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With brain structure and function undergoing complex changes throughout childhood and adolescence, age is a critical consideration in neuroimaging studies, particularly for those of individuals with neurodevelopmental conditions. However, despite the increasing use of large, consortium-based datasets to examine brain structure and function in neurotypical and neurodivergent populations, it is unclear whether age-related changes are consistent between datasets and whether inconsistencies related to differences in sample characteristics, such as demographics and phenotypic features, exist. To address this, we built models of age-related changes of brain structure (regional cortical thickness and regional surface area; N = 1218) and function (resting-state functional connectivity strength; N = 1254) in two neurodiverse datasets: the Province of Ontario Neurodevelopmental Network and the Healthy Brain Network. We examined whether deviations from these models differed between the datasets, and explored whether these deviations were associated with demographic and clinical variables. We found significant differences between the two datasets for measures of cortical surface area and functional connectivity strength throughout the brain. For regional measures of cortical surface area, the patterns of differences were associated with race/ethnicity, while for functional connectivity strength, positive associations were observed with head motion. Our findings highlight that patterns of age-related changes in the brain may be influenced by demographic and phenotypic characteristics, and thus future studies should consider these when examining or controlling for age effects in analyses., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care., Methods: The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10-19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span., Discussion: Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world., (© 2024. The Author(s).)

We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions., (© The Author(s) 2023. Published by Oxford University Press.)

Importance: Neurodevelopmental conditions, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), have highly heterogeneous and overlapping phenotypes and neurobiology. Data-driven approaches are beginning to identify homogeneous transdiagnostic subgroups of children; however, findings have yet to be replicated in independently collected data sets, a necessity for translation into clinical settings., Objective: To identify subgroups of children with and without neurodevelopmental conditions with shared functional brain characteristics using data from 2 large, independent data sets., Design, Setting, and Participants: This case-control study used data from the Province of Ontario Neurodevelopmental (POND) network (study recruitment began June 2012 and is ongoing; data were extracted April 2021) and the Healthy Brain Network (HBN; study recruitment began May 2015 and is ongoing; data were extracted November 2020). POND and HBN data are collected from institutions across Ontario and New York, respectively. Participants who had diagnoses of ASD, ADHD, and OCD or were typically developing (TD); were aged between 5 and 19 years; and successfully completed the resting-state and anatomical neuroimaging protocol were included in the current study., Main Outcomes and Measures: The analyses consisted of a data-driven clustering procedure on measures derived from each participant's resting-state functional connectome, performed independently on each data set. Differences between each pair of leaves in the resulting clustering decision trees in the demographic and clinical characteristics were tested., Results: Overall, 551 children and adolescents were included from each data set. POND included 164 participants with ADHD; 217 with ASD; 60 with OCD; and 110 with TD (median [IQR] age, 11.87 [9.51-14.76] years; 393 [71.2%] male participants; 20 [3.6%] Black, 28 [5.1%] Latino, and 299 [54.2%] White participants) and HBN included 374 participants with ADHD; 66 with ASD; 11 with OCD; and 100 with TD (median [IQR] age, 11.50 [9.22-14.20] years; 390 [70.8%] male participants; 82 [14.9%] Black, 57 [10.3%] Hispanic, and 257 [46.6%] White participants). In both data sets, subgroups with similar biology that differed significantly in intelligence as well as hyperactivity and impulsivity problems were identified, yet these groups showed no consistent alignment with current diagnostic categories. For example, there was a significant difference in Strengths and Weaknesses ADHD Symptoms and Normal Behavior Hyperactivity/Impulsivity subscale (SWAN-HI) between 2 subgroups in the POND data (C and D), with subgroup D having increased hyperactivity and impulsivity traits compared with subgroup C (median [IQR], 2.50 [0.00-7.00] vs 1.00 [0.00-5.00]; U = 1.19 × 104; P = .01; η2 = 0.02). A significant difference in SWAN-HI scores between subgroups g and d in the HBN data was also observed (median [IQR], 1.00 [0.00-4.00] vs 0.00 [0.00-2.00]; corrected P = .02). There were no differences in the proportion of each diagnosis between the subgroups in either data set., Conclusions and Relevance: The findings of this study suggest that homogeneity in the neurobiology of neurodevelopmental conditions transcends diagnostic boundaries and is instead associated with behavioral characteristics. This work takes an important step toward translating neurobiological subgroups into clinical settings by being the first to replicate our findings in independently collected data sets.

