FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

Statistical and Machine Learning Analysis in Brain-Imaging Genetics: A Review of Methods.

Brain-imaging-genetic analysis is an emerging field of research that aims at aggregating data from neuroimaging modalities, which characterize brain structure or function, and genetic data, which capture the structure and function of the genome, to explain or predict normal (or abnormal) brain performance. Brain-imaging-genetic studies offer great potential for understanding complex brain-related diseases/disorders of genetic etiology. Still, a combined brain-wide genome-wide analysis is difficult to perform as typical datasets fuse multiple modalities, each with high dimensionality, unique correlational landscapes, and often low statistical signal-to-noise ratios. In this review, we outline the progress in brain-imaging-genetic methodologies starting from early massive univariate to current deep learning approaches, highlighting each approach's strengths and weaknesses and elongating it with the field's development. We conclude by discussing selected remaining challenges and prospects for the field.

The role of epigenetic mechanisms in the long-term effects of early-life adversity and mother-infant relationship on physiology and behavior of offspring in laboratory rats and mice.

Maternal care during the early postnatal period of altricial mammals is a key factor in the survival and adaptation of offspring to environmental conditions. Natural variations in maternal care and experimental manipulations with maternal-child relationships modeling early-life adversity (ELA) in laboratory rats and mice have a strong long-term influence on the physiology and behavior of offspring in rats and mice. This literature review is devoted to the latest research on the role of epigenetic mechanisms in these effects of ELA and mother-infant relationship, with a focus on the regulation of hypothalamic-pituitary-adrenal axis and brain-derived neurotrophic factor. An important part of this review is dedicated to pharmacological interventions and epigenetic editing as tools for studying the causal role of epigenetic mechanisms in the development of physiological and behavioral profiles. A special section of the manuscript will discuss the translational potential of the discussed research.

Cognitive and academic performance of rural Zambian youth exposed to HIV.

Studies focusing on children affected by HIV have shown that they have generally lower academic performance, however, few studies separate children who are HIV exposed and infected (CHEI) and those who are HIV exposed but uninfected (CHEU). Importantly, in rural sub-Saharan Africa, the majority of studies on CHEI and CHEU examine academic performance indirectly based on cognitive test scores. Therefore, studies assessing the effects of HIV on academic achievement directly for CHEI and CHEU are needed. This article evaluates the effects of HIV-infection on cognitive and academic performance by comparing CHEI (n = 82) and CHEU (n = 1045) aged 7-17 years old using cross-sectional data from an ongoing longitudinal study in a rural area of Zambia. Youth completed cognitive and academic assessments; their height and weight were assessed to generate Body Mass Index (BMI). Caregiver questionnaires provided information on youths' years in school and household socio-economic status (SES). Results indicated that while HIV infection status did explain some of the variance in performance between CHEI and CHEU, age, BMI, years of schooling and SES accounted for additional variance. The effect of years of schooling on both cognitive and academic performance demonstrated that CHEI's performance may be greatly improved by consistent school enrollment.

Racial/ethnic disparities of the pact in predicting recidivism and court dispositions for justice-involved youth.

OBJECTIVE: Responding to the concern about racial/ethnic disparities (R/ED) in the use of risk assessment instruments (RAIs) in justice systems, previous research has overwhelmingly tested the extent to which RAI scores consistently predict recidivism across race and ethnicity (predictive bias). However, little is known about R/ED in the association between RAI measures and court dispositions (disparate application) for justice-involved youths. This study investigated predictive bias and disparate application of three risk measures-criminal history, social history, and the overall risk level-produced by the Positive Achievement Change Tool (PACT) for White, Black, and Hispanic justice-involved youths. HYPOTHESES: Given the mixed evidence in existing research for predictive bias and lack of evidence for disparate application, we did not make any specific hypothesis but conducted exploratory analyses. From a clinical perspective, however, we anticipated little or no evidence to support predictive bias and disparate application of the PACT among White, Black, and Hispanic youths in the jurisdiction we examined. METHOD: The sample consisted of 5,578 youths (11.4% White, 43.9% Black, and 44.7% Hispanic) who completed the PACT while in the Harris County Juvenile Probation Department, Texas. The outcome variables included recidivism (general and violent reoffending) and court dispositions (deferred adjudication, probation without placement, and probation with placement). We ran a series of moderating binary logistic regression models and moderating ordinal logistic regression models to evaluate predictive bias and disparate application. RESULTS: Race and ethnicity influenced how the criminal history score related to violent recidivism: This compromised the validity of the score as a predictor of recidivism. Moreover, evidence showed that the overall risk of reoffending was associated with harsher sanctioning decisions for Black and Hispanic youths than for White youths. CONCLUSION: Ensuring that RAI results are consistently interpreted and used in informing decisions is as important as ensuring that RAI scores function equally well in predicting recidivism regardless of race and ethnicity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pediatric Symptom Checklist-17: Factor Structure and Uniform Differential Item Functioning Across Gender and Age in HIV Orphans and Vulnerable Children in Zambia.

