Search

Abstract Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson’s disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4–5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

Abstract DNA methylation (DNAm) is the most commonly measured epigenetic mechanism in human populations, with most studies using Illumina arrays to assess DNAm levels. In 2023, Illumina updated their DNAm arrays to the EPIC version 2 (EPICv2), building on prior iterations, namely the EPIC version 1 (EPICv1) and 450K arrays. Whether DNAm measurements are stable across these three generations of arrays has yet not been investigated, limiting the ability of researchers—especially those with longitudinal data—to compare and replicate results across arrays. Here, we present results from a study of 30 child participants (15 male; 15 female) from the Drakenstein Child Health Study, who had DNAm measured on all three of the latest arrays: 450K, EPICv1, and EPICv2. Using these data, we created an annotation of probe quality across arrays, which includes the intraclass correlations, interquartile ranges, correlations, and array bias (i.e., the extent to which DNAm levels were explained by array type) of all CpGs. We also present results from an analysis of sex differences, where we found that CpGs with lower replicability across arrays had higher array-based variance, suggesting this variance metric help guide replication efforts. We also showed that epigenetic age estimates across arrays were more stable when using the principal component versions of epigenetic clocks. Ultimately, this collection of results provides a framework for investigating the replicability and longitudinal stability of epigenetic changes across multiple versions of Illumina DNAm arrays.

African populations are currently underrepresented in global psychiatric genetics research. Here, we highlight the importance of conducting psychiatric genetics research in Africa, key issues which have hindered such research, and ongoing initiatives and strategies to overcome these issues.

Abstract Background Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p

Abstract The progression of Parkinson’s disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20–89 years; 33% female) and 885 controls (age: 19–84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen’s d effect sizes reached d = −1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Deer mice (Peromyscus maniculatus bairdii), a wildtype species native to North America, have been investigated for their spontaneous compulsive-like behaviour. The repetitive and persistence nature of three unique compulsive-like phenotypes in deer mice, i.e., high stereotypy (HS), large nesting behaviour (LNB) and high marble burying (HMB), are characterized by behavioural and cognitive rigidity. In this narrative review, we summarize key advances in the model's application to study obsessive-compulsive disorder (OCD), emphasizing how it may be used to investigate neurobiological and neurocognitive aspects of rigidity. Indeed, deer mice provide the field with a unique naturalistic and spontaneous model system of behavioural and cognitive rigidity that is useful for investigating the psychobiological mechanisms that underpin a range of compulsive-like phenotypes. Throughout the review, we highlight new opportunities for future research.

Background: The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) is a tool to assess the capacity of participants to consent in psychiatric research. However, little is known about the psychometric properties in low and middle-income countries. This study aimed to examine the psychometric properties of the UBACC. Methods: We examined the reliability, latent factor structure, and item response of the first attempt of the UBACC items in a sample of 32,208 adults (16,467 individuals with psychosis and 15,741 controls) in Ethiopia, Kenya, South Africa, and Uganda; exploring these properties in the full sample and stratified by country, diagnostic status, sex, and ethnolinguistic language groups. Results: Exploratory factor analysis (EFA) suggested a two-factor model for the overall sample. However, a three-factor model was more appropriate when examining the latent structure across country, language, and sex. Confirmatory factor analyses (CFA) revealed an adequately fitting three-factor model for the full sample and across country, sex, and language. A two-factor model, however, was more appropriate for English and Amharic languages. Across all groups, the internal consistency of the UBACC was low, indicating below-threshold reliability (Cronbach's α (95 % CI = 0.58 (0.57–0.59). Using a multidimensional item-response theory framework for the full sample revealed that UBACC item 8, measuring understanding of the benefits of study participation, was the most discriminating item. Many of the other items had below-threshold discriminating characteristics. Conclusion: EFA and CFA converged towards a two and three-dimensional structure for the UBACC, in line with the developers of the original scale. The differences in properties between populations and language groups, low internal consistency, and below-threshold item functioning suggest that investigations into the cultural and linguistic nuances are still warranted. Understanding the utility of consent tools, such as the UBACC, in underrepresented populations will be a part of the larger process which ensures that research participants are adequately protected.

Abstract Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.

Abstract Background Magnetic Resonance Imaging (MRI)-based imaging techniques are useful for assessing white matter (WM) structural and microstructural integrity in the context of infection and inflammation. The purpose of this scoping review was to assess the range of work on the use of WM neuroimaging approaches to understand the impact of congenital and perinatal viral infections or exposures on the developing brain. Methods This scoping review was conducted according to the Arksey and O’ Malley framework. A literature search was performed in Web of Science, Scopus and PubMed for primary research articles published from database conception up to January 2022. Studies evaluating the use of MRI-based WM imaging techniques in congenital and perinatal viral infections or exposures were included. Results were grouped by age and infection. Results A total of 826 articles were identified for screening and 28 final articles were included. Congenital and perinatal infections represented in the included studies were cytomegalovirus (CMV) infection (n = 12), human immunodeficiency virus (HIV) infection (n = 11) or exposure (n = 2) or combined (n = 2), and herpes simplex virus (HSV) infection (n = 1). The represented MRI-based WM imaging methods included structural MRI and diffusion-weighted and diffusion tensor MRI (DWI/ DTI). Regions with the most frequently reported diffusion metric group differences included the cerebellar region, corticospinal tract and association fibre WM tracts in both children with HIV infection and children who are HIV-exposed uninfected. In qualitative imaging studies, WM hyperintensities were the most frequently reported brain abnormality in children with CMV infection and children with HSV infection. Conclusion There was evidence that WM imaging techniques can play a role as diagnostic and evaluation tools assessing the impact of congenital infections and perinatal viral exposures on the developing brain. The high sensitivity for identifying WM hyperintensities suggests structural brain MRI is a useful neurodiagnostic modality in assessing children with congenital CMV infection, while the DTI changes associated with HIV suggest metrics such as fractional anisotropy have the potential to be specific markers of subtle impairment or WM damage in neuroHIV.

