Journal of Child Psychology and Psychiatry

Objective: Mental health challenges are highly prevalent in autism, but the degree to which they are similar in experience and etiology to the general population remains unclear. This study's objective was characterization of phenotypic and genetic architectures of psychiatric symptomatology in versus out-of-autism. Methods: Psychiatric symptoms were evaluated using the Child Behavior Checklist (CBCL) in 22,152 children (8-15 years): 11,111 autistic children with verbal abilities from SPARK and 11,041 non-autistic children from ABCD. The CBCL's canonical, population-wide factor structure and genetic associations were compared between cohorts. In parallel, exploratory factor analysis was conducted in SPARK, with resulting dimensions associated with key clinical phenotypes (cognitive ability, co-occurring neuropsychiatric diagnoses), polygenic scores (PGS) for psychiatric disorders, and de novo burden in autism-associated genes. Results: Confirmatory factor analysis supported the canonical structure in ABCD but not in SPARK. Psychiatric PGS associations with canonical CBCL subscales were weaker in SPARK than in ABCD, with the ADHD PGS association to Attention problems lower in SPARK ({beta}=0.05 [CI: 0.04,0.06] than in ABCD ({beta}=0.17 [0.13,0.21]). SPARK exploratory factor analysis replicated canonical internalizing factors while revealing other structural departures, including a distinct Developmental Delays factor and dispersion of social problems across multiple factors. The Developmental Delays factor had the strongest associations with de novo burden and lower cognitive ability but was weakly associated with psychiatric PGS. In contrast, common genetic variation explained larger proportions of variances in somatic and inattentive factors and had stronger PGS associations. Conclusions: Correlation structures and genetic architectures of psychiatric symptoms differed in autism compared to the broader population, emphasizing the need for autism-specific approaches in assessment and treatment.

Background: ADHD symptoms follow heterogeneous trajectories across childhood and adolescence, with important implications for later functioning. Early-life factors, including perinatal health, family environment, cognition, socioeconomic conditions, and community exposures, may contribute to this variability. The present study examined (1) early-life predictors of ADHD symptom trajectories, and (2) ADHD symptom trajectories as predictors of later substance use, suicidality, and new-onset psychiatric disorders. Methods: Growth models were used to fit longitudinal trajectories of inattention, hyperactivity, and irritability measures in two independent samples: the Oregon ADHD-1000 cohort (N=1,215; 49.17% ADHD; 39.9% female, ages 7-23) and a subsample of the Adolescent Brain Cognitive Development (ABCD) study (N=1,252; 33.3% ADHD; 31.6% female, ages 9-16). Regression analyses examined multiple risk factors as predictors of symptom growth parameters as well as associations between symptom trajectories and later adverse outcomes. Results: In both cohorts, growth models fit well (CFI > .96, RMSEA < .04), with all symptoms decreasing over time (ps < .001) and hyperactivity declining significantly faster than inattention. ADHD polygenic risk, family conflict, parenting, and cognition were associated with symptom intercepts in both cohorts (ps < .001). In Oregon ADHD-1000, poorer baseline working memory and processing speed predicted slower declines in inattention (ps < .001), but these effects did not replicate in ABCD; no other early-life factors predicted symptom trajectories. Increasing irritability trajectories predicted new disorder onset in both cohorts (ORs = 1.73 - 2.09, ps < .001), while more positive inattention slopes predicted new disorder onset in ABCD (OR = 3.07, p < .001) and showed a weaker association in Oregon ADHD-1000 (OR = 1.50, p = .007). Conclusion: While several early risk factors were associated with ADHD symptoms initially, none robustly predicted symptom trajectories over time. However, increasing irritability and inattention were robustly associated with increased risk for new disorder onsets later in adolescence.

