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

doi:10.1016/j.neubiorev.2016.07.035

Neuroscience & Biobehavioral Reviews

Volume 70, November 2016, Pages 159-170

https://doi.org/10.1016/j.neubiorev.2016.07.035 Get rights and content

Highlights

•
Notable sex differences.
•
Adolescence is a critical period.
•
Multimodal data merging needed.

Abstract

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.

Introduction

An extensive literature on brain and behavior has documented sex differences in cognitive, affective and brain imaging parameters. Such measures have been informative in evaluating aberrations in neurodevelopmental disorders where sex differences are prominent, including attention deficit, learning disabilities and autism spectrum disorder. Sexual differentiation of behavior has been related to organizational factors during sensitive periods of development, with the prenatal period most investigated across species. There is growing evidence that puberty is another organizational period with long lasting effects on brain and behavior. Adolescence presents an especially informative and dynamic period as brain maturation is accelerated, hormonal changes associated with puberty emerge and social factors increase their impact. The transition to adulthood is influenced by complex interactions where the effects of this critical period may differ for males and females with implications for healthy functioning and psychopathology.

We will begin this review by highlighting sex differences in neurobehavioral measures in adolescence that are linked to brain function. We will then summarize neuroimaging studies examining brain structure, connectivity and perfusion. We will conclude by summarizing literature on the role of hormonal measures and discuss clinical implications.

Section snippets

Behavior linked to brain function

The developmental course of specific behavioral domains has been well documented. Executive-control (e.g., Conklin et al., 2007, Goldberg et al., 2001, Pickering, 2001), language and reasoning (e.g., Friederici and Wartenburger, 2010, Kuhl, 2010) and, more recently, social cognition (e.g., Burnett et al., 2011, Shaw et al., 2012) show improved performance from childhood to young adulthood, especially pronounced during adolescence for executive domains of attention and working memory (Ang and

Volumetric MRI

An extensive literature shows that adolescence is associated with changes in brain structure, including reduced gray matter (GM) volume and increased white matter (WM) volume, which have been related to sex differences (Blakemore et al., 2010, Giedd et al., 1999, Lenroot and Giedd, 2006, Paus, 2005, Sowell et al., 2003). Such maturational processes have been linked to cognitive and affective development during adolescence. Sex differences have been reported in overall brain volume as well as in

Perfusion

Cerebral blood flow (CBF), critical for healthy brain function, is coupled to regional metabolism, responds to activation with cognitive tasks and shows a marked decline throughout childhood and adolescence (Chiron et al., 1992, Takahashi et al., 1999). Compared to the extensive literature on cognitive and structural brain parameters in relation to development, the literature on CBF has been limited. Early technologies to measure CBF, including the Kety–Schmidt nitrous oxide method, ¹³³Xe

Hormonal modulation

The extent to which human behavioral sex differences are influenced by sex hormones that change during sensitive periods of development has been an important area of investigation. Hormonal effects on behavior in early development have been well documented in animal studies establishing the prenatal and early neonatal stage as a sensitive period. More recently, based on rodent research, puberty has been considered as another sensitive period along the continuum where brain organization is

Clinical implications

Here we focused on normative sex differences in brain and behavior. These differences should be considered when interpreting effects of diverse brain disorders with manifested psychopathology. Developmental disorders may emerge early and are more prevalent in males. Anxiety and mood disorder commonly emerge later in development and are more frequent in females. Some of the normative sex differences may explain or modulate effect of disorders such as schizophrenia (e.g., Ragland et al., 1999,

Summary and future directions

Sex differences in brain organization that are evident in adults become accentuated during adolescence, implicating hormonal effects of pubescence. Improved executive function and complex and social cognition is associated with increase in the magnitude of sex differences in these domains and such changes in cognition are paralleled by age-related differences in brain parameters.

Results of the PNC, where the sample size permits detection of relatively small effects, show a striking ubiquity of

Acknowledgements

We thank the many colleagues and dedicated staff who made the PNC possible and the many research participants who offered their time and efforts. Supported by NIMH Grants RC2 MH089983, P50MH096891, and R01MH107235.

