Sex Differences In Brain Structure Research Articles

Exploring the Impact of Sex and Gender in Brain Function: Implications and Considerations.

Sex and gender are crucial variables in understanding brain development and disease. Biological sex is determined by genetic and hormonal factors, whereas gender is a multidimensional construct shaped by social and cultural influences. The interplay of these factors contributes to sex-specific susceptibilities and disease progression in psychiatric and neurological disorders. However, sex and gender are often considered as a single variable, which can lead to biased data analysis and interpretation. This commentary aims to analyze how sex and gender influence brain structure and function, with implications for personalized medicine, research, and the development of gender-sensitive clinical guidelines. Findings from various studies employing neuroimaging techniques and animal models are discussed, as well as the impact of biological sex, gender, environmental, cultural, and social factors on brain development, organization, and behavior. Evidence suggests that sex differences in brain structure and function are not only genetically determined but arealso influenced by gender-related experiences and societal contexts. Importantly, discrepancies between male and female brains are reduced in gender-equal societies. Preclinical studies play a pivotal role in determining the influence of biological sex, independent of gender, in different disease models. The findings underscore the need to consider both sex and gender in research and clinical practice to avoid biases and promote equitable health outcomes. Moving forward, we advocate for gender-sensitive approaches to be integrated into brain research and in clinical guidelines to achieve personalized and precision medicine.

More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure.

Background Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. Methods We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. Results The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Conclusions Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.

Sex Differences in Human Brain Structure at Birth

BackgroundSex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain.MethodsHere, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development.ResultsOn average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts).ConclusionsOur findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain.

More similarity than difference: comparison of within- and between-sex variance in early adolescent brain structure.

Adolescent neuroimaging studies of sex differences in the human brain predominantly examine mean differences between males and females. This focus on between-groups differences without probing relative distributions and similarities may contribute to both conflation and overestimation of sex differences and sexual dimorphism in the developing human brain. We aimed to characterize the variance in brain macro- and micro-structure in early adolescence as it pertains to sex at birth using a large sample of 9-11 year-olds from the Adolescent Brain Cognitive Development (ABCD) Study (N=7,723). Specifically, for global and regional estimates of gray and white matter volume, cortical thickness, and white matter microstructure (i.e., fractional anisotropy and mean diffusivity), we examined: within- and between-sex variance, overlap between male and female distributions, inhomogeneity of variance via the Fligner-Killeen test, and an analysis of similarities (ANOSIM). For completeness, we examined these sex differences using both uncorrected (raw) brain estimates and residualized brain estimates after using mixed-effects modeling to account for age, pubertal development, socioeconomic status, race, ethnicity, MRI scanner manufacturer, and total brain volume, where applicable. The overlap between male and female distributions was universally greater than the difference (overlap coefficient range: 0.585 - 0.985) and the ratio of within-sex and between-sex differences was similar (ANOSIM R range: -0.001 - 0.117). All cortical and subcortical volumes showed significant inhomogeneity of variance, whereas a minority of brain regions showed significant sex differences in variance for cortical thickness, white matter volume, fractional anisotropy, and mean diffusivity. Inhomogeneity of variance was reduced after accounting for other sources of variance. Overlap coefficients were larger and ANOSIM R values were smaller for residualized outcomes, indicating greater within- and smaller between-sex differences once accounting for other covariates. Reported sex differences in early adolescent human brain structure may be driven by disparities in variance, rather than binary, sex-based phenotypes. Contrary to the popular view of the brain as sexually dimorphic, we found more similarity than difference between sexes in all global and regional measurements of brain structure examined. This study builds upon previous findings illustrating the importance of considering variance when examining sex differences in brain structure.

Sex Differences in Brain Structure in de novo Parkinson's Disease: A Cross-Sectional and Longitudinal Neuroimaging Study.

Parkinson's disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson's Progression Markers Initiative. Of these, 97 PD patients (66 males) completed 12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies.

Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data.

The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3-4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood.