Family environment is a robust predictor of adolescent internalizing symptoms, yet its strength varies across adolescents. We tested whether this variation is partly captured by how similar an adolescent's cortical structure is to their parent's and whether different forms of this similarity matter in different cortical systems. In 115 parent-child dyads from two cohorts, structural MRI quantified similarity across 400 cortical parcels in two forms: phenotypic similarity in regional morphometry and architectural similarity in interregional morphometric organization. Parent-child similarity was not directly associated with symptoms, whereas its interactions with family environment were jointly significant (chi-square(4) = 14.92, P = 0.005). Phenotypic similarity in the sensory-limbic system and architectural similarity in the association system each moderated the association between family environment and symptoms (both beta = 0.22). In both cases, the association was strongest among less similar dyads. The phenotypic interaction was distributed across sensory-limbic networks and was not reproduced by similarity to unrelated adults or by the child's cortical atypicality. The architectural interaction was concentrated in the dorsal attention and default mode networks and was distinguishable from unrelated-adult similarity but not from child atypicality. Together, these findings raise the possibility that markers of environmental sensitivity need not reside in the child alone. Parent-child cortical similarity may index a dyadic component of this sensitivity, one not adequately represented by a single similarity score but distributed across forms of similarity and cortical systems.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition, and co-occurring autistic traits may shape its phenotypic expression. Although creativity has been discussed as a relative strength in ADHD, it remains unclear whether autistic traits are associated with different dimensions of creativity in adults with ADHD and whether large-scale brain networks contribute to these associations. Methods: We compared divergent thinking (DT) and real-life creativity between 65 adults with ADHD and 73 neurotypical controls. We used subgroup comparisons, partial correlation analyses, and multiple regression models to determine the effects of autistic traits (ATs) on creativity dimensions within the ADHD cohort. Guided by prior creativity-network research, we analyzed resting-state functional connectivity (FC) of the Default Mode Network (DMN) and Frontoparietal Network (FPN) to uncover the neural mechanisms. Results: The ADHD cohort demonstrated significantly higher scores on both DT (ps = 0.002-0.009) and real-life creativity measures (ps = 0.011-0.017) compared to the neurotypical control group. Importantly, increased ATs within the ADHD group were associated with a dissociated creativity profile, showing positive associations with DT but negative associations with real-life creativity. At the neural level, stronger right DMN FPN connectivity mediated positive associations between ATs and DT performance (ps = 0.007-0.018), but mediated a negative association between ATs and self-reported imagination (p = 0.029). Conclusions: In individuals with ADHD, co-occurring ATs exert a paradoxical effect on creativity, enhancing DT while compromising real-life creative achievement. In this subgroup with ADHD and elevated ATs, interventions should capitalize on ATs-associated ideational strengths while circumventing translational barriers, to enhance real-world creative outcomes.

The adolescent social environment and dynamics therein have been linked to divergent brain organization and greater risk of psychopathology later in life, suggesting the neural underpinnings of mental health may depend on social context. To examine this, we leveraged longitudinal ABCD Study data to identify dynamic social envirotypes, or distinct trajectories of social environment change over four years. Dynamic social envirotypes differed in mental health outcomes, changes in mental health, and whole-brain functional connectivity, with each dynamic social envirotype exhibiting a characteristic pattern of brain network organization. Crucially, functional connectivity associations with internalizing and externalizing problems diverged across dynamic social envirotypes, with the highest and lowest social resource envirotypes showing largely opposing associations between connectivity and symptom severity. These findings suggest that dysconnectivity is contextual: there is no single brain connectivity pattern that is universally associated with better mental health. Rather, adolescent brain connectivity relates to mental health in context-specific ways, challenging normative narratives of the neural underpinnings of psychopathology and centering the role of context for understanding and treating mental health.