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples., (© 2022. The Author(s).)

The comorbidity of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) diagnoses is well established. An ASD diagnosis is associated with elevated ADHD traits and symptoms, as well as strengths in attention. In the ASD literature, attentional strengths have been described as maladaptive (e.g., hyperfocus), in contrast with positive portrayals in the typically developing population (e.g., flow). The objective of this study was to (1) compare profiles of attentional strengths and weaknesses in ASD and ADHD and (2) determine whether attentional strengths in ASD are associated with impairment, poorer cognitive flexibility, and perseveration/perfectionism. In a community sample of 5,744 children and youth, 131 children were reported as having a diagnosis of ASD (mean age 10.3 years) and 346 children were reported as having a diagnosis of ADHD (mean age 10.7 years). We used the Strengths and Weaknesses of Attention-Deficit/Hyperactivity-symptoms and Normal-behaviors (SWAN) rating scale to calculate attentional and hyperactive/impulse control strength and weakness counts and scores. The Autism-Spectrum Quotient Switching factor served as a measure of cognitive flexibility. Impairment was assessed with the Columbia Impairment Scale. We used the symmetry/ordering factor on the Toronto Obsessive-Compulsive Scale as a measure of perseveration/perfectionism. No differences were found between the ADHD and ASD groups in SWAN weakness scores, symptoms, or hyperactive/impulse control strengths; however, autistic children had higher rates of attentional strengths [odds ratio: 5.7, 95% CI (2.8, 11.6), p < 0.0001]. Post-hoc pairwise testing identified four attentional strengths with significantly higher rates in ASD than in ADHD. Attentional strength scores were not associated with impairment or poor cognitive flexibility, but predicted levels of perseveration/perfectionism. The effect of attentional strengths on impairment and cognitive flexibility did not differ between autistic and Control children, but the higher perseveration/perfectionism scores seen in ASD were not found in Control children. ASD is associated with a pattern of attentional strengths that is not found in ADHD Characterizing the full range of attentional abilities in autistic children may explain variability in outcomes such as quality-of-life indicators and identify protective factors, providing targets for strength-based behavioral interventions. The clinical and etiological implications of the subgroup of autistic children with attentional strengths require further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dupuis, Mudiyanselage, Burton, Arnold, Crosbie and Schachar.)

Objectives: Canadian province-wide lockdowns have challenged children's mental health (MH) during the COVID-19 pandemic, with autistic children being at particular risk. The purpose of our study was to identify sub-groups of autistic children with distinct mental health change profiles, to understand the child-, parent-, and system-specific factors associated with such profiles in order to ultimately inform future interventions., Methods: Data were drawn from a large Canadian cohort (N=1,570) across Ontario, resulting in 265 autistic children (mean age=10.9 years, 76% male). K-means clustering analyses were employed to partition distinct MH profiles in six MH measures (mood, anxiety, OCD symptoms, irritability, inattention, hyperactivity) and group differences were examined with reference to the above factors. Additionally, we investigated the characteristics of children who accessed acute MH services., Results: The optimal number of clusters was two; one included those experiencing MH deterioration across all six MH measures (61.3%, 95% confidence interval [CI]=54.9 to 67.4), and a second included youth that did not experience MH changes (38.7%, 95%CI=32.6 to 45.1). Child-specific factors associated with MH deterioration included higher pre-existing internalizing symptoms, high levels of COVID stress. Parental MH challenges and system-specific factors, such as the loss of learning supports, access to physicians and material deprivation, were also associated with MH deterioration. Access to acute MH services were primarily associated with financial insecurity and loss of services., Conclusions: More than half of autistic children experienced MH deterioration, and person-specific (pre-existing MH, COVID related stress), parent-specific (Parent MH) and system-level (loss of services and material deprivation) characteristics were associated with such decline, providing clinical and policy opportunities for intervention at multiple levels., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society.)

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., (© 2022. The Author(s).)