Abstract HUP19: Sex Differences In Incidence Of Intraventricular Hemorrhage And Hydrocephalus In Patients With Non-traumatic Intracerebral Hemorrhage

Introduction: Non-traumatic Intracerebral Hemorrhage (ICH) accounts for 2 million strokes annually worldwide. This stroke burden disproportionately impacts minorities, and results in severe neurological deficits. Sex differences in brain structure and function, such as a larger mean length of frontal horn in males and increased global cerebral blood flow in women, can contribute to hematoma volume and expansion of ICH into nearby structures. No studies have yet to investigate sex differences in the incidence of Intraventricular Hemorrhage (IVH) and hydrocephalus as sequelae of ICH, both or which correlate with poor long-term outcomes. Methods: A retrospective review of a comprehensive stroke center spontaneous ICH database from 2019-2022 was performed, including patient characteristics such as history of diabetes mellitus, hypertension, coronary artery disease, tobacco use, and anticoagulant use in addition to ICH characteristics such as hematoma location volume, expansion, incidence of IVH and hydrocephalus. A logistic regression model controlling for these covariates was built to investigate sex differences in incidence of IVH and hydrocephalus. Results: This cohort had 100 patients with spontaneous, non-traumatic ICH, of which 39% were female. Overall, 52/100 (52%) patients had IVH and 21/100 (21%) patients developed hydrocephalus. Among males, 29/61(48%) had IVH as opposed to 23/39 (59%) in females, p = 0.264. There was similar development of hydrocephalus in both males 13/61(21%) and females 8/39 (21%). Logistic regression showed females had higher odds of IVH. Higher diastolic blood pressure and anticoagulant use on admission also had higher odds of IVH. Conclusion: This pilot study demonstrates a trend towards higher incidence of IVH among females when controlling for history of diabetes mellitus, hypertension, coronary artery disease, tobacco use, and anticoagulant use. Higher odds of IVH in patients with higher diastolic blood pressure on admission adds to the previously investigated association between systolic blood pressure and ICH hematoma volume. Our sample validated the higher odds of IVH in patients with anticoagulant use on admission.

P85. Sex Differences in Regional Patterns of Brain-Age-Gap Estimates

Neuroimaging studies have been instrumental in identifying sex-differences in brain structure, and there is robust evidence for age-related changes in brain structure throughout the lifespan. However, the literature on sex-differences in regional patterns of age-related changes in young adulthood remains limited. To address this, we availed of a machine learning model to obtain local brain-age-gap estimates (L-brainAGE), which reflect voxel-wise differences between an individual’s chronological and biological brain age.

Structural brain differences do not mediate the relations between sex and personality or psychopathology.

Males and females tend to exhibit small but reliable differences in personality traits and indices of psychopathology that are relatively stable over time and across cultures. Previous work suggests that sex differences in brain structure account for differences in domains of cognition. We used data from the Human Connectome Project (N=1098) to test whether sex differences in brain morphometry account for observed differences in the personality traits neuroticism and agreeableness, as well as symptoms of internalizing and externalizing psychopathology. We operationalized brain morphometry in three ways: omnibus measures (e.g., total gray matter volume), Glasser regions defined through a multi-modal parcellation approach, and Desikan regions defined by structural features of the brain. Most expected sex differences in personality, psychopathology, and brain morphometry were observed, but the statistical mediation analyses were null: sex differences in brain morphometry did not account for sex differences in personality or psychopathology. Men and women tend to exhibit meaningful differences in personality and psychopathology, as well as in omnibus morphometry and regional morphometric differences as defined by the Glasser and Desikan atlases, but these morphometric differences appear unrelated to the psychological differences.

Sex differences across developmental domains among children with a familial risk of severe mental disorders.

Sex differences in brain structure and neurodevelopment occur in non-clinical populations. We investigated whether sex had a similar effect on developmental domains amongst boys and girls with a familial risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and controls. Through Danish registries, we identified 522 7-year-old children (242 girls) with FHR-SZ, FHR-BP, and controls. We assessed their performance within the domains of neurocognition, motor function, language, social cognition, social behavior, psychopathology, and home environment. FHR-SZ boys compared with FHR-SZ girls had a higher proportion of disruptive behavior and attention-deficit hyperactivity disorder (ADHD) and exhibited lower performance in manual dexterity, balance, and emotion recognition. No sex differences were found between boys and girls within FHR-BP group. Compared with controls, both FHR-SZ boys and FHR-SZ girls showed impaired processing speed and working memory, had lower levels of global functioning, and were more likely to live in an inadequate home environment. Compared with control boys, FHR-SZ boys showed impaired manual dexterity, social behavior, and social responsiveness, and had a higher proportion of ADHD and disruptive behavior disorder diagnoses. Stress and adjustment disorders were more common in FHR-BP boys compared with control boys. We found no differences between FHR-BP girls and control girls. Impairment within neurodevelopmental domains associated within FHR-SZ boys v. FHR-SZ girls was most evident among boys, whereas no sex differences were found within the FHR-BP group (FHR-BP boys v. FHR-BP girls). FHR-SZ boys exhibited the highest proportion of early developmental impairments.