References (119)

G.K. Aguirre et al.
The development and future of perfusion fMRI for dynamic imaging of human brain activity
Neuroimage
(2012)
G. Alarcon et al.
Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone
Brain Res.
(2014)
S. Bava et al.
Longitudinal characterization of white matter maturation during adolescence
Brain Res.
(2010)
S. Bava et al.
Sex differences in adolescent white matter architecture
Brain Res.
(2011)
S.A. Berenbaum et al.
Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones
Front. Neuroendocrinol.
(2011)
S. Burnett et al.
The social brain in adolescence: evidence from functional magnetic resonance imaging and behavioural studies
Neurosci. Biobehav. Rev.
(2011)
M.E. Calkins et al.
Sex differences in familiality effects on neurocognitive performance in schizophrenia
Biol. Psychiatry
(2013)
B.J. Casey et al.
Adolescence: what do transmission, transition, and translation have to do with it
Neuron
(2010)
A. Cservenka et al.
The effects of age, sex, and hormones on emotional conflict-related brain response during adolescence
Brain Cogn.
(2015)
R.J. Erwin et al.
Facial emotion discrimination: I. Task construction and behavioral findings in normal subjects
Psychiatry Res.
(1992)

J.N. Giedd et al.

Puberty-related influences on brain development

Mol. Cell. Endocrinol.

(2006)

A.L. Goddings et al.

The influence of puberty on subcortical brain development

Neuroimage

(2014)

R.C. Gur et al.

An fMRI study of sex differences in regional activation to a verbal and a spatial task

Brain Lang.

(2000)

R.E. Gur et al.

A sexually dimorphic ratio of orbitofrontal to amygdala volume is altered in schizophrenia

Biol. Psychiatry

(2004)

R.C. Gur et al.

A cognitive neuroscience-based computerized battery for efficient measurement of individual differences: standardization and initial construct validation

J. Neurosci. Methods

(2010)

M. Hines

Sex-related variation in human behavior and the brain

Trends Cogn. Sci.

(2010)

J.-L. Hsu et al.

Gender differences and agerelated white matter changes of the human brain: a diffusion tensor imaging study

Neuroimage

(2008)

E.T. Klapwijk et al.

Increased functional connectivity with puberty in the mentalising network involved in social emotion processing

Horm. Behav.

(2013)

P.K. Kuhl

Brain mechanisms in early language acquisition

Neuron

(2010)

R.K. Lenroot et al.

Brain development in children and adolescents: insights from anatomical magnetic resonance imaging

Neurosci. Biobehav. Rev.

(2006)

R.K. Lenroot et al.

Sex differences in the adolescent brain

Brain Cogn.

(2010)

R.K. Lenroot et al.

Sexual dimorphism of brain developmental trajectories during childhood and adolescence

Neuroimage

(2007)

C. Leth-Steensen et al.

Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach

Acta Psychol.

(2000)

E.D. Nottelmann 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

J. Adolesc. Health Care

(1987)

Y. Ou et al.

DRAMMS: deformable registration via attribute matching and mutual-saliency weighting

Med. Image Anal.

(2011)

T. Paus

Mapping brain maturation and cognitive development during adolescence

Trends Cogn. Sci.

(2005)

T. Paus

Growth of white matter in the adolescent brain: myelin or axon

Brain Cogn.

(2010)

J.S. Perrin et al.

Sex differences in the growth of white matter during adolescence

Neuroimage

(2009)

J.D. Power et al.

Functional network organization of the human brain

Neuron

(2011)

J.D. Power et al.

Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion

Neuroimage

(2012)

J.D. Ragland et al.

Sex differences in brain-behavior relationships between verbal episodic memory and resting regional cerebral blood flow

Neuropsychologia

(2000)

D.R. Roalf et al.

White matter organization and neurocognitive performance variability in schizophrenia

Schizophr. Res.

(2013)

K. Rubia et al.

Effects of age and sex on developmental neural networks of visual-spatial attention allocation

Neuroimage

(2010)

K. Rubia et al.

Effects of age and gender on neural networks of motor response inhibition: from adolescence to mid-adulthood

Neuroimage

(2013)

T.A. Salthouse

Localizing age-related individual differences in a hierarchical structure

Intelligence

(2004)

T.D. Satterthwaite et al.

Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth

Neuroimage

(2012)

T.D. Satterthwaite et al.

Neuroimaging of the Philadelphia Neurodevelopmental Cohort

Neuroimage

(2014)

S. Schneider et al.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents

Neuroimage

(2011)

K.M. Schulz et al.