Background: There is a need to develop a multipurpose obsessive-compulsive disorder (OCD) measure that is useful for cross disorder research and as a reliable clinical rating scale. The current study examined the psychometric properties and established clinical cutoffs for the parent-report version of the Toronto Obsessive-Compulsive Scale (TOCS), a 21-item rating scale of obsessive-compulsive traits., Method: Participants ranged in age from 6 to 21 years old and had a primary diagnosis of OCD ( n  = 350, 50% female), attention-deficit/hyperactivity disorder (ADHD) ( n  = 820, 25% female), autism spectrum disorder (ASD) ( n  = 794, 22% female), or were typically developing controls ( n  = 391, 51% female). Confirmatory factor analyses, internal consistency reliability, and convergent and divergent validity of the TOCS were examined in the OCD group. Using various scoring approaches, receiver operating characteristic (ROC) analyses were used to establish a clinical cut-off by splitting the OCD group into a discovery sample (166 OCD cases, 164 controls) and a validation sample (184 OCD cases, 227 controls). Classification accuracy and TOCS scores were compared across OCD, ADHD, and ASD groups., Results: The psychometric properties of the TOCS were confirmed. ROC analyses across TOCS scoring approaches in the discovery sample indicated excellent diagnostic discrimination (AUC ≥0.95, sensitivity 77%-92%, specificity 92%-98%). Established cutoffs, when applied in the independent validation sample of OCD cases and controls, showed an overall classification accuracy of 85%-90%. The TOCS total score and symptom count showed good discrimination of OCD from ADHD (AUC ≥0.86) and ASD (AUC ≥0.81). The OCD group scored significantly higher on all TOCS dimensions (except Hoarding) than the ADHD and ASD groups., Conclusion: The TOCS is a reliable and valid rating scale with strong sensitivity and specificity in discriminating OCD cases from controls, as well as from ASD and ADHD. It is a quantitative OCD measure with important clinical and research applications, with particular relevance for cross disorder phenotyping and population-based studies., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2021 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: With high survival rates for pediatric acute lymphoblastic leukemia (ALL), long-term quality of life is a prominent consideration in treatment. We concurrently evaluated cognition, behavior, and quality of life in child and adolescent ALL survivors and determined associations between them., Methods: The sample included 83 controls (mean age: 12.5 years) and 71 ALL survivors (mean age: 11.9 years, mean age at diagnosis: 3.8 years). Participants completed measures of general intellectual abilities, math achievement, and fine motor skills. Parents and teachers completed a survey assessing child participants' cognitive, behavioral, and emotional function. Parents additionally completed a survey about their child's quality of life., Results: Survivors had lower scores on measures of working memory, processing speed, timed math, and fine motor skills (effect size 0.5-1, p < 0.001). Parents identified more problems with executive function and learning in survivors than controls (effect size > 0.7, p < 0.001), and indicated a lower quality of life in all categories evaluated (effect size > 0.7, p < 10 -4 ). Reduced quality of life was associated with lower math achievement scores and with inattention and executive function problems., Conclusions: ALL survivors experience diffuse cognitive, behavioral, and motor impairments, which are associated with reduced quality of life. These findings underscore the need to address these challenges in ALL survivors., Impact: Compared with cancer-free peers, parents of childhood acute lymphoblastic leukemia survivors treated with chemotherapy only reported reduced quality of life. Math difficulties and behavioral problems increased the risk for reduced quality of life. Reduced quality of life is associated with mild cognitive and behavioral difficulties, suggesting that even relatively mild impairments have broad implications for ALL survivors. Screening and early intervention targeting cognitive and behavioral function may enhance quality of life for ALL survivors., (© 2020. International Pediatric Research Foundation, Inc.)

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10 -8 ). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (r g  = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.