This study aimed to investigate the psychometric properties of the Pediatric Symptom Checklist-17 (PSC-17) in a sample of children orphaned or made vulnerable (OVC) by HIV in Zambia. Caregivers of 1,076 OVC (55.1% boys; Mage = 12.91 years) completed the PSC-17. Competing models, including confirmatory factor analysis (CFA), hierarchical CFA, bifactor CFA, exploratory structural equation modeling (ESEM), and bifactor ESEM, were tested to evaluate the optimal factor structure of the PSC-17. Results showed that the bifactor ESEM provided the best approximation of the PSC-17 data with a well-defined general psychosocial problems factor explaining 72% of the reliable variance in the total score and an internalizing factor containing 63% of reliable variance unique from the general factor. The observed overall psychosocial problems score was associated with lower academic achievement and working memory (with small effect sizes), supporting the discriminant validity of score interpretation. Results of multiple indicators multiple causes (MIMIC) analyses revealed that all items functioned equivalently across child gender and age.

The Role of Neural and Genetic Processes in Learning to Read and Specific Reading Disabilities: Implications for Instruction.

To learn to read, the brain must repurpose neural systems for oral language and visual processing to mediate written language. We begin with a description of computational models for how alphabetic written language is processed. Next, we explain the roles of a dorsal sublexical system in the brain that relates print and speech, a ventral lexical system that develops the visual expertise for rapid orthographic processing at the word level, and the role of cognitive control networks that regulate attentional processes as children read. We then use studies of children, adult illiterates learning to read, and studies of poor readers involved in intervention, to demonstrate the plasticity of these neural networks in development and in relation to instruction. We provide a brief overview of the rapid increase in the field's understanding and technology for assessing genetic influence on reading. Family studies of twins have shown that reading skills are heritable, and molecular genetic studies have identified numerous regions of the genome that may harbor candidate genes for the heritability of reading. In selected families, reading impairment has been associated with major genetic effects, despite individual gene contributions across the broader population that appear to be small. Neural and genetic studies do not prescribe how children should be taught to read, but these studies have underscored the critical role of early intervention and ongoing support. These studies also have highlighted how structured instruction that facilitates access to the sublexical components of words is a critical part of training the brain to read.

Widespread effects of dMRI data quality on diffusion measures in children.

Diffusion magnetic resonance imaging (dMRI) datasets are susceptible to several confounding factors related to data quality, which is especially true in studies involving young children. With the recent trend of large-scale multicenter studies, it is more critical to be aware of the varied impacts of data quality on measures of interest. Here, we investigated data quality and its effect on different diffusion measures using a multicenter dataset. dMRI data were obtained from 691 participants (5-17 years of age) from six different centers. Six data quality metrics-contrast to noise ratio, outlier slices, and motion (absolute, relative, translation, and rotational)-and four diffusion measures-fractional anisotropy, mean diffusivity, tract density, and length-were computed for each of 36 major fiber tracts for all participants. The results indicated that four out of six data quality metrics (all except absolute and translation motion) differed significantly between centers. Associations between these data quality metrics and the diffusion measures differed significantly across the tracts and centers. Moreover, these effects remained significant after applying recently proposed harmonization algorithms that purport to remove unwanted between-site variation in diffusion data. These results demonstrate the widespread impact of dMRI data quality on diffusion measures. These tracts and measures have been routinely associated with individual differences as well as group-wide differences between neurotypical populations and individuals with neurological or developmental disorders. Accordingly, for analyses of individual differences or group effects (particularly in multisite dataset), we encourage the inclusion of data quality metrics in dMRI analysis.

Neurite density and arborization is associated with reading skill and phonological processing in children.