IntroductionTobacco and alcohol are the two most common substances used during pregnancy, and both can disrupt neurodevelopment, resulting in cognitive and behavioral deficits including language difficulties. Previous studies show that children with prenatal substance exposure exhibit microstructural alterations in major white matter pathways, though few studies have investigated the impact of prenatal substance exposure on white matter microstructure and language skills during the toddler years.MethodsIn this study, 93 children (34 exposed to alcohol and/or tobacco) aged 23 years from the Drakenstein Child Health Study, South Africa, completed Expressive and Receptive Communication assessments from the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and underwent diffusion MRI scans. Diffusion images were preprocessed, and 11 major white matter tracts were isolated. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted for each white matter tract. Linear regression was used to examine differences between the tobacco/alcohol exposed group and unexposed controls for FA, MD, and language scores, as well as relationships between brain metrics and language. There were no significant group differences in language scores or FA.ResultsChildren with alcohol or tobacco exposure had lower average MD in the splenium of the corpus callosum compared to unexposed controls. Significant interactions between prenatal substance exposure and language scores were seen in 7 tracts but did not survive multiple comparisons correction.DiscussionOur findings show that prenatal alcohol and/or tobacco exposure appear to alter the relationship between white matter microstructure and early language skills in this population of toddlers, potentially laying the basis of language deficits observed later in older children with prenatal substance exposure, which may have implications for learning and interventions.

Background/Aims The emerging concept of retinal age, a biomarker derived from retinal images, holds promise in estimating biological age. The retinal age gap (RAG) represents the difference between retinal age and chronological age, which serves as an indicator of deviations from normal ageing. This scoping review aims to collate studies on retinal age to determine its potential clinical utility and to identify knowledge gaps for future research.Methods Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist, eligible non-review, human studies were identified, selected and appraised. PubMed, Scopus, SciELO, PsycINFO, Google Scholar, Cochrane, CINAHL, Africa Wide EBSCO, MedRxiv and BioRxiv databases were searched to identify literature pertaining to retinal age, the RAG and their associations. No restrictions were imposed on publication date.Results Thirteen articles published between 2022 and 2023 were analysed, revealing four models capable of determining biological age from retinal images. Three models, ‘Retinal Age’, ‘EyeAge’ and a ‘convolutional network-based model’, achieved comparable mean absolute errors: 3.55, 3.30 and 3.97, respectively. A fourth model, ‘RetiAGE’, predicting the probability of being older than 65 years, also demonstrated strong predictive ability with respect to clinical outcomes. In the models identified, a higher predicted RAG demonstrated an association with negative occurrences, notably mortality and cardiovascular health outcomes.Conclusion This review highlights the potential clinical application of retinal age and RAG, emphasising the need for further research to establish their generalisability for clinical use, particularly in neuropsychiatry. The identified models showcase promising accuracy in estimating biological age, suggesting its viability for evaluating health status.

Background: There are several established structured diagnostic interviews that cover common mental disorders seen in general psychiatry clinics. The administration of more focused diagnostic interviews may be useful in specialty clinics, such as OCD clinics. A semi-structured clinician-administered interview for obsessive-compulsive spectrum disorders (SCID-OCSD) was developed and adapted for DSM-5/ICD-11 obsessive-compulsive and related disorders as well as other putative obsessive-compulsive spectrum conditions. Objective: To introduce a semi-structured diagnostic interview for in-depth assessment of obsessive-compulsive spectrum disorders (OCSDs), and to report on its implementation in adults with primary OCD attending an OCD-specialized unit. Methods: Patients with primary OCD were interviewed using the SCID-OCSD. The SCID-OCSD assesses disorders drawn from several diagnostic categories that share some core features of obsessive-compulsive phenomenology and that are often comorbid in OCD (e.g., obsessive-compulsive related disorders, impulse-control disorders, and a spectrum of compulsive-impulsive conditions such as tics, eating disorders, non-suicidal self-injury, and behavioral addictions. Participants had to be at least moderately symptomatic on the Yale-Brown Obsessive-Compulsive Severity scale (YBOCS, i.e., a total score ≥ 14) to be included in the current study. Results: One hundred and one adult patients with current OCD (n = 101, 37 men and 64 women), took part in the study. Forty-two participants (n = 42) had OCD and one or more current or past comorbid OCSDs, with excoriation (skin-picking) disorder (n = 16) and body dysmorphic disorder (n = 14) being the most common. Nine (n = 9) participants reported a history of non-suicidal self-injury, and 6 participants reported a history of comorbid tics. Conclusions: In OCD clinics, the SCID-OCSD may help diagnose the full range of putative OCSDs, and so facilitate treatment planning and research on these conditions.

Abstract Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are ‘modern’. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, ‘mya’), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are ‘ancient’, meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as ‘medium-aged’. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