Objective: Emotion dysregulation and irritability occur across pediatric disorders, complicating distinctions between general symptom burden and specific clinical presentations. Person-centered analyses can look at profiles of scores to identify groups with similar presentations. We examined whether modeling shared and domain-specific symptom variance identified differentiated profiles in youth. Method: Caregivers of 2,187 US youth ages 6-18 completed 87 items assessing emotion dysregulation, depression, mania-related symptoms, sleep-related impairment, and attention and behavioral problems. An ordinal bifactor model estimated one general and 13 specific factors. Latent profile analyses used standardized scores on all 14 factors, with an expanded raw-score analysis as a comparator. We examined caregiver-reported diagnoses and functioning and approximately two-week classification agreement among 166 recontacted caregivers. Results: The general factor accounted for 62% of common variance ({omega}H=.94), although model fit was mixed (CFI=.884; RMSEA=.058; SRMR=.092). A provisional four-class solution distinguished population-modal (67.4%), internalizing (11.8%), attention/hyperactivity (11.0%), and unusual-thought/elevated-mood (9.8%) profiles. Entropy was .83, but model enumeration and initialization checks did not establish a unique solution. Profiles showed overlapping diagnostic and functional correlates. Recontact agreement was 78.9% ({kappa}=.60). Irritability-specific reliability was limited, constraining interpretation of its weak profile differentiation. Conclusions: General symptom burden coexisted with differentiated residual symptom patterns. These findings support evaluating severity alongside symptom configuration, without equating profiles with diagnoses or weak residual irritability signals with limited clinical relevance. Measurement refinement, model-selection verification, and confirmation of classification-error-adjusted associations are needed before clinical application, but profiles could simplify clinical interpretation of sets of scales.

Language alterations are recognized as early markers of psychopathological vulnerability, yet genetic and environmental factors underlying language-related brain regions remain unknown. We applied univariate twin analyses and risk-discordant comparisons to multimodal dataset from 31 healthy twin pairs (9-31 years) and 17 pairs discordant for psychopathological risk (10-27 years). Gray matter volume (GMV), cortical thickness (CT), and functional interactions, specifically effective connectivity (EC), were assessed in eight bilateral language-related regions, alongside linguistic, emotional-behavioural, temperamental, and personality-related phenotypes. In healthy twin pairs (27-31 pairs, depending on data completeness), genetic and environmental determinants were estimated for all phenotypes. In 17 pairs discordant for psychopathological risk, intra-pair neuroimaging differences were tested for association with psychopathological discordance and zygosity, and individual brain measures were compared across high-risk twins, their low-risk co-twins, and healthy controls. Environmental factors predominated in structural and functional brain variability, while genetic contributions were limited, region-specific. Narrative fluency and psychological traits showed stronger heritability. Findings converged on the right middle frontal gyrus, where GMV and CT alterations reflected non-shared environment and risk expression. Despite the small sample, preliminary results suggest neurobiological vulnerability in language networks arises from environmental rather than genetic factors, informing environmental susceptibility to adolescent mental illness.

Background: Across phenotypic and genotypic studies, executive functioning (EF) has been shown to be associated with externalizing behaviors, including attention-deficit/hyperactivity disorder (ADHD), aggression, and substance use, and is a proposed underlying mechanism of these behaviors. However, there is limited research on the shared biological mechanisms underpinning EF and externalizing behaviors, including their overlap at the level of genomic regions. Methods: The current study used genome-wide association study summary statistics of EF, ADHD, aggressive behavior, alcohol use, and alcohol use disorder to examine whether the heritability of these traits or the co-heritability between them is enriched for genes expressed in particular tissues or stratified by other annotation types. Additionally, the study examined the genomic regions contributing to the covariation between EF and the externalizing traits to identify genetic variants and genes that may be underlying their overlap. Results: First, across all phenotypes, there was evidence for enrichment of genetic signals in DNase hypersensitive sites and H3K4me1 regions, and significant enrichment among genes expressed in the anterior cingulate cortex and frontal cortex. Second, when combining results across regional methods, there was evidence for associations between EF and each of the externalizing behaviors in regions on chromosomes 1, 11, and 15. Conclusions: These findings highlight biological pathways that may link the relations between EF and externalizing behaviors and provides additional evidence of EF as an underlying mechanism of externalizing behavior.

Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occurs with distinct personality profiles, but whether ADHD shapes personality (scar model) or personality influences the development of ADHD (vulnerability model) remains unclear. Leveraging genome-wide association study (GWAS) data, we examined directional associations between ADHD and the Big Five personality traits (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). We estimated genetic correlations and conducted bidirectional two-sample Mendelian Randomization (MR) analyses between ADHD and the Big Five. Robustness was evaluated using multiple sensitivity tests, including MR-CAUSE, which accounts for correlated and uncorrelated pleiotropy, and colocalization analyses on fine-mapped variants. Higher genetic liability to Neuroticism and Extraversion, alongside lower liability to Conscientiousness, increased ADHD risk, consistent with the vulnerability model. Conversely, ADHD genetic liability was associated with lower Agreeableness, supporting the scar model. Associations were generally robust across sensitivity analyses, with MR-CAUSE supporting the Neuroticism and Agreeableness associations and colocalization providing variant-level support for associations between ADHD and Neuroticism, Conscientiousness, and Agreeableness. These findings provide early, population-level insight into personality-related vulnerability to ADHD and motivate further work on the role of personality traits in ADHD risk.

Childhood adversity is robustly linked to differences in amygdala and hippocampal volume. However, findings across studies have been inconsistent and contradictory. This inconsistency stems partly from the many reasonable but arbitrary choices that researchers make when operationalizing brain regions, stress exposure, and covariates. To deal with this variability, we applied a multiverse analysis approach using adolescent data from the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study to evaluate how multiple analytic choices influence the relationships between stress and hippocampal/amygdala volume. Our primary analysis crossed three region-of-interest operationalizations (left, right, total), four intracranial volume scaling methods, and multiple sociodemographic covariates. Greater lifetime stress severity was associated with smaller amygdala volume across 72% of specifications, and with smaller hippocampal volume across 52% of specification models. Statistical significance was strongly influenced by the region of interest. Our secondary multiverse analysis tested six operationalizations of stress exposure (total/acute/chronic x count/severity). This analysis found that the laterality pattern in the primary analysis was not strongly influenced by stress operationalization. These findings demonstrate the robustness of the stress-medial temporal lobe association and identify specific analytic choices (i.e. hemisphere operationalization) that most strongly drive the variability observed in previous literature. Our study is one of the first that utilized multiverse analysis for adversity-neuroimaging research, and provides a strong framework for evaluating and interpreting inconsistent findings.

Objective: Brief measures of depressive symptoms and family psychiatry history may support the identification of youth who warrant further assessment, but their interpretation requires population-based measurement evidence. This study evaluated the Very Quick Inventory of Depressive Symptomatology (VQIDS) and Family Index of Risk for Mood (FIRM) in the BENCHMARK 2025 national survey. Method: The sample consisted of 2,252 parent reports for children aged 6-18 years and 1,008 linked adolescent self-reports aged 12-18 years. Analyses examined VQIDS dimensionality, reliability, item functioning, age- and sex-based norms, and informant agreement, alongside FIRM score distributions, alternative scoring approaches, and associations with depressive symptoms. Results: VQIDS findings supported a single dimension and good internal consistency, with greatest IRT precision at elevated symptom levels and no practically meaningful differential item functioning across age or sex. Two-week stability was moderate, and parent-adolescent agreement was lower within more symptomatic subsets. FIRM totals showed stronger cross-informant agreement and retest stability. Family history scores were associated with higher VQIDS percentiles and discriminated scores at or above the 90th percentile across informants (AUROC = .670-.698). FIRMs associations were strongest with internalizing symptoms, although evidence was mixed for mood specificity. Conclusions: These findings provide a measurement and normative foundation for brief depressive symptom assessment and support family history as a complementary correlate of symptom elevation. Diagnostic and prospective prediction utility require further evaluation.