Background: A decreased ability to inhibit a speeded motor response is a well-studied deficit in Attention Deficit Hyperactivity Disorder (ADHD), and has been proposed as an endophenotype. Inhibitory control has been assessed reliably with the Stop Signal Task (SST) and is associated with prior documented differences in regional brain function using f-MRI. Here, we advance on these findings by examining their structural connectivity and white matter integrity with the goal of identifying a network underlying a core cognitive deficit in ADHD., Methods: Healthy controls (N=16) and youth diagnosed with ADHD (N=60) were recruited through the Province of Ontario Neurodevelopmental Disorders Network (POND) and the Hospital for Sick Children. An f-MRI activation difference map was co-registered with each participant's white matter imaging data, representing the specific network nodes where ADHD youth diverged significantly from controls while performing the SST. Probabilistic tractography was applied from these nodes, and white matter integrity indices such as fractional anisotropy (FA) within the tracts of interest were contrasted between the groups and correlated with SST output measures, including the measure of inhibitory control, the stop signal reaction time (SSRT)., Results: The tracts that connected the network nodes belonged primarily to the inferior fronto-occipital fasciculus (IFOF) and cingulum. ADHD subjects showed trend differences in FA compared to controls between right inferior frontal gyrus (IFG) and right superior temporal gyrus (P= 0.09), right IFG and right posterior cingulate (P= 0.01), right anterior cingulate to posterior cingulate (p= 0.08), and between left middle temporal gyrus (BA 39) and left posterior cingulate (P=0.02). A trend correlation was found between radial diffusivity within IFG to STG white matter (IFOF) and SSRT., Conclusions: We identified potential white matter tracts related to deficient inhibitory control, elucidating the brain mechanisms of an important cognitive deficit in ADHD. These findings could be integrated into future endophenotypic biomarker studies, incorporating altogether brain structure, function, and behavior for future studies of ADHD and other psychiatric conditions that exhibit this deficit., (Copyright © 2020 Tremblay, Hammill, Ameis, Bhaijiwala, Mabbott, Anagnostou, Lerch and Schachar.)

Background: Altered brain activity that has been observed in attention deficit hyperactivity disorder (ADHD) while performing cognitive control tasks like the stop signal task (SST) has generally been interpreted as reflecting either weak (under-active) or compensatory (over-active) versions of the same functions as in healthy controls. If so, then regional activities that correlate with the efficiency of inhibitory control (i.e. stop signal reaction time, SSRT) in healthy subjects should also correlate with SSRT in ADHD. Here we test the alternate hypothesis that BOLD (blood-oxygen-level-dependent) differences might instead reflect the redirection of neural processing resources normally used for task-directed inhibitory control, towards actively managing symptomatic behaviour. If so, then activities that correlate with SSRT in TD should instead correlate with inattentive and hyperactive symptoms in ADHD., Methods: We used fMRI (functional magnetic resonance imaging) in 14 typically developing (TD) and 14 ADHD adolescents performing the SST, and in a replication sample of 14 healthy adults. First, we identified significant group BOLD differences during all phases of activity in the SST (i.e. warning, response, reactive inhibition, error detection and post-error slowing). Next, we correlated these phases of activity with SSRT in TD and with SSRT, inattentive and hyperactive symptom scores in ADHD. We then identified whole brain significant correlations in regions of significant group difference in activity., Results: Only three regions of significant group difference were correlated with SSRT in TD and replication groups (left and right inferior frontal gyri (IFG) during error detection and hypothalamus during post-error slowing). Consistent with regions of altered activity managing symptomatic behaviour instead of task-directed behaviour, left IFG correlated with greater inattentive score, right IFG correlated with lower hyperactive score and hypothalamus correlated with greater inattentive score and oppositely correlated with SSRT compared to TD., Conclusions: Stimuli that elicit task-directed integration of neural processing in healthy subjects instead appear to be directing integrated function towards managing symptomatic behaviour in ADHD. The ability of the current approach to determine whether altered neural activities reflect comparable functions in ADHD and control groups has broad implications for the development and monitoring of therapeutic interventions.