Abstract Background There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exposed and uninfected (HEU) compared to HIV-unexposed (HU) children and to examine the relationship with neurodevelopment. Methods The Drakenstein Child Health birth cohort study enrolled pregnant women from a high HIV prevalence area in South Africa with longitudinal follow-up of mother–child pairs. High-resolution magnetic resonance imaging scans from 162 children (70 HEU; 92 HU) were acquired at 2–3 years of age. All HEU children were born to mothers taking antiretroviral therapy. Measures of brain structure (cortical thickness and surface area) in the prefrontal cortex regions were extracted from T1-weighted images and compared between groups using multivariate analysis of variance and linear regression. Child development, assessed using the Bayley Scales of Infant and Toddler Development-III, was correlated with cortical structure, and mediation analyses were performed. Results Analyses demonstrated an association between HIV exposure and cortical thickness across the prefrontal cortex (p = 0.035). Children who were HEU had thicker cortices in prefrontal regions, with significantly greater cortical thickness in the medial orbitofrontal cortex (mOFC) bilaterally compared to HU children (3.21 mm versus 3.14 mm, p = 0.009, adjusted effect size 0.44 [95% CI 0.12 to 0.75]). Estimates held across multiple sensitivity analyses. There were no group differences in cortical surface area. Language scores, which were lower in HEU versus HU children (81.82 versus 86.25, p = 0.011, effect size − 0.44 [95% CI − 0.78 to − 0.09]), negatively correlated with prefrontal cortical thickness in both groups. Cortical thickness in the mOFC mediated the relationship between HIV exposure and poor language outcomes (Sobel test p = 0.032). Conclusions In this cohort study, exposure to HIV during pregnancy was associated with altered cortical structure in early life. Our findings indicate that differences in cortical thickness development in the prefrontal region in children who are HEU may be a pathway leading to language impairment. Longitudinal studies are needed to determine the lasting impact.

Abstract Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.

Abstract Background Mental health service providers are increasingly interested in patient perspectives. We examined rates and predictors of patient-reported satisfaction and perceived helpfulness in a cross-national general population survey of adults with 12-month DSM-IV disorders who saw a provider for help with their mental health. Methods Data were obtained from epidemiological surveys in the World Mental Health Survey Initiative. Respondents were asked about satisfaction with treatments received from up to 11 different types of providers (very satisfied, satisfied, neither satisfied nor dissatisfied, somewhat dissatisfied, very dissatisfied) and helpfulness of the provider (a lot, some, a little, not at all). We modelled predictors of satisfaction and helpfulness using a dataset of patient-provider observations (n = 5,248). Results Most treatment was provided by general medical providers (37.4%), psychiatrists (18.4%) and psychologists (12.7%). Most patients were satisfied or very satisfied (65.9-87.5%, across provider) and helped a lot or some (64.4-90.3%). Spiritual advisors and healers were most often rated satisfactory and helpful. Social workers in human services settings were rated lowest on both dimensions. Patients also reported comparatively low satisfaction with general medical doctors and psychiatrists/psychologists and found general medical doctors less helpful than other providers. Men and students reported lower levels of satisfaction than women and nonstudents. Respondents with high education reported higher satisfaction and helpfulness than those with lower education. Type of mental disorder was unrelated to satisfaction but in some cases (depression, bipolar spectrum disorder, social phobia) was associated with low perceived helpfulness. Insurance was unrelated to either satisfaction or perceived helpfulness but in some cases was associated with elevated perceived helpfulness for a given level of satisfaction. Conclusions Satisfaction with and perceived helpfulness of treatment varied as a function of type of provider, service setting, mental status, and socio-demographic variables. Invariably, caution is needed in combining data from multiple countries where there are cultural and service delivery variations. Even so, our findings underscore the utility of patient perspectives in treatment evaluation and may also be relevant in efforts to match patients to treatments.

Abstract Central nervous system involvement in HIV infection leads to neurobehavioural sequelae. Although apathy is a well-recognised symptom in adults living with HIV linked to alterations in brain structure, there is scarce research examining motivation in children living with HIV (CLWH). We used the Children’s Motivation Scale (CMS; normative mean = 50, SD = 10) to assess motivation levels in 76 CLWH aged 6–16 years (63 on antiretroviral therapy [ART]; 13 ART-naïve slow progressors) in South Africa. Overall, CLWH scored low on the CMS (mean = 35.70 [SD = 5.87]). Motivation levels were significantly reduced in children taking ART compared to ART-naïve slow progressors (p = 0.02), but were not correlated with markers of HIV disease (CD4 + cell count or viral load), or neurocognitive function (p > 0.05). CMS scores were correlated with diffusion tensor imaging metrics of white matter microstructure in specific frontostriatal brain regions (p

Background: Benzodiazepines and antidepressants are effective agents for the treatment of generalized anxiety disorder (GAD), with the HAM-A frequently used as a primary outcome measure. The GAD literature is inconsistent regarding which medications are more effective for somatic versus psychic symptoms of GAD, and treatment guidelines do not advocate for prescribing based on subtype. This meta-analysis aimed to determine whether benzodiazepines and antidepressants have a differential impact on the somatic versus psychic subscales of the HAM-A in GAD. Methods: An electronic search was undertaken for randomized controlled trials of either benzodiazepines or antidepressants for GAD that reported treatment response using the HAM-A subscales. Data were extracted by independent reviewers. A random effects assessment of weighted mean difference with 95% confidence intervals and subgroup difference was applied. All analysis was done on SPSS 26. An assessment of bias, and of quality of evidence was performed. Results: 24 randomized controlled trials met the inclusion criteria: 18 antidepressant trials, 5 benzodiazepine trials and 1 of both. 14 studies were assessed as having between some and high risk of bias, while 10 were assessed as having low risk of bias. Benzodiazepines (WMD of 1.81 [CI 1.03, 2.58]) were significantly more effective than antidepressants (WMD of 0.83 [CI 0.64, 1.02]) for reducing somatic symptoms of GAD (Chi2 = 5.81, p = 0.02), and were also more effective (WMD of 2.46 [CI 1.83, 3.09]) in reducing psychic symptoms than antidepressants (WMD of 1.83 [CI 1.55, 2.10]), although this comparison did not reach statistical significance (Chi2 = 3.31, p = 0.07). Conclusion: The finding that benzodiazepines were significantly more effective than antidepressants for somatic symptoms needs to be weighed up against potential benefits of antidepressants over benzodiazepines. It may be useful for future treatment guidelines for GAD to explicitly consider symptom subtype.

