Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Perinatal and neonatal factors and mental disorders in children and adolescents: looking for the contributions of the early environment to common and dissociable aspects of psychopathology.

High rates of co-occurrence of mental disorders have been hypothesized to represent a result of common susceptibility to overall psychopathology. The purpose of this study is to test the hypothesis that commonalities among psychiatric disorders might be partially driven by sharable perinatal and neonatal environmental factors for mental disorders. Participants were 6-14 years of age children and their parents. Primary caregivers provided data on perinatal and neonatal information assessed retrospectively (n = 2231). Psychiatric disorders diagnoses were assessed using the Development and Well Being Behavior Assessment (DAWBA). We used bifactor models to disentangle common from dissociable aspects of psychopathology. These models allow modeling psychiatric disorders as the result of a common domain of psychopathology (p-factor) and three dissociable domains (fear, distress, and externalizing symptoms). Associations were tested using linear and tobit regression models. The p-factor was associated with male sex, low socioeconomic status, gestational smoking, gestational drinking, low levels of maternal education and presence of mental disorder in the mother. Associations with specific factors also emerged suggesting some risk factors might also have some role for fear, distress and externalizing factors. Our study supports the hypothesis that overall susceptibility to psychopathology might be partially driven by sharable perinatal and neonatal factors.

Replication of a predictive model for youth ADHD in an independent sample from a developing country.

BACKGROUND: Very few predictive models in Psychiatry had their performance validated in independent external samples. A previously developed multivariable demographic model for attention-deficit/hyperactivity disorder (ADHD) accurately predicted young adulthood ADHD using clinical and demographical information collected in childhood in three samples from developed countries, but failed to replicate its performance in a sample from a developing country. Furthermore, consolidated risk factors for ADHD were not included among its predictors. METHODS: Participants were 1905 children and adolescents from a community-based sample and followed from ages 6 to 14 years at baseline to ages 14 to 23 years (mean age 18) at follow-up. We applied the intercept and weights of the original model to the data, calculating the predicted probability of each participant according to the set of predictors collected in childhood, and compared the estimates with the actual outcome (ADHD) collected during adolescence and young adulthood. We explored the performance of the original model, and of models including novel predictors (prematurity, family history of ADHD, and polygenic risk score for ADHD). RESULTS: The observed area under the curve of the original model was .76 (95% Confidence Interval .70 to .82). The multivariable demographical model outperformed single variable models using only prematurity, family history, or the ADHD PRS. Adding either of these variables, or all at once, did not improve the performance of the original demographical model. CONCLUSIONS: Our findings suggest that the originally developed ADHD predictive model is suitable for use in different settings for clinical and research purposes.

Disentangling the influences of parental genetics on offspring's cognition, education, and psychopathology via genetic and phenotypic pathways.

BACKGROUND: Specific pathways of intergenerational transmission of behavioral traits remain unclear. Here, we aim to investigate how parental genetics influence offspring cognition, educational attainment, and psychopathology in youth. METHODS: Participants for the discovery sample were 2,189 offspring (aged 6-14 years), 1898 mothers and 1,017 fathers who underwent genotyping, psychiatric, and cognitive assessments. We calculated polygenic scores (PGS) for cognition, educational attainment, attention-deficit hyperactivity disorder (ADHD), and schizophrenia for the trios. Phenotypes studied included educational and cognitive measures, ADHD and psychotic symptoms. We used a stepwise approach and multiple mediation models to analyze the effect of parental PGS on offspring traits via offspring PGS and parental phenotype. Significant results were replicated in a sample of 1,029 adolescents, 363 mothers, and 307 fathers. RESULTS: Maternal and paternal PGS for cognition influenced offspring general intelligence and executive function via offspring PGS (genetic pathway) and parental education (phenotypic pathway). Similar results were found for parental PGS for educational attainment and offspring reading and writing skills. These pathways fully explained associations between parental PGS and offspring phenotypes, without residual direct association. Associations with maternal, but not paternal, PGS were replicated. No associations were found between parental PGS for psychopathology and offspring specific symptoms. CONCLUSIONS: Our findings indicate that parental genetics influences offspring cognition and educational attainment by genetic and phenotypic pathways, suggesting the expression of parental phenotypes partially explain the association between parental genetic risk and offspring outcomes. Multiple mediations might represent an effective approach to disentangle distinct pathways for intergenerational transmission of behavioral traits.

The synergistic effect of genetic and environmental factors in the development of attention-deficit/hyperactivity disorder symptoms in children and adolescents.