Effects of sex and age on presumed inhibitory interactions in 6 areas of the human cerebral cortex as revealed by the fMRI Human Connectome Project.

Cortical inhibition is theorized to reflect an underlying property of human brain function, sharpening tuning and shaping connectivity. Although age and sex effects on large-scale resting-state brain connectivity have been well documented, effects on local cortical inhibition have received relatively limited attention. Here, we evaluated age and sex effects on presumed local inhibitory interactions in 6 lateral cortical areas using resting-state functional magnetic resonance imaging (fMRI) data acquired from 1054 young adults who participated in the Human Connectome Project. For each area, all possible pairwise crosscorrelations between prewhitened blood oxygenation level-dependent (BOLD) time series were calculated, and the highest value (CCmax) was retained to determine the mean and percentage of negative and positive CCmax. Here, we focused on the percentage of negative CCmax which we referred to as presumed "percent inhibition". The results documented regional differences in percent inhibition as well as age and sex effects, such that women's brains were characterized by significantly higher percent inhibition than men overall and in 4 of the 6 cortical areas, and the percent inhibition increased significantly with age in all 6 areas for women but in only one area for men. The findings from this young adult sample are presumed to reflect ongoing maturational processes involving local network connectivity that may be shaped by sex differences in brain structure, function, and neurochemistry.

Are Sex Differences in Human Brain Structure Associated With Sex Differences in Behavior?

On average, men and women differ in brain structure and behavior, raising the possibility of a link between sex differences in brain and behavior. But women and men are also subject to different societal and cultural norms. We navigated this challenge by investigating variability of sex-differentiated brain structure within each sex. Using data from the Queensland Twin IMaging study (n = 1,040) and Human Connectome Project (n = 1,113), we obtained data-driven measures of individual differences along a male–female dimension for brain and behavior based on average sex differences in brain structure and behavior, respectively. We found a weak association between these brain and behavioral differences, driven by brain size. These brain and behavioral differences were moderately heritable. Our findings suggest that behavioral sex differences are, to some extent, related to sex differences in brain structure but that this is mainly driven by differences in brain size, and causality should be interpreted cautiously.

Sex differences in Brain Structure in individuals with knee osteoarthritis pain.

There is evidence of sex differences in the prevalence of chronic musculoskeletal pain as well as in experimental pain sensitivity. However, the neurobiological mechanisms contributing to these sex differences are poorly understood, especially with respect to brain structure. The aim of the present study is to examine sex differences in brain structure in persons with knee osteoarthritis (KOA) pain. Participants (mean age=58 years) with KOA pain (n=146, 65% female) completed demographic, self-reported and experimental pain assessments including temporal summation and conditioned pain modulation along with a 3T high-resolution, T1-weighted anatomical scan at 2 study sites in the US. FreeSurfer software (v.7.1.0, http://surfer.nmr.mgh.harvard.edu ) was used to examine sex differences in gray matter volume and cortical thickness as well as associations with experimental variables. Maps were set at a vertex-wise threshold of P 0.05). The results suggest that brain morphological differences between females and men with KOA pain are associated with distinct pain modulatory measures in men, but not in women. Future studies are needed to characterize potential neurobiological mechanisms underlying endogenous pain modulatory capacity across the sexes to further understand the individualized pain experience. R01AG059809, R01AG067757.