The focus of debates about conversational artificial intelligence (CAI) has largely been on social and ethical concerns that arise when we speak to machines—what is gained and what is lost when we replace our human interlocutors, including our human therapists, with AI. In this viewpoint, we focus instead on a distinct and growing phenomenon: letting machines speak for us. What is at stake when we replace our own efforts at interpersonal engagement with CAI? The purpose of these technologies is, in part, to remove effort, but effort has enormous value, and in some cases, even intrinsic value. This is true in many realms, but especially in interpersonal relationships. To make an effort for someone, irrespective of what that effort amounts to, often conveys value and meaning in itself. We elaborate on the meaning, worth, and significance that may be lost when we relinquish effort in our interpersonal engagements as well as on the opportunities for self-understanding and growth that we may forsake.

The Kessler Psychological Distress Scale (K10) has been widely used to screen psychological distress across many countries. However, its performance has not been extensively studied in Africa. The present study sought to evaluate and compare measurement properties of the K10 across four African countries: Ethiopia, Kenya, Uganda, and South Africa. Our hypothesis is that the measure will show equivalence across all.Data are drawn from a neuropsychiatric genetic study among adult participants (N = 9179) from general medical settings in Ethiopia (n = 1928), Kenya (n = 2556), Uganda (n = 2104), and South Africa (n = 2591). A unidimensional model with correlated errors was tested for equivalence across study countries using confirmatory factor analyses and the alignment optimization method. Results displayed 30 % noninvariance (i.e., variation) for both intercepts and factor loadings across all countries. Monte Carlo simulations showed a correlation of 0.998, a good replication of population values, indicating minimal noninvariance, or variation. Items “so nervous,” “lack of energy/effortful tasks,” and “tired” were consistently equivalent for intercepts and factor loadings, respectively. However, items “depressed” and “so depressed” consistently differed across study countries (R2 = 0) for intercepts and factor loadings for both items.The K10 scale likely functions equivalently across the four countries for most items, except “depressed” and “so depressed.” Differences in K10 items were more common in Kenya and Ethiopia, suggesting cultural context may influence the interpretation of some items and the potential need for cultural adaptations in these countries.

Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Abstract Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P

Abstract Introduction Lifestyle factors such as smoking, alcohol use, suboptimal diet, and inadequate physical activity have been associated with increased risk of cardiovascular diseases. There are limited data on these risk factors among patients with psychosis in low- and middle-income countries. Objectives This study aimed to establish the prevalence of lifestyle cardiovascular risk factors, and the 10-year cardiovascular risk scores and associated factors in patients with psychosis compared to controls at Moi Teaching and Referral Hospital in Eldoret, Kenya. Methods A sample of 297 patients with schizophrenia, schizoaffective disorder, or bipolar mood disorder; and 300 controls matched for age and sex were included in this analysis. A study specific researcher-administered questionnaire was used to collect data on demographics, antipsychotic medication use, smoking, alcohol intake, diet, and physical activity. Weight, height, abdominal circumference, and blood pressure were also collected to calculate the Framingham 10-year Cardiovascular Risk Score (FRS), while blood was drawn for measurement of glucose level and lipid profile. Pearson’s chi-squared tests and t-tests were employed to assess differences in cardiovascular risk profiles between patients and controls, and a linear regression model was used to determine predictors of 10-year cardiovascular risk in patients. Results Compared to controls, patients with psychosis were more likely to have smoked in their lifetimes (9.9% vs. 3.3%, p = 0.006) or to be current smokers (13.8% vs. 7%, p = 0.001). Over 97% of patients with psychosis consumed fewer than five servings of fruits and vegetables per week; 78% engaged in fewer than three days of vigorous exercise per week; and 48% sat for more than three hours daily. The estimated 10-year risk of CVD was relatively low in this study: the FRS in patients was 3.16, compared to 2.93 in controls. The estimated 10-year cardiovascular risk in patients was significantly associated with female sex (p = 0.007), older patients (p

Abstract Background Mental health problems are common and impairing among university students, yet only a minority of students with psychological disorders access treatment. Understanding barriers to treatment is integral to planning services, especially in resource constrained settings like South Africa (SA). Methods Data collected across 17 institutions in the online SA National Student Mental Health Survey were used to: (1) estimate 12-month prevalence of common mental health problems and self-harm; (2) estimate the proportion of students receiving treatments for the various mental health problems; (3) explore barriers to treatment; and (4) investigate sociodemographic predictors of treatment mediated through the various barriers endorsed by students with mental health problems. Prevalence analyses were carried out using cross-tabulations and prediction analyses using modified Poisson regression models. Results Prevalence of clinically significant mental health problems is high relative to international comparisons, with the prevalence of severe, mild and moderate symptoms of any disorder and/or self-harm of 24.8% (SD = 0.3), 18.8% (SD = 0.3) and 27.6% (SD = 0.4) respectively. Treatment rates were 35.2% (S.E. = 0.6) among students with mental health problems who perceived need for treatment and 21.3% (S.E. = 0.4) irrespective of perceived need. Treatment rates were highest for mood disorders (29.9%, S.E. = 0.6) and lowest for externalising disorders (23.8%, S.E. = 0.5). Treatment rates were much less variable across disorder types among students with perceived need than irrespective of perceived need, indicating that perceived need mediated the associations of disorder types with received treatment. Adjusting for disorder profile, probability of obtaining treatment was significantly and positively associated with older age, female gender, study beyond the first year, traditional sexual orientation, and diverse indicators of social advantage (full-time study, high parent education, and attending Historically White Institutions). Among students with mental health problems, numerous barriers to treatment were reported adjusting for disorder profile, including lack of perceived need (39.5%, S.E. = 0.5) and, conditional on perceived need, psychological (54.4%, S.E. = 1.0), practical (77.3%, S.E. = 1.1), and other (79.1%, S.E. = 1.1) barriers. Typically, students reported multiple barriers to treatment. Differences in perceived need explained the gender difference in treatment, whereas practical barriers were most important in accounting for the other predictors of treatment. Conclusion Mental health problems are highly prevalent but seldom treated among SA university students. Although many barriers were reported, practical barriers were especially important in accounting for the associations of social disadvantage with low rates of treatment. Many of these practical barriers are however addressable.

