Importance:Adverse prenatal exposures (APEs) often co-occur and independently associate with risk for childhood psychopathology. Whether exposure to multiple APEs associates with persistent clinical effects through adolescence or underlying changes in brain maturation remains uncertain. Objective:To evaluate longitudinal associations among cumulative APE burden, risk for psychopathology, and age-related cortical thinning in adolescents. Design Setting and Participants:This cohort study analyzed 4-year follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study, which enrolled 11,868 youth aged 9 to 10 years beginning in 2016. Sibling-comparison analysis was performed on 414 non-adopted sibling pairs with discordant APEs. Statistical analysis occurred from March to June 2025. Exposures:Cumulative APE burden was calculated by summing six binary prenatal exposures that independently associated with psychopathology at baseline: unplanned pregnancy; early maternal prenatal alcohol, tobacco, or marijuana use; complicated pregnancy; and complicated birth. Main Outcomes and Measures:Outcomes included annual Child Behavior Checklist (CBCL) scores of dimensional psychopathology, using both continuous and thresholded outcomes; and biennial cortical thickness measures from structural magnetic resonance imaging, analyzed using linear mixed-effects models. Results:Of 8,515 singleton children (4,055 females [47.6%]), 78% were exposed to at least one APE. Multiple APEs persistently and dose-dependently associated with increased odds of clinically significant psychopathology (CBCL total problems: odds ratio=2.01-6.75; corrected P=.0065-1.31×10-13). Associations of APEs with attention-deficit/hyperactivity disorder symptoms attenuated over time (interaction: F=13.51; corrected P=7.13×10-8), while those with depressive symptoms potentiated (interaction: F=5.82; corrected P=.0019). Greater APE burden associated with accelerated age-related cortical thinning in 36 of 68 cortical regions (interactions: F=3.26-8.89; corrected P's=0.039-4.86×10-4). Siblings with more exposures demonstrated persistently higher CBCL total problems (T=2.25; P=0.025) and accelerated cortical thinning (interactions: T=-3.00--2.10; P's<.05) in 5 of the 36 regions implicated in the larger sample. Conclusions and Relevance:Multiple prenatal adversities associated with altered developmental trajectories of psychopathology and cortical maturation into mid-adolescence. These findings highlight the importance of fetal programming to mental health across life course, and the need for additional study of risk and resiliency-conferring factors in utero.

Genome-wide studies are yielding a growing catalog of common and rare variants that confer risk for psychopathology. However, despite representing unprecedented progress, emerging data also indicate that the full promise of psychiatric genetics-including understanding pathophysiology and improving personalized care-will not be fully realized by targeting traditional dichotomous diagnostic categories. The current article provides reflections on themes that emerged from a 2021 National Institute of Mental Health-sponsored conference convened to address strategies for the evolving field of psychiatric genetics. As anticipated by the National Institute of Mental Health's Research Domain Criteria framework, multilevel investigations of dimensional and transdiagnostic phenotypes, particularly when integrated with biobanks and big data, will be critical to advancing knowledge. The path forward will also require more diverse representation in source studies. Additionally, progress will be catalyzed by a range of converging approaches, including capitalizing on computational methods, pursuing biological insights, working within a developmental framework, and engaging health care systems and patient communities.

Processing Speed (PS) has become established as an area of concern in pediatric populations. Research suggests that it can differentially impact academic, social, and adaptive outcomes. A relationship between cognitive ability, PS weakness, and psychosocial outcomes has been indicated in recent literature. The current study sought to explore the relationship between those with higher cognitive ability and a relative difficulty in PS (Weschler VCI > 110 and Weschler VCI - PSI ≥ 15) in parent and teacher reported behaviors, specifically school engagement and services, social relationships, adaptability/resilience, and negative legal outcomes (e.g. substance use). Data were used from a clinically referred sample of 679 children ages 6-17 (11.2 ± 3.2; 37.3% girls) with high cognitive ability that were part of a larger study (Longitudinal Study of Genetic Influences on Cognition (LOGIC)). Results suggest that parents and teachers observe children with a relative PS difficulty to have more struggle with their approach to work. There were particularly strong associations on teacher rating scales. Discussion highlights the importance of teacher input as an indicator of academic struggle in these youth and discuss implications for further research.

Large, population-based magnetic resonance imaging (MRI) studies of adolescents promise transformational insights into neurodevelopment and mental illness risk. However, youth MRI studies are especially susceptible to motion and other artifacts that introduce non-random noise. After visual quality control of 11,263 T1 MRI scans obtained at age 9-10 years through the Adolescent Brain Cognitive Development study, we uncovered bias in measurements of cortical thickness and surface area in 55.1% of the samples with suboptimal image quality. These biases impacted analyses relating structural MRI and clinical measures, resulting in both false-positive and false-negative associations. Surface hole number, an automated index of topological complexity, reproducibly identified lower-quality scans with good specificity, and its inclusion as a covariate partially mitigated quality-related bias. Closer examination of high-quality scans revealed additional topological errors introduced during image preprocessing. Correction with manual edits reproducibly altered thickness measurements and strengthened age-thickness associations. We demonstrate here that inadequate quality control undermines advantages of large sample size to detect meaningful associations. These biases can be mitigated through additional automated and manual interventions.