Children with neurodevelopmental disorders (NDDs) share common behavioural manifestations despite distinct categorical diagnostic criteria. Here, we examined canonical resting-state network connectivity in three diagnostic groups (autism spectrum disorder, attention-deficit/hyperactivity disorder and paediatric obsessive-compulsive disorder) and typically developing controls (TD) in a large single-site sample (N = 407), applying diagnosis-based and dimensional approaches to understand underlying neurobiology across NDDs. Each participant's functional network graphs were computed using five graph metrics. In diagnosis-based comparisons, an analysis of covariance was performed to compare all NDDs to TD, followed by pairwise comparisons between NDDs. In the dimensional approach, participants' functional network graphs were correlated with continuous behavioural measures, and a data-driven k-means clustering analysis was applied to determine if subgroups of participants were seen, without diagnostic information having been included. In the diagnosis-based comparisons, children with NDDs did not differ significantly from the TD group and the NDD categorical groups also did not differ significantly from each other, across all graph metrics. In the dimensional, diagnostic-independent approach, however, subcortical functional connectivity was significantly correlated with participants' general adaptive functioning across all participants. The clustering analysis identified an optimal solution of two clusters, and participants assigned in the same data-driven cluster were highly heterogeneous in diagnosis. Neither cluster exclusively contained a specific diagnostic group, nor did NDDs separate cleanly from TDs. Each participant's distance ratio between the two clusters was significantly correlated with general adaptive functioning, social deficits and attentional problems. Our results suggest the neurobiological similarity and dissimilarity between NDDs need to be investigated beyond DSM/ICD-based, behaviourally-defined diagnostic categories., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Cure rates for pediatric acute lymphoblastic leukemia (ALL) have reached an all-time high (>90%); however, neurocognitive difficulties continue to affect quality of life in at least a subset of survivors. There are relatively few quantitative neuroimaging studies in child and adolescent ALL survivors treated with chemotherapy only. Use of different outcome measures or limited sample sizes restrict our ability to make inferences about patterns of brain development following chemotherapy treatment. In this study, we used magnetic resonance imaging (MRI) to evaluate brain outcomes in ALL survivors, comparing against a group of typically developing, cancer free peers., Materials and Methods: Participants included 71 ALL survivors, on average 8 years after diagnosis and 8-18 years of age, and 83 typically developing controls. Anatomical MRI was performed to evaluate brain structure; diffusion and magnetization transfer MRI were used to examine brain tissue microstructure., Results: Successful MRI scans were acquired in 67 survivors (94%) and 82 controls (99%). Structurally, ALL survivors exhibited widespread reductions in brain volume, with 6% less white matter and 5% less gray matter than controls (p = 0.003 and 0.0006 respectively). Much of the brain appeared affected - 71 of 90 evaluated structures showed smaller volume - with the most notable exception being the occipital lobe, where no significant differences were observed. Average full-scale IQ in the survivor and control groups were 95 (CI 92-99) and 110 (CI 107-113), respectively. Using data from the NIH Pediatric MRI Data Repository, we evaluated the extent to which elevated IQ in the control group might affect the structural differences observed. We estimated that two thirds of the observed brain differences were attributable to ALL and its treatment. In addition to the structural changes, survivors showed, on average, globally lower white matter fractional anisotropy (-3%) and higher radial diffusivity (+5%) (p < 10 -6 ), but no differences in magnetization transfer ratio., Conclusions: Neuroanatomical alterations in late childhood and adolescent ALL survivors treated with chemotherapy-only protocols are widespread, with white matter being somewhat more affected than gray matter. These MRI results indicate brain development is altered in ALL survivors and highlight the need to examine how these alterations emerge., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Response inhibition is essential for navigating everyday life. Its derailment is considered integral to numerous neurological and psychiatric disorders, and more generally, to a wide range of behavioral and health problems. Response-inhibition efficiency furthermore correlates with treatment outcome in some of these conditions. The stop-signal task is an essential tool to determine how quickly response inhibition is implemented. Despite its apparent simplicity, there are many features (ranging from task design to data analysis) that vary across studies in ways that can easily compromise the validity of the obtained results. Our goal is to facilitate a more accurate use of the stop-signal task. To this end, we provide 12 easy-to-implement consensus recommendations and point out the problems that can arise when they are not followed. Furthermore, we provide user-friendly open-source resources intended to inform statistical-power considerations, facilitate the correct implementation of the task, and assist in proper data analysis., Competing Interests: FV, GB, PB, AB, JB, CC, HC, LC, BC, JC, AD, DE, HG, IG, AH, RH, SJ, JK, IL, CL, GL, DM, SM, AM, MP, RP, KR, MR, JS, AS, KT, Mv, LV, MV, JW, RW, BZ, CB No competing interests declared, AA, NS Reviewing editor, eLife, CB has received payment for consulting and speaker's honoraria from GlaxoSmithKline, Novartis, Genzyme, and Teva. He has recent research grants with Novartis and Genzyme, SC consults for Shire, Ieso Digital Health, Cambridge Cognition, and Promentis. Dr Chamberlain's research is funded by Wellcome Trust (110049/Z/15/Z), TR consults for Cambridge Cognition, Mundipharma and Unilever. He receives royalties from Cambridge Cognition (CANTAB) and has recent research grants with Shionogi and SmallPharma, KR has received speaker's honoraria and grants for other projects from Eli Lilly and Shire, RS has consulted to Highland Therapeutics, Eli Lilly and Co., and Purdue Pharma. He has commercial interest in a cognitive rehabilitation software company, eHave, (© 2019, Verbruggen et al.)