Abstract Background The negative impact of prenatal alcohol and tobacco exposure (PAE and PTE) on fetal development and birth outcomes are well described, yet pathophysiologic mechanisms are less clear. Our aim was to investigate (1) the associations between quantity, frequency and timing (QFT) of PAE and PTE with blood flow velocities in arteries of the fetal-placental-maternal circulation and (2) the extent to which combined effect of QFT of PAE and/or PTE and Doppler flow velocity waveforms (FWV) predict infant birth weight. Methods The Safe Passage Study is a cohort based in urban Cape Town, South Africa. Recruitment occurred between 2007 and 2015. Information on QFT of PAE and PTE was collected prospectively at up to 4 occasions during pregnancy using a modified Timeline Follow-Back approach. Ultrasound examinations consisted of Doppler flow velocity waveforms of the uterine, umbilical (UA) and fetal middle cerebral arteries for the pulsatility index (PI) at 20–24 and 34–38 weeks. Exclusion criteria included: twin pregnancies, stillbirths, participants exposed to other drugs. The sample was divided into three groups (controls, PAE and PTE) and included 1396 maternal-fetal-dyads assessed during the second trimester; 1398 assessed during the third trimester. Results PTE was associated with higher UA PI values in second and third trimesters (p

Background: Adverse childhood experiences (ACEs) are associated with impaired cognitive function in adult life in the general population as well as in people living with schizophrenia (PLS). Research on cognitive function in PLS in low- and middle-income countries (LMIC) is, however, limited. The objectives of this study were to investigate the association between ACE types and various cognitive domains in a sample of PLS and matched medical controls, and to determine the moderating effect of group membership (PLS vs. medical controls) on these associations, in the South African setting. Methods: Participants (n PLS = 520; n medical controls = 832) completed the Childhood Trauma Questionnaire-Short Form, the Structured Clinical Interview for DSM-IV (SCID-I), and the University of Pennsylvania Computerized Neurocognitive Battery (PennCNB). An efficiency or speed score was used to assess performance across 9 cognitive domains. The association between exposure to different ACE types and 9 cognitive domains was examined using partial correlations and multiple linear regression models, adjusting for sex, age and education years. Finally, potential moderating effects of group membership (PLS vs. medical controls) on the association between ACEs and cognitive domains were tested. Results: In the entire sample, emotional and physical abuse predicted worse performance on sensorimotor and emotion identification domains. Also, emotional abuse was negatively associated with motor function, physical abuse was negatively associated with spatial processing, and physical neglect was negatively associated with face memory and emotion identification. In contrast, emotional neglect was related to better performance on abstraction and mental flexibility. No moderating effect of group membership was found on any of these associations. Conclusion: Exposure to ACEs was associated with social and non-social cognition in adulthood, although the magnitude of these relationships was small and similar between PLS and matched medical controls. The nature of these associations differed across ACE subtype, suggesting the need for a nuanced approach to studying a range of mechanisms that may underlie different associations. However, a number of ACE subtypes were associated with worse performance on emotional identification, indicating that some underlying mechanisms may have more transversal impact. These findings contribute to the sparse body of literature on ACEs and cognition in PLS in LMIC.

Background: The publication of South Africa's National Mental Health Policy Framework and Strategic Plan 2023–2030 and the proposed National Health Insurance (NHI) make it timely to review that state of mental health services in the country, and to emphasize the importance of prioritising mental health as a pivotal component of holistic healthcare. Method: We searched the published literature on mental health using Google Scholar, Pubmed, and Bing Chat, focusing on these words: epidemiology of mental health disorders, depression and anxiety disorders, mental health services, mental health facilities, human resources, financing and impact of COVID-19 on mental health in South Africa and beyond. We also searched the grey literature on mental health policy that is publicly available on Google. Results: We provided information on the epidemiology and economic impact of mental health disorders, the availability of mental health services, enabling policies, human resources, financing, and the infrastructure for mental health service delivery in South Africa. We detail the high lifetime prevalence rates of common mental disorders, as well as the profound impact of socioeconomic determinants such as poverty, unemployment, and trauma on mental health disorders. We note the exacerbating effect of the COVID-19 pandemic, and emphasize the pressing need for a robust mental health care system. Conclusion: In addition to outlining the challenges, such as limited mental health service availability, a shortage of mental health professionals, and financial constraints, the review proposes potential solutions, including task-sharing, telehealth, and increasing the production of mental health professionals. The paper underscores the necessity of crafting a comprehensive NHI package of mental health services tailored to the local context. This envisioned package would focus on evidence-based interventions, early identification, and community-based care. By prioritising mental health and addressing its multifaceted challenges, South Africa can aspire to render accessible and equitable mental health services for all its citizens within the framework of the National Health Insurance.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