There is, in the content of the Journal, an embarrassment of riches, and picking a "best" seems to demand a certain qualification: is the "best" the most interesting, most surprising, most educational, most important, most provocative, most enjoyable? How to choose? We are hardly unbiased and can admit to a special affection for the ones that we and the authors worked hardest on, modifying version after version into shape. Acknowledging these biases, here are the 2024 articles that we think deserve your attention or at least a second read.

Objective: Research establishing the validity of neuropsychological assessment using telehealth (teleNP) is much needed in pediatric populations. Method: Current analyses compared performances on twelve common neuropsychological measures completed at home via teleNP or in-person during the COVID-19 pandemic in 476 youth (ages 6 to 17, M(age )11.4 +/- 3.0). Results: No differences were found on nine measures. In-person performances on three verbal tests were similar to 1 scaled score point lower (all p(adjusted) <.05). Post-hoc analyses showed that the in-person pandemic performances were comparable to an in-person pre-pandemic cohort (unmasked). Conclusions: Overall, teleNP was comparable to in-person assessment. Results indicate that teleNP administration does not result in substantially different performance in pediatric patients undergoing clinical evaluations.

Objective: We leveraged common genetic variation underlying ADHD, educational attainment (EA) and cognition (COG) to understand the nature of the Behavior Rating Inventory for Executive Functions (BRIEF) and its relationship to academic functioning. Method: Participants were 991 youth, ages 7 to 17, consecutively referred for neuropsychiatric evaluation. Polygenic scores (PGS) for ADHD, EA, and COG were related to the BRIEF using regression analyses. Structural equation models were used to examine the associations between the PGS, BRIEF and academic outcomes (math, reading, and special education services [EDPLAN]). Results: After modeling the PGS together, only the EA and ADHD PGS significantly associated with the BRIEF. The BRIEF partially mediated the relationships between EA PGS with math and EDPLAN and fully mediated the relationship between ADHD PGS and EDPLAN. Conclusion: Genetic data extend evidence that the BRIEF measures a construct relevant to educational success that differs from what is indexed by cognitive testing.

It is well established that mental health conditions, including substance use disorders, are associated with premature mortality. A meta-analysis1 has demonstrated that this association holds across a range of diagnoses. Although the effect is stronger for schizophrenia, depression and anxiety contribute to more deaths overall because of their high prevalence rates. Moreover, more than two-thirds of associated deaths were explained by natural causes.1 The next logical questions, then, are as follows: which mechanisms underlie this association, and can they can be mitigated? In the current issue of JAACAP, Clark et al.2 aim to tie mental health symptoms and substance use to the acceleration of biological aging.

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk 1,2. However, MRI studies of youth are especially susceptible to motion and other artifacts 3,4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies, 5 and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study6. Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen's d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.

Understanding the potential value of polygenic risk scores (PRSs) for child and adolescent psychiatry requires further investigation of how PRSs perform in cohorts of referred youth. We addressed 2 knowledge gaps relevant to clinical translation, that is, specificity and sex-dependent manifestation, in relation to PRS for ADHD, anxiety (ANX), and depression (MDD) in child and adolescent psychiatric outpatients.

Polygenic risk scores (PRSs) based on specific symptom dimensions hold potential to index distinct components of complex neuropsychiatric conditions. This possibility is particularly relevant to ADHD, because clinically referred youth can vary substantially in their levels of inattention and hyperactivity/impulsivity symptoms. We aimed to understand the relationship between PRSs based on inattention and hyperactive/impulsivity symptoms and related phenotypes in child and adolescent psychiatry outpatients. Such work is a necessary first step toward understanding whether symptom-based PRSs could serve as objective indicators of risk and tools for risk stratification in clinical settings.

BACKGROUND: Physical activity is associated with mental health benefits in youth. Here, we used causal inference and triangulation with 2 levels of biology to substantiate relationships between sports participation and dimensional psychopathology in youths. METHODS: Baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, which recruited children from 9 to 10 years of age across the United States, were included in multilevel regression models to assess relationships between lifetime participation in team sports (TS), individual sports, and nonsports activities and Child Behavior Checklist (CBCL) scores. We calculated polygenic risk scores for 8 psychiatric disorders to assess interactions with sports exposure on CBCL scores among European descendants. Following rigorous quality control, FreeSurfer-extracted brain magnetic resonance imaging structural data were examined for mediation of CBCL- RESULTS: Among those with complete data (N = 10,411), causal estimates using inverse probability weighting associated lifetime TS exposure with a 1.05-point reduction in CBCL total (95% CI, -1.54 to -0.56, p , .0001) a relationship that was specific to TS and strengthened with more years of exposure. Associations of attentiondeficit/hyperactivity disorder polygenic loading with CBCL total weakened in European children with TS exposure (n = 4041; beta = -0.93, SE = 0.38, p = .013). Furthermore, TS participation and lower CBCL each associated with increased subcortical volumes (n = 8197). Subcortical volume mediated 5.5% of TS effects on CBCL total. CONCLUSIONS: Our findings support prior associations of TS participation with lower psychopathology in youths through additional studies that demonstrate specificity, dose response, and coherence across 2 levels of biology. Longitudinal studies that further clarify causal relationships may justify interventional studies of TS for high-risk youth.