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD) have been associated with difficulties recognizing and responding to social cues. Neuroimaging studies have begun to map the social brain; however, the specific neural substrates contributing to social deficits in neurodevelopmental disorders remain unclear. Three hundred and twelve children underwent structural magnetic resonance imaging of the brain (controls = 32, OCD = 44, ADHD = 77, ASD = 159; mean age = 11). Their social deficits were quantified on the Social Communication Questionnaire (SCQ) and the Reading the Mind in the Eyes Test (RMET). Multivariable regression models were used to examine the structural neuroimaging correlates of social deficits, with both a region of interest and a whole-brain vertex-wise approach. For the region of interest analysis, social brain regions were grouped into three networks: (1) lateral mentalization (e.g., temporal-parietal junction), (2) frontal cognitive (e.g., orbitofrontal cortex), and (3) subcortical affective (e.g., limbic system) regions. Overall, social communication deficits on the SCQ were associated with thinner cortices in the left lateral regions and the right insula, and decreased volume in the ventral striatum, across diagnostic groups (p = 0.006 to <0.0001). Smaller subcortical volumes were associated with more severe social deficits on the SCQ in ASD and ADHD, and less severe deficits in OCD. On the RMET, larger amygdala/hippocampal volumes were associated with fewer deficits across groups. Overall, patterns of associations were similar in ASD and ADHD, supporting a common underlying biology and the blurring of the diagnostic boundaries between these disorders.

Purpose: Chemotherapy for childhood acute lymphoblastic leukemia (ALL) can cause late-appearing side effects in survivors that affect multiple organs, including the heart and brain. However, the complex ALL treatment regimen makes it difficult to isolate the causes of these side effects and impossible to separate the contributions of individual chemotherapy agents by clinical observation. Using a mouse model, we therefore assessed each of eight representative, systemically-administered ALL chemotherapy agents for their impact on postnatal brain development and heart function., Experimental Design: Mice were treated systemically with a single chemotherapy agent at an infant equivalent age, then allowed to age to early adulthood (9 weeks). Cardiac structure and function were assessed using in vivo high-frequency ultrasound, and brain anatomy was assessed using high-resolution volumetric ex vivo MRI. In addition, longitudinal in vivo MRI was used to determine the time course of developmental change after vincristine treatment., Results: Vincristine, doxorubicin, and methotrexate were observed to produce the greatest deficiencies in brain development as determined by volumes measured on MRI, whereas doxorubicin, methotrexate, and l-asparaginase altered heart structure or function. Longitudinal studies of vincristine revealed widespread volume loss immediately following treatment and impaired growth over time in several brain regions., Conclusions: Multiple ALL chemotherapy agents can affect postnatal brain development or heart function. This study provides a ranking of agents based on potential toxicity, and thus highlights a subset likely to cause side effects in early adulthood for further study., (©2018 American Association for Cancer Research.)

Obsessive-compulsive disorder (OCD) is a heritable childhood-onset psychiatric disorder that may represent the extreme of obsessive-compulsive (OC) traits that are widespread in the general population. We report the heritability of the Toronto Obsessive-Compulsive Scale (TOCS), a new measure designed to assess the complete range of OC traits in youth. We also examined the dimensional nature of the TOCS and the degree to which genetic effects are unique or shared between dimensions. OC traits were measured using the TOCS in 16,718 youth (6-18 years) at a science museum. We conducted a factor analysis to identify OC trait dimensions. We used univariate and multivariate twin models to estimate the heritability of OC trait dimensions in a subset of twins (220 pairs). Six OC dimensions were identified: Cleaning/Contamination, Symmetry/Ordering, Rumination, Superstition, Counting/Checking, and Hoarding. The TOCS total score (74%) and each OC dimension was heritable (30-77%). Hoarding was not highly correlated with other OC dimensions, but did share genetic effects. Shared genetics accounted for most of the shared variance among dimensions, whereas unique environment accounted for the majority of dimension-specific variance. One exception was Hoarding, which had considerable unique genetic factors. A latent trait did not account for the shared variance between dimensions. In conclusion, OC traits and individual OC dimensions were heritable, although the degree of shared and dimension-specific etiological factors varied by dimension. The TOCS may be informative for genetic research of OC traits in youth. Genetic research of OC traits should consider both OC dimension and total trait scores.

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p < 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p < 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed.