IntroductionThere are approximately 16 million children who are HIV-exposed and uninfected (CHEU) worldwide. Studies suggest that CHEU are at risk for developmental impairment in infancy, particularly in language domains. However, there is limited research examining neurocognitive function in CHEU older than 2 years, including important pre-school years. This study aimed to investigate associations between HIV exposure without infection and neurocognitive outcomes and to determine risk factors for neurodevelopment in CHEU at age 3-4 years.MethodsThe Drakenstein Child Health Study is a South African population-based birth cohort which enrolled women in pregnancy with ongoing follow up. Neurocognitive outcomes were assessed in children at 3.5 years by trained assessors blinded to HIV status including general cognitive function, language, and memory, measured using the Kaufmann Assessment Battery for Children, Second Edition (KABC-II). Data were compared between CHEU and children who were HIV-unexposed uninfected (CHUU) using multivariable logistic and linear regression, including testing for effect modification; sex-stratified risk factor analyses were performed.ResultsA total of 497 children were included (97 [20%] CHEU; 400 [80%] CHUU; 50% male), with a mean age of 3.5 years (range 3.4-3.6). Groups had similar birth and household characteristics, although mothers of CHEU were older, on average. Overall, CHEU had lower expressive language scores compared to CHUU on unadjusted and adjusted analyses (effect size: -0.23 [95% CI -0.45, -0.01]). There were no group differences in general cognitive or memory function (p>0.05). On sex-stratified analyses, male CHEU were found to have higher odds of suboptimal cognitive development compared to male CHUU (aOR 2.28 [95% CI 1.06, 4.87], p = 0.034). Several other factors including birthweight, maternal education, maternal ART duration and HIV viral load during pregnancy were associated with cognition, memory, or expressive language outcomes in CHEU, dependent on child sex.InterpretationThe findings suggest that perinatal HIV exposure continues to be associated with impaired language development across the preschool years, highlighting the importance of targeting early interventions to optimise language outcomes. Further, the results suggest the importance of demographic, biological and HIV-related variables influencing developmental outcomes in CHEU. The greater risk of suboptimal cognitive development in male CHEU requires investigation around sex-specific mechanisms.

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to measure IQ across a five-site, multinational study and demonstrate the harmonized measure’s cross-site validity. Culturally appropriate intelligence measures were selected: four short-form Wechsler intelligence tests (Brazil, Netherlands, South Africa, United States) and the Binet Kamat (India). Analyses included IQ scores from 255 healthy participants (age 18–50; 42% male). Regression analyses tested between-site differences in IQ scores, as well as expected associations with sociodemographic factors (sex, socioeconomic status, education) to assess validity. Harmonization (e.g., a priori selection of tests) yielded the compatibility of IQ measures. Higher IQ was associated with higher socioeconomic status, suggesting good convergent validity. No association was found between sex and IQ at any site, suggesting good discriminant validity. Associations between higher IQ and higher years of education were found at all sites except the United States. Harmonized IQ scores provide a measure of IQ with evidence of good validity that can be used in neurocognitive and circuit-based studies to control for intelligence across global sites.

Objective: Evidence shows that dialogic book-sharing improves language development in young children in low-middle income countries (LMICs), particularly receptive and expressive language. It is unclear whether this intervention also boosts development of other neurocognitive and socio-emotional domains in children. Using a randomized controlled trial (RCT) nested in the Drakenstein Child Health Study (DCHS), a book-sharing intervention was implemented in caregivers of 3.5-year-old preschool children living in low-income South African communities. Methods: 122 Caregivers and their children (mean age 3.5 years) were randomly assigned to an intervention group (n = 61) or waitlist control group (n = 61). A neurocognitive battery determined baseline receptive and expressive language, executive function, theory of mind, and behavior scores. Results: No differences were observed between intervention and control groups on receptive and expressive language, or any of the neurocognitive or socio-emotional measures from baseline (3.5 years) to 4 months post-intervention administration (4 years). Conclusion: The benefits noted in prior literature of book-sharing in infants did not appear to be demonstrated at 4 months post-intervention, in children from 3.5 to 4 years of age. This suggests the importance of early intervention and emphasizes the need for further research on adaptation of book-sharing for older participants in a South African context.Trial registration: retrospectively registered on 03/04/2022 PACTR202204697674974.

IntroductionThere are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance.MethodsWe estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method.ResultsThe results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = −0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments.DiscussionOur findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Recent efforts have focused on developing methylation risk scores (MRS), a weighted sum of the individual’s DNA methylation (DNAm) values of pre-selected CpG sites. Most of the current MRS approaches that utilize Epigenome-wide association studies (EWAS) summary statistics only include genome-wide significant CpG sites and do not consider co-methylation. New methods that relax the p-value threshold to include more CpG sites and account for the inter-correlation of DNAm might improve the predictive performance of MRS. We paired informed co-methylation pruning with P-value thresholding to generate pruning and thresholding (P+T) MRS and evaluated its performance among multi-ancestry populations. Through simulation studies and real data analyses, we demonstrated that pruning provides an improvement over simple thresholding methods for prediction of phenotypes. We demonstrated that European-derived summary statistics can be used to develop P+T MRS among other populations such as African populations. However, the prediction accuracy of P+T MRS may differ across multi-ancestry population due to environmental/cultural/social differences.

Background: Trauma exposure is widespread and linked to chronic physical and mental health conditions including posttraumatic stress disorder. However, there are major gaps in our knowledge of trauma exposure in Africa and on the validity of instruments to assess potentially life-threatening trauma exposure. Objective: The Life Events Checklist for the DSM-5 (LEC-5) is a free, widely used questionnaire to assess traumatic events that can be associated with psychopathology. As part of a case–control study on risk factors for psychosis spectrum disorders, we used the LEC-5 to examine the frequency of traumatic events and to assess the questionnaire’s factor structure in South Africa (N = 6,765). Method: The prevalence of traumatic events was measured by individual items on the LEC-5 across the study sample, by case–control status, and by sex. Cumulative trauma burden was calculated by grouping items into 0, 1, 2, 3, and ≥4 traumatic event types. Psychometric properties of the LEC-5 were assessed through exploratory and confirmatory factor analyses. Results: More than 92% of the study sample reported experiencing ≥1 traumatic event; 38.7% reported experiencing ≥4 traumatic event types. The most endorsed item was physical assault (65.0%), followed by assault with a weapon (50.2%). Almost 94% of cases reported ≥1 traumatic event compared to 90.5% of controls (p