There is a growing recognition that dichotomous psychiatric diagnoses do not accurately reflect the underlying biology of psychopathology and may even hinder our understanding of pathophysiology by collapsing phenotypes with potentially different etiologic underpinnings. This is particularly relevant in ADHD, one of the most prevalent neurodevelopmental disorders. The diagnosis of ADHD is based on two separate symptom domains: hyperactivity/impulsivity (HI) and inattention (IN) that are continuously distributed across individuals in the population. In clinics, patients often present with symptoms that vary on these distinct domains, including some who do not meet the full diagnostic criteria, despite experiencing functional impairment. Thus, polygenic scores (PGSes) derived from the specific ADHD domains may be informative in referred youth if they can serve as objective indicators linking symptoms to biological mechanisms. If so, PGSes of ADHD domains may extend the identification of children with emerging psychopathology and/or at high risk for developing adverse outcomes. In this study, we aimed to gain insight into the relevance of ADHD domain-specific PGSes to ADHD-related phenotypes in an outpatient child psychiatry sample. The Longitudinal Study of Genetic Influences on Cognition (LOGIC), a cohort of youth consecutively referred for neuropsychiatric evaluation, was used. The sample of 1,137 youth (NPsychchip=505; NGSA=632) was genotyped and imputed in two batches following standard procedures. PGSes of ADHD domains (PGS-IN and PGS-HI) were calculated using PRScs software based on summary statistics from a genome-wide association study on the ADHD domains in children and adolescents in the general population (N up to 53,258). Only unrelated probands aged 6 – 17 without intellectual disability were included in the analyses (N=976; meanage = 11.0 ± 3.10; 35.5% girls). ADHD diagnoses (N = 596 (61.1%)) were established based on DSM criteria and parent rated symptoms of IN and HI were measured via the Child Symptom Inventory or Child and Adolescent Symptom Inventory. The associations between these PGSes and ADHD domains was examined using linear regression, adjusting for sex, age, first five principal components and medication. The results from the two batches were meta-analyzed using a random effects inverse variance method. Preliminary results show that PGS-IN was significantly associated with IN and nominally associated with HI (IN: beta=0.33,95%CI=0.15-0.51, p=0.0003; HI: beta=0.22,95%CI=0.03-0.40,p=0.0232), while PGS-HI did not show any significant associations (IN: beta=0.16, 95%CI=-0.25-0.57, p=0.4383; HI: beta=0.18, 95%CI=-0.15-0.52,p=0.2806). This pattern of associations was also observed after controlling for ADHD diagnosis. Further, PGS-IN also revealed the same pattern of associations when the analyses were restricted to individuals with ADHD (IN: beta=0.38, 95%CI=0.18-0.59, p=0.0003; HI: beta=0.25,95%CI=0.05-0.44, p=0.0147). The PGS-HI did not show any associations (all p > 0.40). These results add to the notion that the genetic underpinnings of specific ADHD symptoms can be dissected and related to phenotypes in the clinical setting, even after accounting for diagnosed disorder. Studies are needed to further clarify how the genetics of ADHD domains may have utility as objective indices of risk for manifesting or emerging ADHD psychopathology in help seeking youth.

This study examined the impact of the COVID-19 pandemic on cognitive and academic functioning in 574 youth presenting for outpatient clinical neuropsychiatric evaluations. We extended the prior literature by (a) determining the extent to which academic difficulties documented in population and community samples also occurred in child psychiatric outpatients; (b) evaluating the impact of the pandemic on neuropsychological functions relevant to academic performance (overall cognition, executive functions, and graphomotor skill); and (c) investigating the moderating impact of attention deficit hyperactivity disorder (ADHD) diagnosis. We compared cross-sectional scores on standardized measures for groups of youth evaluated at three time periods related to the COVID-19 pandemic: (a) prior to onset (PRIOR; N = 198), (b) during Year 1 (Y1; N = 149), and (c) during Year 2 (Y2; N = 227). Relative to overall cognitive ability, math scores were lower in Y1 and Y2 and reading scores were lower in Y2. Additionally, relative to overall cognitive ability, youth showed lower working memory in Y1 and lower processing speed in Y1 and Y2. Graphomotor skill and parent-rated executive functions (EF) did not vary significantly across the three time periods. ADHD status did not moderate psychometric test scores but did moderate parent-rated EF. These data suggest that the COVID-19 pandemic has negatively impacted academic and executive functions in child psychiatry outpatients. More research is needed to understand the long-term implications for development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood. The authors associate a novel genomic risk score with a broad set of psychiatric symptoms in children. They trace the impact of associated genes on cerebellar developmental processes that originate in fetal life and endure through early adolescence.