Introduction: Survival rates for children with acute lymphoblastic leukemia (ALL) approach 95%. At the same time, there is growing concern that chemotherapy causes alterations in brain development and cognitive abilities. We performed MRI measurements of white and gray matter volume to explore how variation in brain structure may be related to cognitive abilities in ALL survivors and healthy controls., Methods: The sample included 24 male ALL survivors who had completed contemporary treatment 3-11 years prior, and 21 age- and sex-matched controls. Participants were between 8 and 18 years old. Working memory and motor response inhibition were measured with the N-Back and Stop Signal Tasks (SST), respectively. Participants underwent 3T structural MRI to assess white and gray matter volumes overall, lobe-wise, and in cortical and atlas-identified subcortical structures. Mental health was assessed with the Child Behavioral Checklist., Results: ALL survivors performed more poorly on measures of working memory and response inhibition than controls. Frontal and parietal white matter, temporal and occipital gray matter volume, and volumes of subcortical white and gray matter structures were significantly reduced in ALL survivors compared with controls. Significant structure-function correlations were observed between working memory performance and volume of the amygdala, thalamus, striatum, and corpus callosum. Response inhibition was correlated with frontal white matter volume. No differences were found in psychopathology., Conclusions: Compared with controls, a reduction in volume across brain regions and tissue types, was detectable in ALL survivors years after completion of therapy. These structural alterations were correlated with neurocognitive performance, particularly in working memory. Confirming these observations in a larger, more representative sample of the population is necessary. Additionally, establishing the time course of these changes-and the treatment, genetic, and environmental factors that influence them-may provide opportunities to identify at-risk patients, inform the design of treatment modifications, and minimize adverse cognitive outcomes.

Objective: Traumatic brain injury (TBI) is the most common cause of death and disability in children and adolescents. Psychopathology is an established risk factor for, and a frequent consequence of, TBI. This paper reviews the literature relating psychopathology and TBI., Method: Selective literature review., Results: The risk of sustaining a TBI is increased by pre-existing psychopathology (particularly ADHD and aggression) and psychosocial adversity. Even among individuals with no psychopathology prior to the injury, TBI is frequently followed by mental illness especially ADHD, personality change, conduct disorder and, less frequently, by post-traumatic stress and anxiety disorders. The outcome of TBI can be partially predicted by pre-injury adjustment and injury severity, but less well by age at injury. Few individuals receive treatment for mental illness following TBI., Conclusion: TBI has substantial relevance to mental health professionals and their clinical practice. Available evidence, while limited, indicates that the risk for TBI in children and adolescents is increased in the presence of several, potentially treatable mental health conditions and that the outcome of TBI involves a range of mental health problems, many of which are treatable. Prevention and management efforts targeting psychiatric risks and outcomes are an urgent priority. Child and adolescent mental health professionals can play a critical role in the prevention and treatment of TBI through advocacy, education, policy development and clinical practice.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Objective: The purpose of the present study was to develop reliable and valid parent and teacher scales for measurement of functional impairment in children and adolescents in order to assist the diagnosis of attention-deficit/hyperactivity disorder (ADHD)., Methods: Seventy-two children with ADHD fulfilling the Diagnostic and Statistical Manual of Mental Disorder, 4th Edition criteria and forty-two normal controls were enrolled in this study. Parents and teachers of the subjects completed the parent and teacher form of the preliminary items of Child and Adolescent Functioning Impairment Scale (CAFIS) made up by the authors. Based on the reliability and factor analysis, the final parent (CAFIS-parent form) and teacher version (CAFIS-teacher form) were constructed. Scales were analyzed for reliability and validity. Relative operating characteristics curve was drawn to calculate the cutoff scores of these scales for children with ADHD., Results: The CAFIS-parent and CAFIS-teacher forms consist of four and three factors, respectively. Internal consistency and test-retest correlation of the scales were satisfactory. The CAFIS and Children's Global Assessment Scale were significantly correlated. All scores of subscales of CAFIS in ADHD group were significantly higher than those of control group. The sensitivity and specificity of the subscales were mostly at an appropriate level., Conclusion: The CAFIS is a brief layperson-administered scale to assess functional impairment of children and adolescents. It can be a useful tool for parents and teachers to objectively measure the functions of children at home and in school. This scale was found to be reliable and valid, and it appears to be a valuable instrument in Korean language.