Background: Early detection of psychosis improves treatment outcomes, but there is limited research evaluating the validity of psychosis screening instruments, particularly in low-resourced countries. Aim: This study aims to assess the construct validity and psychometric properties of the psychosis screening questionnaire (PSQ) in South Africa. Setting: This study was conducted at several health centres in the Western and Eastern Cape provinces in South Africa. Methods: The sample consisted of 2591 South African adults participating as controls in a multi-country case-control study of psychiatric genetics. Using confirmatory factor analysis and item response theory, we evaluated the psychometric properties of the PSQ. Results: Approximately 11% of the participants endorsed at least one psychotic experience on the PSQ, and almost half of them (49%) occurred within the last 12 months. A unidimensional model demonstrated good fit (root mean square error of approximation [RMSEA] = 0.023, comparative fit index [CFI] = 0.977 and Tucker–Lewis Index [TLI] = 0.954). The mania item had the weakest association with a single latent factor (standardised factor loading = 0.14). Model fit improved after removing the mania item (RMSEA = 0.025, CFI = 0.991 and TLI = 0.972). With item response theory analysis, the PSQ provided more information at higher latent trait levels. Conclusion: Consistent with prior literature, the PSQ demonstrated a unidimensional factor structure among South Africans. In our study, the PSQ in screening for psychosis performed better without the mania item, but future criterion validity studies are warranted. Contribution: This study highlights that PSQ can be used to screen for early psychosis.

No abstract available.

Introduction: Despite being a widely used screening questionnaire, there is no consensus on the most appropriate measurement model for the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, there have been limited studies on its measurement invariance across cross-cultural subgroups, genders, and sexual orientations. Aims: The present study aimed to examine the fit of different measurement models for the AUDIT and its measurement invariance across a wide range of subgroups by country, language, gender, and sexual orientation. Methods: Responses concerning past-year alcohol use from the participants of the cross-sectional International Sex Survey were considered (N = 62,943; Mage: 32.73; SD = 12.59). Confirmatory factor analysis, as well as measurement invariance tests were performed for 21 countries, 14 languages, three genders, and four sexual-orientation subgroups that met the minimum sample size requirement for inclusion in these analyses. Results: A two-factor model with factors describing ‘alcohol use’ (items 1–3) and ‘alcohol problems’ (items 4–10) showed the best model fit across countries, languages, genders, and sexual orientations. For the former two, scalar and latent mean levels of invariance were reached considering different criteria. For gender and sexual orientation, a latent mean level of invariance was reached. Conclusions: In line with the two-factor model, the calculation of separate alcohol-use and alcohol-problem scores is recommended when using the AUDIT. The high levels of measurement invariance achieved for the AUDIT support its use in cross-cultural research, capable also of meaningful comparisons among genders and sexual orientations.

Abstract Patients with depression require thorough clinical assessment, which should include symptom profile, severity and staging, personality factors, antecedent and concurrent psychiatric comorbidity, physical comorbidity, neurocognitive function, exposure to stressors in early life (e.g. trauma) or recently (e.g. bereavement), and protective factors. The presence of anxiety symptoms in a depressed patient is associated with more severe depression, increased suicidality and worse outcomes compared with non-anxious depression. A network meta-analysis of antidepressant treatments found that agomelatine, citalopram, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were all significantly more effective than other antidepressants for the treatment of depression, and that agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were better tolerated than other antidepressants. Agomelatine has been shown to have two major effects—relieving depressive symptoms, and supporting symptomatic and functional recovery—and these benefits have been demonstrated in patients with depression as well as in patients with generalised anxiety disorder, including those with more severe symptoms. Agomelatine has also been shown to be efficacious and well tolerated in patients with depression plus concomitant anxiety symptoms. A pooled analysis of data from six agomelatine studies of depression (three placebo-controlled and three with active comparators—fluoxetine, sertraline and venlafaxine) found that agomelatine was significantly more effective than placebo at relieving the anxiety subscore on the Hamilton Depression Rating Scale, and that the difference between agomelatine and placebo was even more marked in the subgroup of patients with severe anxiety symptoms at baseline. Irrespective of the pharmacotherapy used in patients with depression, the likelihoods of response and remission are increased when pharmacotherapy is combined with psychotherapy, with this approach being more effective than either pharmacotherapy or psychotherapy alone. Persistence with treatment is important, and clinicians should therefore encourage patients to keep trying to obtain relief.

Abstract Background Posttraumatic stress disorder (PTSD) is associated with significant morbidity, but efficacious pharmacotherapy and psychotherapy are available. Data from the World Mental Health Surveys were used to investigate extent and predictors of treatment coverage for PTSD in high-income countries (HICs) as well as in low- and middle-income countries (LMICs). Methods Seventeen surveys were conducted across 15 countries (9 HICs, 6 LMICs) by the World Health Organization (WHO) World Mental Health Surveys. Of 35,012 respondents, 914 met DSM-IV criteria for 12-month PTSD. Components of treatment coverage analyzed were: (a) any mental health service utilization; (b) adequate pharmacotherapy; (c) adequate psychotherapy; and (d) effective treatment coverage. Regression models investigated predictors of treatment coverage. Results 12-month PTSD prevalence in trauma exposed individuals was 1.49 (S.E., 0.08). A total of 43.0% (S.E., 2.2) received any mental health services, with fewer receiving adequate pharmacotherapy (13.5%), adequate psychotherapy (17.2%), or effective treatment coverage (14.4%), and with all components of treatment coverage lower in LMICs than HICs. In a multivariable model having insurance (OR = 2.31, 95 CI 1.17, 4.57) and severity of symptoms (OR = .35, 95% CI 0.18, 0.70) were predictive of effective treatment coverage. Conclusion There is a clear need to improve pharmacotherapy and psychotherapy coverage for PTSD, particularly in those with mild symptoms, and especially in LMICs. Universal health care insurance can be expected to increase effective treatment coverage and therefore improve outcomes.