Importance: Pediatric obesity affects 1 in 5 US children and has been linked to brain structural differences. Most evidence is cross-sectional and models body mass index (BMI) linearly, with metrics that compress severe obesity. Objective: To examine associations between brain structure and BMI for age across the weight spectrum and Centers for Disease Control and Prevention (CDC) weight status categories, distinguishing between and within person associations, and their age and sex moderation. Design, Setting, and Participants: Longitudinal cohort study of youth aged 8 to 10 years at baseline in the US community based Adolescent Brain Cognitive Development Study (4 waves, 2016 to 2025; ages 8 to 18 years). Exposures: Extended CDC BMI-for-age z-score, grouped by wave-mean z-score: underweight (<5th percentile, n=297), healthy weight (5th to <85th, n=7,452), overweight (85th to <95th, n=1,919), and obesity ([&ge;]95th, n=1,842). Main Outcomes and Measures: Cortical thickness (12 regions) and subcortical volume (7 regions) from T1 weighted magnetic resonance imaging (MRI), defined a priori. Results: Among 11,510 participants contributing 32,212 observations (mean [SD] age, 12.6 [2.5] years; 52.2% male), higher between person BMI for age z was associated with lower frontal and temporal thickness (6 regions) and larger subcortical volume (5 regions; all q < .001), but associations were nonlinear (17 of 19 regions). Youth with obesity had lower thickness than healthy weight youth in 8 frontal and temporal regions (largest, -0.21 SD; q < .001), with dorsal frontal differences decreasing across adolescence; underweight youth had smaller subcortical volumes. Higher BMI for age z was associated with larger subcortical volume (all 7 regions) within the healthy weight category and lower cortical thickness (11 of 12 regions; fusiform: {beta} = -0.27; q < .001) within the obesity category, steeper than in healthy weight youth in 10 regions, but not in overweight or underweight youth. Within person associations did not reproduce the obesity associations, reversed from negative at age 10 to positive at age 16, and were more negative in female than male participants. Conclusions and Relevance: Youth with obesity had lower cortical thickness than healthy weight peers, but associations between brain structure and BMI for age differed between CDC weight status groups, suggesting a complex relationship between adiposity and brain structure.

Objective: The Genetic Risk for Serious Mental Illness and Development ("Paisa Kids") Study is establishing a longitudinal cohort of 3,000 youth enriched transdiagnostically for risk for serious mental illnesses (SMI; i.e., schizophrenia, bipolar disorder, and severe depression) from the Paisa region of Colombia. Its objective is to clarify the early clinical, neurobehavioral, genetic, and environmental profiles associated with later SMI and distinguish transdiagnostic from disorder-specific pathways. This paper describes the study infrastructure, recruitment streams, and baseline assessment battery, and characterizes the first two-thirds of the cohort. Method: Youth aged 6-15 years are being recruited. Youth recruited for high SMI risk either have a first or second degree adult relative with a SMI diagnosis or a psychiatric diagnosis themselves identified through electronic medical records (EMRs) associated with later SMI. Lower-risk youth have a relative without a SMI diagnosis. Baseline measures include psychiatric and developmental history, neurobehavioral functioning, environmental exposures, and genome-wide genotyping. Psychiatric EMRs provide longitudinal follow-up. Results: Among 2,384 participants enrolled thus far (mean age=11.2 years, 45.0% female), 2,211 were recruited for high SMI-risk and 173 for lower SMI-risk. Overall, 73.2% met criteria for a history of one or more psychiatric disorders. Logistic regression comparing rates of diagnoses and ACEs between recruitment streams showed elevated rates of depressive and anxiety disorders, attention-deficit/hyperactivity disorder, oppositional defiant disorder, and several ACEs among high versus lower SMI-risk youth. Conclusion: Integrating multidomain phenotyping, genomic data, and longitudinal EMR follow-up, the Paisa Kids cohort provides a unique resource for investigating pathways of risk and resilience to SMI.

Robust sex differences in brain morphology and function exist from birth onwards. While traditionally conceptualized as categorical, they were recently shown to be best described along a female-to-male continuum. Here, we probed the under-explored implications of this proposal for understanding early life vulnerability to psychiatric conditions with sex-biased prevalence. We analyzed environmental, clinical and resting state functional neuroimaging data from 411 participants in Developing Human Connectome Project (dHCP) and 214 children from the Oregon ADHD 1000 study. In the dHCP, we identified complementary patterns of neonatal alignment with sex-typical young adult architecture, which overlapped areas rich in nicotinic cholinergic receptors and predicted the same psychiatric symptoms across sexes in toddlerhood. Specifically, for association (compared to sensorimotor) areas, greater alignment with female-typical functional connectivity (FC) patterns foreshadowed higher anxiety, whereas greater alignment with male-typical FC patterns forecasted autism-related problems. The latter effect was weaker among toddlers with an older epigenetic age at birth and exposure to fewer maternal health problems, but greater environmental enrichment. In the independent child sample, patterns of alignment with sex-typical FC, overlapping those observed in neonates, distinguished a history of depression and generalized anxiety (greater alignment with female-typical FC) from a history of separation anxiety, behavioral problems and current ADHD (greater alignment with male-typical FC). Our study speaks to the psychiatric relevance of sex-related functional brain architecture from birth onwards, its value in identifying vulnerable youths and its promise in monitoring the success of environmental interventions.