Back to the future: the organizational?activational hypothesis adapted to puberty and adolescence

Horm. Behav.

(2009)

A.J. Schwarz et al.

Community structure and modularity in networks of correlated brain activity

Magn. Reson. Imaging

(2008)

S.Y. Ang et al.

Exploring developmental differences in visual short-term memory and working memory

Dev. Psychol.

(2010)

B.B. Biswal et al.

Simultaneous assessment of flow and BOLD signals in resting-state functional connectivity maps

NMR Biomed.

(1997)

B.B. Biswal et al.

Toward discovery science of human brain function

Proc. Natl. Acad. Sci. U. S. A.

(2010)

S.-J. Blakemore et al.

The role of puberty in the developing adolescent brain

Hum. Brain Mapp.

(2010)

R.M. Brouwer et al.

Longitudinal development of hormone levels and grey matter density in 9 and 12-year-old twins

Behav. Genet.

(2015)

M.E. Calkins 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

Am. J. Psychiatry

(2010)

C. Chiron et al.

Changes in regional cerebral blood flow during brain maturation in children and adolescents

J. Nucl. Med.

(1992)

J.D. Clayden et al.

Normative development of white matter tracts: similarities and differences in relation to age, gender, and intelligence

Cereb. Cortex

(2012)

H.M. Conklin et al.

Working memory performance in typically developing children and adolescents: behavioral evidence of protracted frontal lobe development

Dev. Neuropsychol.

(2007)

M.D. De Bellis et al.

Sex differences in brain maturation during childhood and adolescence

Cereb. Cortex

(2001)

Cited by (85)