BACKGROUND: Studies exploring neuroanatomic correlates of reading have associated white matter tissue properties with reading disability and related componential skills (e.g., phonological and single-word reading skills). Mean diffusivity (MD) and fractional anisotropy (FA) are widely used surrogate measures of tissue microstructure with high sensitivity; however, they lack specificity for individual microstructural features. Here we investigated neurite features with higher specificity in order to explore the underlying microstructural architecture. METHODS: Diffusion weighted images (DWI) and a battery of behavioral and neuropsychological assessments were obtained from 412 children (6 - 16 years of age). Neurite indices influenced by orientation and density were attained from 23 major white matter tracts. Partial correlations were calculated between neurite indices and indicators of phonological processing and single-word reading skills using age, sex, and image quality metrics as covariates. In addition, mediation analysis was performed using structural equation modeling (SEM) to evaluate the indirect effect of phonological processing on reading skills. RESULTS: We observed that orientation dispersion index (ODI) and neurite density index (NDI) were negatively correlated with single-word reading and phonological processing skills in several tracts previously shown to have structural correlates with reading efficiency. We also observed a significant and substantial effect in which phonological processing mediated the relationship between neurite indices and reading skills in most tracts. CONCLUSIONS: In sum, we established that better reading and phonological processing skills are associated with greater tract coherence (lower ODI) and lower neurite density (lower NDI). We interpret these findings as evidence that reading is associated with neural architecture and its efficiency.

Altered neural processing of emotional words in adults with a history of institutionalization: Evidence from the emotional Stroop task.

We investigated neural correlates of traumatic experience related to the lack of family care in adults with a history of institutionalization (IC) using the Emotional Stroop paradigm. The goals of our study were twofold: we investigated whether adults with IC history (n = 24; Mage  = 22.17, SD = 6.7) demonstrate atypical processing of emotionally salient words in general, and whether they exhibit selective processing bias toward family related words compared to adults raised in biological families (BFC; n = 28; Mage  = 22.25, SD = 4.9). Results demonstrated significant differences in accuracy but not response times between groups on the behavioral level, indicating that the IC group was overall less accurate in identifying the color of the font. Contrary to our prediction, there were no significant differences between neural response to family related versus unrelated words in the IC and BFC groups. The absence of group differences can be explained by the selection of stimuli, which were associated with family rather than institutional history. The IC group showed a larger N280-380 component in response to negative words compared to the BFC group, and larger negativity in the right parietal area in response to positive words in the same time window. Results demonstrate that institutional history is marked by altered emotional processing in the subpopulation of institutional care-leavers, but the footprint is not specific to traumatic experience and extends from general sensitivity to emotional words.

Clinical characterization of individuals with the distal 1q21.1 microdeletion.

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

A systematic review and meta-analysis of imaging genetics studies of specific reading disorder.

The imaging genetics of specific reading disabilities (SRD) is an emerging field that aims to characterize the disabilities' neurobiological causes, including atypical brain structure and function and distinct genetic architecture. The present review aimed to summarize current imaging genetics studies of SRD, characterize the effect sizes of reported results by calculating Cohen's d, complete a Fisher's Combined Probability Test for genes featured in multiple studies, and determine areas for future research. Results demonstrate associations between SRD risk genes and reading network brain phenotypes. The Fisher's test revealed promising results for the genes DCDC2, KIAA0319, FOXP2, SLC2A3, and ROBO1. Future research should focus on exploratory approaches to identify previously undiscovered genes. Using comprehensive neuroimaging (e.g., functional and effective connectivity) and genetic (e.g., sequencing and epigenetic) techniques, and using larger samples, diverse stages of development, and longitudinal investigations, would help researchers understand the neurobiological correlates of SRD to improve early identification.

Reducing neurodevelopmental disorders and disability through research and interventions.