Importance. Anorexia nervosa (AN) is a severe metabo-psychiatric disorder with heterogeneous outcomes and elevated mortality. Characterizing severity trajectories may improve early risk stratification and targeted intervention. Objective. To identify AN severity trajectories using a register-based severity index (AN-RSI) and examine their associations with polygenic scores (PGS), preceding (prior to AN diagnosis) as well as subsequent (5 years post AN diagnosis) psychiatric and somatic disorders. Design. Population-based cohort study. Setting. Nationwide study in Denmark. Participants. Individuals born between 1969 and 2013 with diagnosed AN (N = 9,534 individuals). Genetic data were available in a subsample comprising 5,126 individuals. Exposures. Forty-one PGS indexing traits relevant to AN, and psychiatric and somatic disorders prior to AN diagnosis. Main Outcomes and Measures. The main outcomes of interest were the AN-RSI trajectories and psychiatric and somatic disorders 5 years post AN diagnosis. Results. Three trajectories were identified: "low and stable" (32.6%), "medium and stable" (53.5%), and "high increasing" (14.0%). The "low and stable" group was used as the comparison group for all analyses. Each 1 standard deviation (SD) increase in AN PGS corresponded with 13% greater odds of following the "high increasing" trajectory. Increases in BMI and attention-deficit/hyperactivity disorder PGS corresponded with 15% and 14% lower odds of following the "high increasing" trajectory, respectively. No preceding psychiatric or somatic disorders were significantly associated with trajectory assignment. In contrast, psychiatric and somatic disorders were more likely to occur subsequent to an AN diagnosis in those in the "high increasing" trajectory with odds ratios (OR) ranging between 1.73 and 3.81 for psychiatric disorders and between 1.61 and 5.38 for somatic disorders with a notable exception of obesity which showed a lower OR of 0.27. Conclusions and Relevance. Our findings hold significant clinical relevance by demonstrating that individuals with AN follow distinct severity trajectories that have different genetic risk as measured by PGS and clear differences in post-diagnosis morbidity patterns but no discernable differences in pre-diagnosis psychiatric or somatic morbidity. As the eating disorders genetics field progresses, incorporating PGS into comprehensive assessments at first presentation may aid in early identification, personalized intervention, and resource allocation for individuals at higher risk of developing a severe illness trajectory.

Abstract Background: The 52-item Ontario Child Health Study Emotional Behavioural Scales (OCHS-EBS) has demonstrated reliability and validity evidence in Canadian population-based samples. This study evaluated an adapted item set of the Ontario Child Health Study Emotional Behavioural Scales (OCHS-EBS-A) intended to measure selected mental disorder symptoms while reducing respondent burden in population-based research. Methods: A prespecified candidate set of 21 items from selected OCHS-EBS disorder scales assessed depression (4 items), generalized anxiety (4 items), oppositional behaviour (6 items), and attention-deficit/hyperactivity (7 items). The 2023 Longitudinal Canadian Health Survey on Children and Youth (L-CHSCY; ages 5-21 years; n= 22,740) provided calibration and internal-validation samples. The Ontario Provincial Assessment and Tracking of Child and Family Health Study (ONPATH; Wave 5: n=719 parent and n=116 youth respondents) provided an independent sample for further evaluation. Analyses examined factorial validity, internal consistency reliability, convergent and discriminant validity, and measurement invariance across sex assigned at birth within age/informant groups. Findings: The analyses supported a refined 20-item OCHS-EBS-A with three correlated factors representing internalizing, oppositional behaviour, and inattention/hyperactivity symptoms. Prespecified criteria for internal consistency reliability and convergent and discriminant validity were met within the reported L-CHSCY age/informant groups. Measurement invariance across sex assigned at birth was supported in the L-CHSCY groups and for children and parents in and youth-reported internalizing symptoms in ONPATH. However, not for ONPATH youth-reported oppositional behaviour symptoms. Interpretation: Results from these population-based samples provide factorial-validity, internal-consistency, and convergent- and discriminant-validity evidence for scores from the 20-item OCHS-EBS-A among children, youth, and emerging adults aged 5-21 years.