A developmental framework for understanding the influence of sex and gender on health: Pediatric pain as an exemplar
2024, Neuroscience and Biobehavioral Reviews
Sex differences are a robust finding in many areas of adult health, including cardiovascular disease, psychiatric disorders, and chronic pain. However, many sex differences are not consistently observed until after the onset of puberty. This has led to the hypothesis that hormones are primary contributors to sex differences in health outcomes, largely ignoring the relative contributions of early developmental influences, emerging psychosocial factors, gender, and the interaction between these variables. In this paper, we argue that a comprehensive understanding of sex and gender contributions to health outcomes should start as early as conception and take an iterative biopsychosocial-developmental perspective that considers intersecting social positions. We present a conceptual framework, informed by a review of the literature in basic, clinical, and social science that captures how critical developmental stages for both sex and gender can affect children’s health and longer-term outcomes. The literature on pediatric chronic pain is used as a worked example of how the framework can be applied to understanding different chronic conditions.
The interaction of genetic sex and prenatal alcohol exposure on health across the lifespan
2023, Frontiers in Neuroendocrinology
Prenatal alcohol exposure (PAE) can reprogram the development of cells and tissues, resulting in a spectrum of physical and neurobehavioral teratology. PAE immediately impacts fetal growth, but its effects carry forward post-parturition, into adolescence and adulthood, and can result in a cluster of disabilities, collectively termed Fetal Alcohol Spectrum Disorders. Emerging preclinical and clinical research investigating neurological and behavioral outcomes in exposed offspring point to genetic sex as an important modifier of the effects of PAE. In this review, we discuss the literature on sex differences following PAE, with studies spanning the fetal period through adulthood, and highlight gaps in research where sex differences are likely, but currently under-investigated. Understanding how sex and PAE interact to affect offspring health outcomes across the lifespan is critical for identifying the full complement of PAE-associated secondary conditions, and for refining targeted interventions to improve the quality of life for individuals with PAE.
Brain-Based Predictions of Psychiatric Illness–Linked Behaviors Across the Sexes
2023, Biological Psychiatry
Individual differences in functional brain connectivity can be used to predict both the presence of psychiatric illness and variability in associated behaviors. However, despite evidence for sex differences in functional network connectivity and in the prevalence, presentation, and trajectory of psychiatric illnesses, the extent to which disorder-relevant aspects of network connectivity are shared or unique across the sexes remains to be determined.
In this work, we used predictive modeling approaches to evaluate whether shared or unique functional connectivity correlates underlie the expression of psychiatric illness–linked behaviors in males and females in data from the Adolescent Brain Cognitive Development Study (N = 5260; 2571 females).
We demonstrate that functional connectivity profiles predict individual differences in externalizing behaviors in males and females but predict internalizing behaviors only in females. Furthermore, models trained to predict externalizing behaviors in males generalize to predict internalizing behaviors in females, and models trained to predict internalizing behaviors in females generalize to predict externalizing behaviors in males. Finally, the neurobiological correlates of many behaviors are largely shared within and across sexes: functional connections within and between heteromodal association networks, including default, limbic, control, and dorsal attention networks, are associated with internalizing and externalizing behaviors.
Taken together, these findings suggest that shared neurobiological patterns may manifest as distinct behaviors across the sexes. Based on these results, we recommend that both clinicians and researchers carefully consider how sex may influence the presentation of psychiatric illnesses, especially those along the internalizing-externalizing spectrum.
Development of Iron Status Measures during Youth: Associations with Sex, Neighborhood Socioeconomic Status, Cognitive Performance, and Brain Structure
2023, American Journal of Clinical Nutrition
Iron is essential to brain function, and iron deficiency during youth may adversely impact neurodevelopment. Understanding the developmental time course of iron status and its association with neurocognitive functioning is important for identifying windows for intervention.
This study aimed to characterize developmental change in iron status and understand its association with cognitive performance and brain structure during adolescence using data from a large pediatric health network.
This study included a cross-sectional sample of 4899 participants (2178 males; aged 8–22 y at the time of participation, M [SD] = 14.24 [3.7]) who were recruited from the Children’s Hospital of Philadelphia network. Prospectively collected research data were enriched with electronic medical record data that included hematological measures related to iron status, including serum hemoglobin, ferritin, and transferrin (33,015 total samples). At the time of participation, cognitive performance was assessed using the Penn Computerized Neurocognitive Battery, and brain white matter integrity was assessed using diffusion-weighted MRI in a subset of individuals.
Developmental trajectories were characterized for all metrics and revealed that sex differences emerged after menarche such that females had reduced iron status relative to males [all R²_partial > 0.008; all false discovery rates (FDRs) < 0.05]. Higher socioeconomic status was associated with higher hemoglobin concentrations throughout development (R²_partial = 0.005; FDR < 0.001), and the association was greatest during adolescence. Higher hemoglobin concentrations were associated with better cognitive performance during adolescence (R²_partial = 0.02; FDR < 0.001) and mediated the association between sex and cognition (mediation effect = −0.107; 95% CI: −0.191, −0.02). Higher hemoglobin concentration was also associated with greater brain white matter integrity in the neuroimaging subsample (R²_partial = 0.06, FDR = 0.028).
Iron status evolves during youth and is lowest in females and individuals of low socioeconomic status during adolescence. Diminished iron status during adolescence has consequences for neurocognition, suggesting that this critical period of neurodevelopment may be an important window for intervention that has the potential to reduce health disparities in at-risk populations.
Proportional intracranial volume correction differentially biases behavioral predictions across neuroanatomical features, sexes, and development
2022, NeuroImage
Citation Excerpt :
Accordingly, the use of ICV correction may influence relationships between neuroanatomical properties and other variables of interest, an effect that could vary in impact across populations. The presence of sex and/or gender differences in brain anatomy (e.g., Joel et al., 2015; Chekroud et al., 2016) and associated brain-behavior relationships has been a subject of pointed debate in the field (Ingalhalikar et al., 2014; Wierenga et al., 2019; Gur and Gur 2016). Several groups have investigated multivariate brain-behavior relationships in males and females (Dhamala et al., 2022; Jiang et al., 2020, et al. 2020).
Individual differences in brain anatomy can be used to predict variations in cognitive ability. Most studies to date have focused on broad population-level trends, but the extent to which the observed predictive features are shared across sexes and age groups remains to be established. While it is standard practice to account for intracranial volume (ICV) using proportion correction in both regional and whole-brain morphometric analyses, in the context of brain-behavior predictions the possible differential impact of ICV correction on anatomical features and subgroups within the population has yet to be systematically investigated. In this work, we evaluate the effect of proportional ICV correction on sex-independent and sex-specific predictive models of individual cognitive abilities across multiple anatomical properties (surface area, gray matter volume, and cortical thickness) in healthy young adults (Human Connectome Project; n = 1013, 548 females) and typically developing children (Adolescent Brain Cognitive Development study; n = 1823, 979 females). We demonstrate that ICV correction generally reduces predictive accuracies derived from surface area and gray matter volume, while increasing predictive accuracies based on cortical thickness in both adults and children. Furthermore, the extent to which predictive models generalize across sexes and age groups depends on ICV correction: models based on surface area and gray matter volume are more generalizable without ICV correction, while models based on cortical thickness are more generalizable with ICV correction. Finally, the observed neuroanatomical features predictive of cognitive abilities are unique across age groups regardless of ICV correction, but whether they are shared or unique across sexes (within age groups) depends on ICV correction. These findings highlight the importance of considering individual differences in ICV, and show that proportional ICV correction does not remove the effects of cranial volume from anatomical measurements and can introduce ICV bias where previously there was none. ICV correction choices affect not just the strength of the relationships captured, but also the conclusions drawn regarding the neuroanatomical features that underlie those relationships.
Cannabis effects on the adolescent brain
2022, Cannabis and the Developing Brain
Chronic cannabis exposure during adolescence can result in persistent deficits in cognitive domains such as attention, memory, and processing speed. Cannabis use during adolescence is also linked to an increased risk for psychiatric disorders, including psychosis (schizophrenia), depression, anxiety, and substance use disorders, later in life. Notably, not all cannabis users exhibit these long-lasting behavioral and cognitive impairments, suggesting there is a genetic vulnerability, i.e., a gene-environment relationship for cannabis sensitivity. Unfortunately, little is known about the mechanisms of individual susceptibilities to the adverse effects of cannabis use in adolescence. The molecular mechanisms of gene and environment interactions differ across cell types, and recent studies have only begun to identify the molecular cascades activated by delta-9-tetrahydrocannabinol (Δ⁹-THC) in a cell-type-specific manner. In this chapter, we review these interactions and their contributions to cannabis sensitivity and to the development of long-lasting behavioral abnormalities. We also lay out the known cell-type-specific mechanisms of the susceptibilities to the adverse effects of cannabis and discuss the proinflammatory signaling pathways involved in Δ⁹-THC-induced behavioral impairments. Finally, we highlight new avenues to study the vulnerability to adverse effects of Δ⁹-THC exposure, specifically, changes in brain cell energetics and the insights gleaned from studies in humans and animal models.