We define neurodevelopment as the dynamic inter-relationship between genetic, brain, cognitive, emotional and behavioural processes across the developmental lifespan. Significant and persistent disruption to this dynamic process through environmental and genetic risk can lead to neurodevelopmental disorders and disability. Research designed to ameliorate neurodevelopmental disorders in low- and middle-income countries, as well as globally, will benefit enormously from the ongoing advances in understanding their genetic and epigenetic causes, as modified by environment and culture. We provide examples of advances in the prevention and treatment of, and the rehabilitation of those with, neurodevelopment disorders in low- and middle-income countries, along with opportunities for further strategic research initiatives. Our examples are not the only possibilities for strategic research, but they illustrate problems that, when solved, could have a considerable impact in low-resource settings. In each instance, research in low- and middle-income countries led to innovations in identification, surveillance and treatment of a neurodevelopmental disorder. These innovations have also been integrated with genotypic mapping of neurodevelopmental disorders, forming important preventative and rehabilitative interventions with the potential for high impact. These advances will ultimately allow us to understand how epigenetic influences shape neurodevelopmental risk and resilience over time and across populations. Clearly, the most strategic areas of research opportunity involve cross-disciplinary integration at the intersection between the environment, brain or behaviour neurodevelopment, and genetic and epigenetic science. At these junctions a robust integrative cross-disciplinary scientific approach is catalysing the creation of technologies and interventions for old problems. Such approaches will enable us to achieve and sustain the United Nations moral and legal mandate for child health and full development as a basic global human right.

A focus on adolescence to reduce neurological, mental health and substance-use disability.

Globally, there is a crucial need to prioritize research directed at reducing neurological, mental health and substance-use disorders in adolescence, which is a pivotal age for the development of self-control and regulation. In adolescence, behaviour optimally advances towards adaptive long-term goals and suppresses conflicting maladaptive short-lived urges to balance impulsivity, exploration and defiance, while establishing effective societal participation. When self-control fails to develop, violence, injury and neurological, mental health and substance-use disorders can result, further challenging the development of self-regulation and impeding the transition to a productive adulthood. Adolescent outcomes, positive and negative, arise from both a life-course perspective and within a socioecological framework. Little is known about the emergence of self-control and regulation in adolescents in low- and middle-income countries where enormous environmental threats are more common (for example, poverty, war, local conflicts, sex trafficking and slavery, early marriage and/or pregnancy, and the absence of adequate access to education) than in high-income countries and can threaten optimal neurodevelopment. Research must develop or adapt appropriate assessments of adolescent ability and disability, social inclusion and exclusion, normative development, and neurological, mental health and substance-use disorders. Socioecological challenges in low- and middle-income countries require innovative strategies to prevent mental health, neurological and substance-use disorders and develop effective interventions for adolescents at risk, especially those already living with these disorders and the consequent disability.

Cognitive and Educational Interventions for Orphans and Vulnerable Children Affected by HIV/AIDS: A Meta-Analysis.

Orphans and vulnerable children affected by HIV/AIDS (HIV OVC) are at risk for cognitive difficulties and lack of access to education. Interventions addressing cognitive or educational outcomes for HIV OVC worldwide were examined through systematic searches conducted from October 2016 to 2019. We examined the summative effectiveness of interventions and the specific effects of participant age and intervention length. Interventions targeting cognitive outcomes had a small, significant effect, with no effect of moderating variables. Interventions targeting educational outcomes had significant effects. Educational interventions over 1 year were effective, but effects of intervention length were not significant. Overall, this review provides support for the effectiveness of interventions targeting cognitive and educational outcomes for OVC and highlights the need for more research on such interventions.

Early institutionalized care disrupts the development of emotion processing in prosody.

Millions of children worldwide are raised in institutionalized settings. Unfortunately, institutionalized rearing is often characterized by psychosocial deprivation, leading to difficulties in numerous social, emotional, physical, and cognitive skills. One such skill is the ability to recognize emotional facial expressions. Children with a history of institutional rearing tend to be worse at recognizing emotions in facial expressions than their peers, and this deficit likely affects social interactions. However, emotional information is also conveyed vocally, and neither prosodic information processing nor the cross-modal integration of facial and prosodic emotional expressions have been investigated in these children to date. We recorded electroencephalograms (EEG) while 47 children under institutionalized care (IC) (n = 24) or biological family care (BFC) (n = 23) viewed angry, happy, or neutral facial expressions while listening to pseudowords with angry, happy, or neutral prosody. The results indicate that 20- to 40-month-olds living in IC have event-related potentials (ERPs) over midfrontal brain regions that are less sensitive to incongruent facial and prosodic emotions relative to children under BFC, and that their brain responses to prosody are less lateralized. Children under IC also showed midfrontal ERP differences in processing of angry prosody, indicating that institutionalized rearing may specifically affect the processing of anger.

Neuroendocrine and autonomic stress systems activity in young adults raised by mothers with mental health and substance abuse problems: A prospective cohort study.