Abstract Maternal perinatal depression is associated with risk of adverse child developmental outcomes and differences in offspring brain structure. Evidence from low- and middle-income countries is lacking as is an investigation of antenatal, postnatal, and persistent depression in the same sample. In a South African birth cohort, we investigated the effect of antenatal and postpartum maternal depressive symptoms on offspring brain structure at 2–3 years of age. Magnetic resonance imaging was performed, extracting cortical thickness and surface areas in frontal cortex regions of interest and subcortical volumes using FreeSurfer software. Maternal depressive symptoms were measured using the Edinburgh Postpartum Depression Scale and the Beck Depression Inventory II antenatally and at 6–10 weeks, 6 months, 12 months, and 18 months postpartum and analyzed dichotomously and continuously. Linear regressions were used controlling for child age, sex, intracranial volume, maternal education, age, smoking, alcohol use and HIV. 146 children were included with 38 (37%) exposed to depressive symptoms antenatally and 44 (35%) exposed postnatally. Of these, 16 (13%) were exposed to both. Postpartum, but not antenatal, depressive symptoms were associated with smaller amygdala volumes in children (B = −74.73, p = 0.01). Persistent maternal depressive symptoms across pregnancy and postpartum were also independently associated with smaller amygdala volumes (B = −78.61, p = 0.047). Differences in amygdala volumes among children exposed to postnatal as well as persistent maternal depressive symptomatology underscore the importance of identifying women at-risk for depression during the entire perinatal period.

Abstract Background Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 μm or less (PM10) was measured inside participants’ homes during the second trimester of pregnancy. Results A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10 and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. Conclusions Our findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.

ObjectiveAlterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure.MethodsWe used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and community-matched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age.ResultsOur study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17–0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35–0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson’s r = −0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson’s r = 0.51, p = 0.032).ConclusionReduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU.

Background: Research has highlighted high rates of exposure to violence among South African youth. However, work to date has been largely cross-sectional, focused on violence exposure during the adolescence period, and has been limited to specific types of violence exposure. We examined violence exposure in South African preschool children between 3 and 6 years of age, capturing both direct and indirect forms of violence, and tested for potential sex differences across the several types of exposures. Methods: Lifetime direct and indirect exposure to domestic and community violence was measured by parental report when children were 3.5 years (N = 530), 4.5 years (N = 749) and 6 years of age (N= 417) in a South African birth cohort located in a peri-urban community. Results: There are three main findings. First, a large proportion of children (72%-75%) were reported as having been exposed to some form of direct or indirect violent experience in their homes or communities from a young age. Second, there was significant polyvictimization, with 49% of the children being exposed to more than one type of violence by age 6. Third, by 4.5 years of age, there was evidence that boys were more likely than girls to be exposed to domestic victimisation (28% vs. 17%) and polyvictimization (38% vs. 28%). Conclusions: These findings highlight the high levels of violence exposure in young South African children, particularly among boys, and the need for prevention at both the community and individual levels.

Abstract Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450 K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R 2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R 2 = 0.006). For PTE, 31 CpG sites and eight CpG sites were identified as significant mediators (ACME and TE P

Individuals across six major psychiatric conditions from the ENIGMA consortium reveals a shared morphological effect, following a sensory-fugal axis, which is related to microstructural gradient and neurotransmitter axes.

Changes to structural and functional connectivity can give rise to neurodegeneration and neurodevelopmental diseases. Here the authors investigate molecular and connectomic patterns in 13 different neurological, psychiatric and neurodevelopmental diseases from the ENIGMA consortium.

BackgroundAlcohol and tobacco are known teratogens. Historically, more severe prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) have been examined as the principal predictor of neurodevelopmental alterations, with little incorporation of lower doses or ecological contextual factors that can also impact neurodevelopment, such as socioeconomic resources (SER) or adverse childhood experiences (ACEs). Here, a novel analytical approach informed by a socio-ecological perspective was used to examine the associations between SER, PAE and/or PTE, and ACEs, and their effects on neurodevelopment.MethodsN = 313 mother-child dyads were recruited from a prospective birth cohort with maternal report of PAE and PTE, and cross-sectional structural brain neuroimaging of child acquired via 3T scanner at ages 8–11 years. In utero SER was measured by maternal education, household income, and home utility availability. The child’s ACEs were measured by self-report assisted by the researcher. PAE was grouped into early exposure (=12 weeks), and no exposure controls. PTE was grouped into exposed and non-exposed controls.ResultsGreater access to SER during pregnancy was associated with fewer ACEs (maternal education: β = −0.293,p = 0.01; phone access: β = −0.968,p = 0.05). PTE partially mediated the association between SER and ACEs, where greater SER reduced the likelihood of PTE, which was positively associated with ACEs (β = 1.110,p = 0.01). SER was associated with alterations in superior frontal (β = −1336.036, q = 0.046), lateral orbitofrontal (β = −513.865, q = 0.046), caudal anterior cingulate volumes (β = −222.982, q = 0.046), with access to phone negatively associated with all three brain volumes. Access to water was positively associated with superior frontal volume (β=1569.527, q = 0.013). PTE was associated with smaller volumes of lateral orbitofrontal (β = −331.000, q = 0.033) and nucleus accumbens regions (β = −34.800, q = 0.033).ConclusionResearch on neurodevelopment following community-levels of PAE and PTE should more regularly consider the ecological context to accelerate understanding of teratogenic outcomes. Further research is needed to replicate this novel conceptual approach with varying PAE and PTE patterns, to disentangle the interplay between dose, community-level and individual-level risk factors on neurodevelopment.