Sex differences in medial prefrontal and parietal cortex structure in children with disruptive behavior

Sex differences in brain structure in children with disruptive behavior disorders (DBD) remain poorly understood. This study examined sex differences in gray matter volume in children with DBD in a priori regions-of-interest implicated in the pathophysiology of disruptive behavior. We then conducted a whole-brain analysis of cortical thickness to examine sex differences in regions not included in our hypothesis. Exploratory analyses investigated unique associations between structure, and dimensional measures of severity of disruptive behavior and callous-unemotional traits. This cross-sectional study included 88 children with DBD (30 females) aged 8–16 years and 50 healthy controls (20 females). Structural MRI data were analyzed using surface-based morphometry to test for interactions between sex and group. Multiple-regression analyses tested for sex-specific associations between structure, callous-unemotional traits, and disruptive behavior severity. Boys with DBD showed reduced gray matter volume in the left ventromedial prefrontal cortex (vmPFC) and reduced cortical thickness in the supramarginal gyrus, but not girls compared to respective controls. Dimensional analyses revealed associations between sex, callous-unemotional traits, and disruptive behavior for amygdala and vmPFC volume, and ventrolateral prefrontal cortex cortical thickness. Sex-specific differences in prefrontal structures involved in emotion regulation may support identification of neural biomarkers of disruptive behavior to inform target-based treatments.

Testing relationships between multimodal modes of brain structural variation and age, sex and polygenic scores for neuroticism in children and adolescents

Human brain development involves spatially and temporally heterogeneous changes, detectable across a wide range of magnetic resonance imaging (MRI) measures. Investigating the interplay between multimodal MRI and polygenic scores (PGS) for personality traits associated with mental disorders in youth may provide new knowledge about typical and atypical neurodevelopment. We derived independent components across cortical thickness, cortical surface area, and grey/white matter contrast (GWC) (n = 2596, 3–23 years), and tested for associations between these components and age, sex and-, in a subsample (n = 878), PGS for neuroticism. Age was negatively associated with a single-modality component reflecting higher global GWC, and additionally with components capturing common variance between global thickness and GWC, and several multimodal regional patterns. Sex differences were found for components primarily capturing global and regional surface area (boys > girls), but also regional cortical thickness. For PGS for neuroticism, we found weak and bidirectional associations with a component reflecting right prefrontal surface area. These results indicate that multimodal fusion is sensitive to age and sex differences in brain structure in youth, but only weakly to polygenic load for neuroticism.

The influence of microsatellite polymorphisms in sex steroid receptor genes ESR1, ESR2 and AR on sex differences in brain structure

The androgen receptor (AR), oestrogen receptor alpha (ESR1) and oestrogen receptor beta (ESR2) play essential roles in mediating the effect of sex hormones on sex differences in the brain. Using Voxel-based morphometry (VBM) and gene sizing in two independent samples (discovery n ​= ​173, replication ​= ​61), we determine the common and unique influences on brain sex differences in grey (GM) and white matter (WM) volume between repeat lengths (n) of microsatellite polymorphisms AR(CAG)n, ESR1(TA)n and ESR2(CA)n. In the hypothalamus, temporal lobes, anterior cingulate cortex, posterior insula and prefrontal cortex, we find increased GM volume with increasing AR(CAG)n across sexes, decreasing ESR1(TA)n across sexes and decreasing ESR2(CA)n in females. Uniquely, AR(CAG)n was positively associated with dorsolateral prefrontal and orbitofrontal GM volume and the anterior corona radiata, left superior fronto-occipital fasciculus, thalamus and internal capsule WM volume. ESR1(TA)n was negatively associated with the left superior corona radiata, left cingulum and left inferior longitudinal fasciculus WM volume uniquely. ESR2(CA)n was negatively associated with right fusiform and posterior cingulate cortex uniquely. We thus describe the neuroanatomical correlates of three microsatellite polymorphisms of steroid hormone receptors and their relationship to sex differences.