Inhibitory control deficits have long been proposed as a central neurocognitive mechanism underlying childhood Attention Deficit/Hyperactivity Disorder (ADHD). However, neuroimaging findings remain heterogeneous, partly due to methodological variability across developmental samples and experimental paradigms. The present study aimed to characterize the neural architecture of motor response inhibition in typically developing (TD) children and identify reproducible functional abnormalities associated with pediatric ADHD using stringent, developmentally specific inclusion criteria. We conducted two coordinate-based meta-analyses using Activation Likelihood Estimation (ALE). Following a systematic literature search (up to August 2026), we identified 23 task-based fMRI studies reporting inhibitory-control-related activation in TD children (237 foci) and 17 studies comparing children with ADHD and TD peers (114 foci) during the Stop-Signal Task or Go/No-Go Task. All participants were younger than 18 years of age. Statistical significance was determined using cluster-level family-wise error (FWE) correction. In TD children, ALE revealed a robust inhibitory-control network encompassing the bilateral anterior insula (AI), inferior frontal gyrus (IFG), and the midline pre-supplementary motor area (preSMA) and anterior cingulate cortex (ACC). This spatial organization closely resembled the canonical inhibitory-control network consistently observed in adults, suggesting that the core neural architecture supporting motor inhibition is already detectably organized during development. In the between-group analysis, children with ADHD exhibited significant hypoactivation primarily within the preSMA. Notably, this region demonstrated striking spatial overlap with the preSMA cluster reliably recruited in TD children during motor inhibition. These findings provide convergent support for inhibitory-control models of ADHD and identify altered preSMA recruitment as one of the most consistent functional abnormalities associated with pediatric ADHD. While the neural infrastructure supporting inhibitory control is broadly established during childhood, children with ADHD exhibit reduced recruitment of a key cortical node within this network during motor inhibition demands.

Objective: Parent-adolescent disagreement in ratings of attention-deficit/hyperactivity disorder (ADHD) symptoms can complicate clinical assessment. This study examined parent - adolescent agreement in ADHD symptom ratings and characteristics associated with disagreement. Method: Participants were 1,008 parent-adolescent dyads recruited from a nationally stratified U.S. community sample. Adolescents were 12--18 years old (49.6% female) and along with their parents completed measures of ADHD and depressive symptoms. Agreement on Inattention (IN), Hyperactivity/Impulsivity (HI), and Total ADHD scores was examined. Item-level agreement was assessed using weighted kappa, Gwet 's AC2, percent agreement, and polychoric correlations. Associations between age, sex, and severity of ADHD and depression with levels of agreement were analyzed. Results: Agreement for ADHD factor and total symptom scores was moderate (intraclass correlations = 0.67--0.71), with moderate-to-strong rank-order correspondence. Adolescents reported slightly higher ADHD symptom levels than parents, although the mean difference was small. Item-level agreement was moderate to high (Gwet 's AC2 = 0.79--0.95). Several HI items demonstrated the kappa's paradox, with relatively low kappa values despite high Gwet's AC2 and percent agreement. Q-correlations revealed low agreement on relative strengths and weaknesses. Age and sex were not associated with disagreement and parent-reported ADHD severity and adolescent-reported depressive symptoms were associated with disagreement. Conclusions: Parent and adolescent ratings showed moderate agreement across boys and girls ages 12-- 18; however, disagreement related to relative strengths and weaknesses. Disagreement was associated with ADHD and depressive symptom severity. Findings suggest that ratings from parents and adolescents offer unique perspectives on the assessment of ADHD symptoms.