View all citing articles on Scopus

View full text

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

Highlights

Abstract

Introduction

Section snippets

Behavior linked to brain function

Volumetric MRI

Perfusion

Hormonal modulation

Clinical implications

Summary and future directions

Acknowledgements

Neuroimage

Brain Res.

Brain Res.

Brain Res.

Front. Neuroendocrinol.

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Neuron

Brain Cogn.

Psychiatry Res.

Mol. Cell. Endocrinol.

Neuroimage

Brain Lang.

Biol. Psychiatry

J. Neurosci. Methods

Trends Cogn. Sci.

Neuroimage

Horm. Behav.

Neuron

Neurosci. Biobehav. Rev.

Brain Cogn.

Neuroimage

Acta Psychol.

J. Adolesc. Health Care

Med. Image Anal.

Trends Cogn. Sci.

Brain Cogn.

Neuroimage

Neuron

Neuroimage

Neuropsychologia

Schizophr. Res.

Neuroimage

Neuroimage

Intelligence

Neuroimage

Neuroimage

Neuroimage

Horm. Behav.

Magn. Reson. Imaging

Exploring developmental differences in visual short-term memory and working memory

Dev. Psychol.

Simultaneous assessment of flow and BOLD signals in resting-state functional connectivity maps

NMR Biomed.

Toward discovery science of human brain function

Proc. Natl. Acad. Sci. U. S. A.

The role of puberty in the developing adolescent brain

Hum. Brain Mapp.

Longitudinal development of hormone levels and grey matter density in 9 and 12-year-old twins

Behav. Genet.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients

Am. J. Psychiatry

Changes in regional cerebral blood flow during brain maturation in children and adolescents

J. Nucl. Med.

Normative development of white matter tracts: similarities and differences in relation to age, gender, and intelligence

Cereb. Cortex

Working memory performance in typically developing children and adolescents: behavioral evidence of protracted frontal lobe development

Dev. Neuropsychol.

Sex differences in brain maturation during childhood and adolescence

Cereb. Cortex

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