Gene-environment interactions (GxE) have been increasingly explored in psychiatry but with low replication rates. Attention-deficit/hyperactivity disorder (ADHD) is a suitable candidate for studying GxE due to its high heritability and well-defined environmental risk factors. Here, we explored GxE using polygenic risk score (PRS) to represent the genetic liability to ADHD (ADHD-PRS) and environmental risk score (ERS) to represent the combined effects of environmental risk factors. We analyzed longitudinal data of 2,046 individuals (6-14 years of age at baseline and 14-23 at the last follow-up) from the Brazilian High-Risk Cohort Study for Psychiatric Disorders. Psychiatric evaluation included the Child Behavior Checklist and the Strength and Difficulties Questionnaire. Statistical analyses were performed using mixed-effects models. We observed statistically significant interactions between ADHD-PRS and ERS, suggesting that environmental and genetic factors act synergistically in the development of ADHD symptoms. These effects were not present for depression or anxiety symptoms. No evidence of GxE correlation was detected. Mechanistically, our findings suggest that environmental stressors modulate the genetic risk for ADHD. Future studies should investigate whether the reduction of environmental risks can prevent the development of symptoms of ADHD, especially in children with a family history of the disorder.

Longitudinal associations between positive attributes and psychopathology and their interactive effects on educational outcomes.

Psychopathology is associated with impaired learning and early termination of schooling, whereas positive attributes are associated with better educational outcomes. However, it is important to understand if and how psychopathology and positive attributes longitudinally impact each other so we could shed light on where to intervene to promote educational outcomes through these constructs. A large prospective school-based community cohort of youths (5-15 years of age, 45% female) were assessed and followed up for 3 years (n = 2010; 80% retention). We assessed the longitudinal impact of positive attributes (Youth Strength Inventory) and psychopathology (bifactor model of Strengths and Difficulties Questionnaire) using a cross-lagged panel model. We also used generalized mixed effects models to investigate how these both constructs predict school dropout and literacy, adjusting for confounders and testing their interaction. Positive attributes negatively predicted, and were negatively predicted by, the general factor of psychopathology and conduct problems in the cross-lagged panel model. Positive attributes (OR = 0.57, 95% CI [0.44, 0.73], p < 0.001) and specific conduct symptoms (OR = 2.33, 95% CI [1.64, 3.33], p < 0.001) predicted school dropout, whereas the general factor of psychopathology predicted lower literacy ability (ß = - 0.08, 95% CI [- 0.11, - 0.05], p < 0.001). However, the protective association of positive attributes on school dropout decreases as the general factor of psychopathology increases. These findings provide new evidence that positive attributes and psychopathology mutually influence each other over development and have interactive effects on educational outcomes.

Childhood poverty and mental health disorders in early adulthood: evidence from a Brazilian cohort study.

BACKGROUND: We examined the association between childhood poverty and mental health disorders (MHD) in childhood and early adulthood. We also investigated whether the association between poverty in childhood and MHD is mediated by exposure to stressful life events (SLE). METHODS: We used data from a prospective community cohort of young people assessed at baseline (M = 9.7 years, SD = 1.9), first (M = 13.5 years, SD = 1.9), and second (M = 18.2 years, SD = 2.0) follow-ups (N = 1,590) in Brazil. Poverty was assessed using a standardized classification. Exposure to 20 different SLE was measured using the Life History instrument. Psychiatric diagnoses were evaluated using the Development and Well-Being Assessment. Latent growth models investigated the association between poverty at baseline and the growth of any MHD, externalizing, and internalizing disorders. Mediation models evaluated whether the association between childhood poverty and MHD in early adulthood was mediated by exposure to SLE. RESULTS: Poverty affected 11.4% of the sample at baseline and was associated with an increased propensity for presenting externalizing disorders in adolescence or early adulthood (standardized estimate = 0.27, p = 0.016). This association was not significant for any disorder or internalizing disorders. Childhood poverty increased the likelihood of externalizing disorders in early adulthood through higher exposure to SLE (OR = 1.07, 95 CI% 1.01-1.14). Results were only replicated among females in stratified analyses. CONCLUSIONS: Childhood poverty had detrimental consequences on externalizing MHD in adolescence, especially among females. Poverty and SLE are preventable risk factors that need to be tackled to reduce the burden of externalizing disorders in young people.

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Long-term stability of the cortical volumetric profile and the functional human connectome throughout childhood and adolescence.

There is compelling evidence showing that between-subject variability in several functional and structural brain features is sufficient for unique identification in adults. However, individuation of brain functional connectomes depends on the stabilization of neurodevelopmental processes during childhood and adolescence. Here, we aimed to (1) evaluate the intra-subject functional connectome stability over time for the whole brain and for large scale functional networks and (2) determine the long-term identification accuracy or 'fingerprinting' for the cortical volumetric profile and the functional connectome. For these purposes, we analysed a longitudinal cohort of 239 children and adolescents scanned in two sessions with an interval of approximately 3 years (age range 6-15 years at baseline and 9-18 years at follow-up). Corroborating previous results using short between-scan intervals in children and adolescents, we observed a moderate identification accuracy (38%) for the whole functional profile. In contrast, identification accuracy using cortical volumetric profile was 95%. Among the large-scale networks, the default-mode (26.8%), the frontoparietal (23.4%) and the dorsal-attention (27.6%) networks were the most discriminative. Our results provide further evidence for a protracted development of specific individual structural and functional connectivity profiles.

Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities.

BACKGROUND: Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear. AIMS: We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed. METHOD: This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model. RESULTS: A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure. CONCLUSIONS: Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.