Background: Girls are more likely than boys to experience psychological distress during adolescence. Drivers of this gender gap remain under-studied, despite its large impact on later life and outcomes, especially for women. Explanatory factors can be gendered in their prevalence (differential exposure) and/or in their impact (differential susceptibility). We developed a multi-domain framework of explanatory factors for distress and applied it in four low- and middle-income countries. Methods: We first proposed a framework of explanatory factors for psychological distress grouped into seven domains (biological, cognitive, psychological, behavioural, social, environmental and broader societal). We applied this framework to identify explanatory variables assessed in childhood and adolescence in the Young Lives longitudinal cohort studies in Ethiopia (N=908), India (N=952), Peru (N=634) and Vietnam (N=887). Distress symptoms at 18-19 years were measured with the Strengths and Difficulties Questionnaire Emotional Symptoms scale. Gendered prevalence of each explanatory factor was tested with Mann-Whitney tests, and gendered impact with country-specific linear regressions including a gender-by-factor interaction term. Exploratory boosted-tree machine-learning models, interpreted with SHAP values and permutation feature importance, examined the contribution of these factors to the gender gap in each country. Results: Distress was higher in girls than boys in every country, the gap ranging from 0.62 points in Ethiopia and Vietnam to 1.76 in India and 2.45 in Peru. Some explanatory factors were consistently gendered in prevalence (e.g. girls experienced greater role overload in each country), while others were gendered only in some countries (e.g. study amount was higher for girls in Peru and Vietnam, but not Ethiopia or India). Gendered impacts on distress displayed more variability across countries. For example, higher self-esteem was more protective for boys than girls in India, Peru and Vietnam, but more protective for girls in Ethiopia. The machine-learning models identified important predictors across all framework domains, though their salience varied by country. Conclusions: Our findings underscore the importance of considering multi-domain explanations for mental-health outcomes and observed inequalities in mental health. Large cross-country differences in the gender gap and in the prevalence and influence of explanatory factors caution against generalising drivers of mental-health outcomes and inequalities across contexts.

Background Autism spectrum disorder (ASD) shows wide phenotypic variation, from adults without intellectual disability and with low support needs to minimally verbal children with intellectual disability and severe behavioral symptoms. Genetic studies of this heterogeneity have focused mainly on high-impact de novo variants and polygenic scores; here we investigate, at the molecular level, the role of common variants. Materials and methods We analyzed genotypic and phenotypic data from 9,332 individuals with ASD in the SPARK cohort. We considered 31 traits: six latent factors derived from the Social Communication Questionnaire and the Repetitive Behavior Scale-Revised, 22 co-occurring diagnoses, parent-reported IQ range, age at diagnosis, and age at first walking. We performed within-case genome-wide association studies (GWAS) and, for the 10 traits with evidence of SNP heritability, association analyses with genetically predicted gene and protein expression, splicing, and enhancer activity in brain and blood (xWAS). Nominated genes were tested for enrichment in biological processes, brain cell types, and developmental stages. xWAS-derived transcriptional signatures were compared with chemical perturbation signatures from CMap/LINCS L1000 to prioritize candidate drugs. Results GWAS identified seven genome-wide significant loci for five traits, including loci near GABRG3 and TENM2 associated with co-occurring sleep, feeding or toileting problems. xWAS identified seven gene-trait associations involving three phenotypes (FDR < 0.1), including CACNA1G with communication skills and NEGR1 with learning disability. GWAS and xWAS nominated different genes which however converged on synaptic transmission and gated channel activity, with preferential expression in neurons during later stages of brain development. PARP and p38 MAPK inhibitors were predicted to reverse the signatures of both social-communication and repetitive-behavior phenotypes, whereas several compound classes, including histone deacetylase inhibitors and mTOR inhibitors, were predicted to reverse the signatures of some phenotypes while mimicking those of others. Conclusion Combining within-case GWAS with xWAS nominates candidate genes mediating common-variant effects on ASD heterogeneity, provides biological insight, and suggests candidates for phenotypically stratified drug repositioning.