  Efstathios D. Gennatas,et al.  Linked Sex Differences in Cognition and Functional Connectivity in Youth. , 2015, Cerebral cortex.

[79]  T. Paus,et al.  Sex differences in the growth of white matter during adolescence , 2009, NeuroImage.

[80]  W D Obrist,et al.  Sex and handedness differences in cerebral blood flow during rest and cognitive activity. , 1982, Science.

[81]  Nikos Paragios,et al.  DRAMMS: Deformable Registration via Attribute Matching and Mutual-Saliency Weighting , 2009, IPMI.

[82]  Abraham Z. Snyder,et al.  Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion , 2012, NeuroImage.

[83]  Sarah-Jayne Blakemore,et al.  Increased functional connectivity with puberty in the mentalising network involved in social emotion processing , 2013, Hormones and Behavior.

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

[85]  Marisa O. Hollinshead,et al.  The organization of the human cerebral cortex estimated by intrinsic functional connectivity. , 2011, Journal of neurophysiology.

[86]  Bonnie J Nagel,et al.  The impact of sex, puberty, and hormones on white matter microstructure in adolescents. , 2012, Cerebral cortex.

[87]  Paul M. Thompson,et al.  Sexual dimorphism of brain developmental trajectories during childhood and adolescence , 2007, NeuroImage.

[88]  B. Turetsky,et al.  An fMRI Study of Sex Differences in Regional Activation to a Verbal and a Spatial Task , 2000, Brain and Language.

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

[90]  James M. Tanner,et al.  Variations in pattern of pubertal changes in girls. , 1969 .

[91]  R. Gur,et al.  Neurobehavioral probes for physiologic neuroimaging studies. , 1992, Archives of general psychiatry.

[92]  Alan C. Evans,et al.  Growing Together and Growing Apart: Regional and Sex Differences in the Lifespan Developmental Trajectories of Functional Homotopy , 2010, The Journal of Neuroscience.

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

[94]  Christos Davatzikos,et al.  Sex differences in the effect of puberty on hippocampal morphology. , 2014, Journal of the American Academy of Child and Adolescent Psychiatry.

[95]  Hiroshi Fukuda,et al.  Correlation between gray matter density‐adjusted brain perfusion and age using brain MR images of 202 healthy children , 2011, Human brain mapping.

[96]  M. Linn,et al.  Emergence and characterization of sex differences in spatial ability: a meta-analysis. , 1985, Child development.

[97]  M. Yücel,et al.  Mapping subcortical brain maturation during adolescence: evidence of hemisphere- and sex-specific longitudinal changes. , 2013, Developmental science.

[98]  C Leth-Steensen,et al.  Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach. , 2000, Acta psychologica.

[99]  Carrie L. Masten,et al.  Facing puberty: associations between pubertal development and neural responses to affective facial displays. , 2012, Social cognitive and affective neuroscience.

[100]  Raphael T. Gerraty,et al.  Neuroimaging predictors of cognitive performance across a standardized neurocognitive battery. , 2014, Neuropsychology.

[101]  Alan C. Evans,et al.  Interactive Effects of Dehydroepiandrosterone and Testosterone on Cortical Thickness during Early Brain Development , 2013, The Journal of Neuroscience.

[102]  Alan C. Evans,et al.  Cerebral White Matter in Early Puberty Is Associated with Luteinizing Hormone Concentrations , 2022 .

[103]  Mark A. Elliott,et al.  Impact of in-scanner head motion on multiple measures of functional connectivity: Relevance for studies of neurodevelopment in youth , 2012, NeuroImage.

[104]  Angelo Bifone,et al.  Community structure and modularity in networks of correlated brain activity. , 2007, Magnetic resonance imaging.

[105]  Jeff Duyn,et al.  H215O PET validation of steady‐state arterial spin tagging cerebral blood flow measurements in humans , 2000, Magnetic resonance in medicine.

[106]  Mert R. Sabuncu,et al.  The influence of head motion on intrinsic functional connectivity MRI , 2012, NeuroImage.

[107]  Rhoshel K. Lenroot,et al.  Sex differences in the adolescent brain , 2010, Brain and Cognition.

[108]  S. Orme,et al.  Cognitive dysfunction in patients treated for pituitary tumours. , 1997, Journal of clinical and experimental neuropsychology.

[109]  Murat Yücel,et al.  Brain development during adolescence: A mixed‐longitudinal investigation of cortical thickness, surface area, and volume , 2016, Human brain mapping.

[110]  Vincent J Schmithorst,et al.  Developmental differences in white matter architecture between boys and girls , 2008, Human brain mapping.

[111]  S. Blakemore,et al.  The role of puberty in the developing adolescent brain , 2010, Human brain mapping.

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

[113]  M. Linn,et al.  Gender differences in verbal ability: A meta-analysis. , 1988 .

[114]  Rosalinda Díaz,et al.  Sex-related differences in motor learning and performance , 2010, Behavioral and Brain Functions.

[115]  N. De Stefano,et al.  Longitudinal changes in grey and white matter during adolescence , 2010, NeuroImage.

[116]  Michael F. Green,et al.  Sex Differences in Familiality Effects on Neurocognitive Performance in Schizophrenia , 2013, Biological Psychiatry.

[117]  R. Gur,et al.  Neurocognitive Endophenotypes in a Multiplex Multigenerational Family Study of Schizophrenia , 2007 .

[118]  S. Sato,et al.  Developmental changes of cerebral blood flow and oxygen metabolism in children. , 1999, AJNR. American journal of neuroradiology.

[119]  Monica Luciana,et al.  Working Memory Performance in Typically Developing Children and Adolescents: Behavioral Evidence of Protracted Frontal Lobe Development , 2007, Developmental neuropsychology.

[120]  C. Sisk,et al.  Pubertal hormones organize the adolescent brain and behavior , 2005, Frontiers in Neuroendocrinology.