4516 Sex Differences in the Cortical Structure in Children with Irritability and Disruptive Behavior

OBJECTIVES/GOALS: This study examines sex differences in brain structure in youths with disruptive behavior disorders (DBD). We use measures of gray matter volume (GMV) in regions-of-interest implicated in the pathophysiology of conduct problems and a whole-brain analysis of cortical thickness. We also examine unique associations between brain structure and callous-unemotional traits. METHODS/STUDY POPULATION: This study included 90 children with a DBD (30 females) aged 8-16 and 50 Healthy Controls (20 females) matched for age and IQ. Children received a diagnostic evaluation using the K-SADS. Pre-processing was conducted using FreeSurfer. For ROI analyses, multivariate GLM models were conducted in SPSS for estimates of GMV to examine the main effects of diagnosis and sex, and sex-by-diagnosis interactions. Whole-brain analyses were conducted in FreeSurfer. Associations were examined between structure and parent ratings of callous-unemotional (CU) traits using the Inventory of Callous-Unemotional Traits in regression analyses in the DBD group, while controlling for the variance in aggressive behavior using the Child Behavior Checklist Aggressive Behavior Scale. All analyses controlled for differences in intracranial volume. RESULTS/ANTICIPATED RESULTS: Relative to controls, children with DBD showed reduced GMV in the bilateral amygdala (left: p = .004; right: p = .04). Sex-by-diagnosis interactions were observed in the left ventromedial prefrontal cortex (p = .004), right insula (p = .001), right inferior frontal gyrus (p = .02), and bilateral anterior cingulate (left: p = .02; right: p = .01) in which DBD males showed lower and DBD females showed higher GMV relative to respective controls. For whole-brain analyses, a significant sex-by-diagnosis interaction was observed in the left ventromedial prefrontal cortex and supramarginal gyrus indicating that DBD males showed lower and DBD females showed higher cortical thickness relative to respective controls. Sex-by-CU traits interactions were observed for left amygdala and ACC volumes. DISCUSSION/SIGNIFICANCE OF IMPACT: The current study provides evidence of reduced amygdala volume in children with DBD, and interactions between sex and diagnosis in the ventromedial prefrontal cortex and supramarginal gyrus, which may have implications for identifying sex-sensitive neural biomarkers. CONFLICT OF INTEREST DESCRIPTION: Disclosures: Dr. Sukhodolsky receives royalties from Guilford Press for a treatment manual on CBT for anger and aggression in children. Drs. Ibrahim, He, Pelphrey, McCarthy, and Mr. Li have no biomedical financial interests or potential conflicts of interest to declare related to this present study.

The social brain in female autism: a structural imaging study of twins.

A female advantage in social cognition (SoC) might contribute to women’s underrepresentation in autism spectrum disorder (ASD). The latter could be underpinned by sex differences in social brain structure. This study investigated the relationship between structural social brain networks and SoC in females and males in relation to ASD and autistic traits in twins. We used a co-twin design in 77 twin pairs (39 female) aged 12.5 to 31.0 years. Twin pairs were discordant or concordant for ASD or autistic traits, discordant or concordant for other neurodevelopmental disorders or concordant for neurotypical development. They underwent structural magnetic resonance imaging and were assessed for SoC using the naturalistic Movie for the Assessment of Social Cognition. Autistic traits predicted reduced SoC capacities predominantly in male twins, despite a comparable extent of autistic traits in each sex, although the association between SoC and autistic traits did not differ significantly between the sexes. Consistently, within-pair associations between SoC and social brain structure revealed that lower SoC ability was associated with increased cortical thickness of several brain regions, particularly in males. Our findings confirm the notion that sex differences in SoC in association with ASD are underpinned by sex differences in brain structure.

Neuroendocrine-Immune Crosstalk Shapes Sex-Specific Brain Development.

Sex is an essential biological variable that significantly impacts multiple aspects of neural functioning in both the healthy and diseased brain. Sex differences in brain structure and function are organized early in development during the critical period of sexual differentiation. While decades of research establish gonadal hormones as the primary modulators of this process, new research has revealed a critical, and perhaps underappreciated, role of the neuroimmune system in sex-specific brain development. The immune and endocrine systems are tightly intertwined and share processes and effector molecules that influence the nervous system. Thus, a natural question is whether endocrine-immune crosstalk contributes to sexual differentiation of the brain. In this mini-review, we first provide a conceptual framework by classifying the major categories of neural sex differences and review the concept of sexual differentiation of the brain, a process occurring early in development and largely controlled by steroid hormones. Next, we describe developmental sex differences in the neuroimmune system, which may represent targets or mediators of the sexual differentiation process. We then discuss the overwhelming evidence in support of crosstalk between the neuroendocrine and immune systems and highlight recent examples that shape sex differences in the brain. Finally, we review how early life events can perturb sex-specific neurodevelopment via aberrant immune activation.

Sex differences in brain structure: a twin study on restricted and repetitive behaviors in twin pairs with and without autism

BackgroundFemales with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors.MethodsIn 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks.ResultsCo-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum.LimitationsHowever, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution.ConclusionsOur findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.