Among the well-known physiological consequences of early adverse environments is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. A number of studies demonstrate that negative parenting and living with parents with a history of substance abuse and mental health problems may be associated with HPA axis dysregulation in children. In contrast, studies of more delayed effects in adult offspring, especially prospective, are still scarce. This study was a prospective longitudinal investigation of the association between maternal mental illnesses/substance abuse and maternal negative parenting/parental stress on one side and, on the other side, adult offspring outcomes 10 years later-specifically, we studied the activity of offspring's neuroendocrine (cortisol) and autonomic (heart rate) systems when exposed to a mild psychological stressor. Children of mothers with mental illnesses and/or substance abuse were exposed to more disadvantaged conditions (higher negative parenting and community violence). Despite this, maternal risk groups (having a mother with mental illnesses and/or substance abuse) were not associated with any of the indicators of stress systems activity. Regardless of the risk group, participants with dysregulated HPA axis activity experienced a higher level of negative parenting. Altogether, our study provides evidence that negative parenting may have long-lasting effects on stress-sensitive physiological mechanisms.

A Systematic Review and Meta-Analysis of Interventions for Orphans and Vulnerable Children Affected by HIV/AIDS Worldwide.

BACKGROUND: Worldwide, there are more than 13.3 million orphans and vulnerable children affected by Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) (HIV OVC), defined as individuals below the age of 18 who have lost one or both parents to HIV/AIDS or have been made vulnerable by HIV/AIDS; they are at risk for negative psychosocial and cognitive outcomes. PURPOSE: This meta-analysis aimed to examine the scientific literature on available interventions for HIV OVC, with a focus on community-based interventions (CBI). METHODS: Systematic electronic searches were conducted from four databases between October 2016 and April 2017 to identify articles investigating the effectiveness of interventions for HIV OVC. Effect sizes were calculated for each article which provided enough information and data points for analyses. RESULTS: Seventy-four articles were reviewed, including psychosocial interventions (d = 0.30), cognitive interventions (d = 0.14), social protection interventions (d = 0.36), and community-based interventions (CBI; d = 0.36). Study-specific effect sizes varied widely, ranging from -1.09 to 2.26, that is, from a negative effect to an impressively large positive one, but the majority of studies registered small to medium effects (the overall effect size for all studies was 0.32, SE = 0.03, 95% CI: 0.26-0.37). Social protection interventions had the highest positive outcomes whereas CBI tended to have the fewest significant positive outcomes, with some outcomes worsening instead of improving. CONCLUSIONS: Overall, interventions provided to OVC have potential for improving cognitive, psychosocial, and risk-behavior outcomes. Social protection interventions and CBI had the highest effect sizes, but CBI had positive effects on fewer outcomes and demonstrated some negative effects. CBI warrant scrutiny for improvement, as they represent an important form of culturally embedded services with potentially long-term benefits to OVC, yet appear to be differentially effective. Successful components of other types of intervention were identified, including cash grants, mentorship, and family therapy. In addition, more research is needed that attends to which interventions may be more effective for specific populations, or that studies cost-effectiveness.

Twice Exceptional Students: Gifts and Talents, the Performing Arts, and Juvenile Delinquency.

There is an increasing attention to the phenomenon referred to as "twice exceptional" ("2e") children, namely, children who demonstrate both exceptional abilities and disabilities. In this essay, this concept is applied to delinquency and/or emotional-behavior disorder and gifts (talents) in the performance arts, exploring the presence of this association and the support for it in the literature. The essay asserts that this association does exist, qualifies these youth as another category of 2e students, and calls for research on the manifestation, etiology, and development of this co-occurrence.

The Pharmacogenetics of Efavirenz Metabolism in Children: The Potential Genetic and Medical Contributions to Child Development in the Context of Long-Term ARV Treatment.

Efavirenz (EFV) is a well-known, effective anti-retroviral drug long used in first-line treatment for children and adults with HIV and HIV/AIDS. Due to its narrow window of effective concentrations, between 1 and 4 µg/mL, and neurological side effects at supratherapeutic levels, several investigations into the pharmacokinetics of the drug and its genetic underpinnings have been carried out, primarily with adult samples. A number of studies, however, have examined the genetic influences on the metabolism of EFV in children. Their primary goal has been to shed light on issues of appropriate pediatric dosing, as well as the manifestation of neurotoxic effects of EFV in some children. Although EFV is currently being phased out of use for the treatment of both adults and children, we share this line of research to highlight an important aspect of medical treatment that is relevant to understanding the development of children diagnosed with HIV.