Dataset factors associated with age-related changes in brain structure and function in neurodevelopmental conditions.

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.

Brain-charting autism and attention deficit hyperactivity disorder reveals distinct and overlapping neurobiology.

BACKGROUND: Autism and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental conditions with complex underlying neurobiology that is still poorly understood. Despite overlapping presentation and sex-biased prevalence, autism and ADHD are rarely studied together, and sex differences are often overlooked. Population modelling, often referred to as normative modelling, provides a unified framework for studying age-specific and sex-specific divergences in brain development. METHODS: Here we used population modelling and a large, multi-site neuroimaging dataset (N = 4255 after quality control) to characterise cortical anatomy associated with autism and ADHD, benchmarked against models of average brain development based on a sample of over 75,000 individuals. We also examined sex and age differences, relationship with autistic traits, and explored the co-occurrence of autism and ADHD (autism+ADHD). RESULTS: We observed robust neuroanatomical signatures of both autism and ADHD. Overall, autistic individuals showed greater cortical thickness and volume, that was localised to the superior temporal cortex, whereas individuals with ADHD showed more global increases in cortical thickness, but lower cortical volume and surface area across much of the cortex. The autism+ADHD group displayed a unique pattern of widespread increases in cortical thickness, and certain decreases in surface area. We also found evidence that sex modulates the neuroanatomy of autism but not ADHD, and an age-by-diagnosis interaction for ADHD only. CONCLUSIONS: These results indicate distinct cortical differences in autism and ADHD that are differentially impacted by age, sex, and potentially unique patterns related to their co-occurrence.

A protocol for the formative evaluation of the implementation of patient-reported outcome measures in child and adolescent mental health services as part of a learning health system.

BACKGROUND: Mental health conditions affect one in seven young people and research suggests that current mental health services are not meeting the needs of most children and youth. Learning health systems are an approach to enhancing services through rapid, routinized cycles of continuous learning and improvement. Patient-reported outcome measures provide a key data source for learning health systems. They have also been shown to improve outcomes for patients when integrated into routine clinical care. However, implementing these measures into health systems is a challenging process. This paper describes a protocol for a formative evaluation of the implementation of patient-reported measures in a newly operational child and adolescent mental health centre in Calgary, Canada. The purpose is to optimize the collection and use of patient-reported outcome measures. Our specific objectives are to assess the implementation progress, identify barriers and facilitators to implementation, and explore patient, caregivers and clinician experiences of using these measures in routine clinical care. METHODS: This study is a mixed-methods, formative evaluation using the Consolidated Framework for Implementation Research. Participants include patients and caregivers who have used the centre's services, as well as leadership, clinical and support staff at the centre. Focus groups and semi-structured interviews will be conducted to assess barriers and facilitators to the implementation and sustainability of the use of patient-reported outcome measures, as well as individuals' experiences with using these measures within clinical care. The data generated by the patient-reported measures over the first five months of the centre's operation will be analyzed to understand implementation progress, as well as validity of the chosen measures for the centres' population. DISCUSSION: The findings of this evaluation will help to identify and address the factors that are affecting the successful implementation of patient-reported measures at the centre. They will inform the co-design of strategies to improve implementation with key stakeholders, which include patients, clinical staff, and leadership at the centre. To our knowledge, this is the first study of the implementation of patient-reported outcome measures in child and adolescent mental health services and our findings can be used to enhance future implementation efforts in similar settings.

The trajectory of depression and anxiety among children and adolescents over two years of the COVID-19 pandemic.

Longitudinal research examining children's mental health (MH) over the course of the COVID-19 pandemic is scarce. We examined trajectories of depression and anxiety over two pandemic years among children with and without MH disorders. Parents and children 2-18 years completed surveys at seven timepoints (April 2020 to June 2022). Parents completed validated measures of depression and anxiety for children 8-18 years, and validated measures of emotional/behavioural symptoms for children 2-7 years old; children ≥10 years completed validated measures of depression and anxiety. Latent growth curve analysis determined depression and anxiety trajectories, accounting for demographics, child and parent MH. Data were available on 1315 unique children (1259 parent-reports; 550 child-reports). Trajectories were stable across the study period, however individual variation in trajectories was statistically significant. Of included covariates, only initial symptom level predicted symptom trajectories. Among participants with pre-COVID data, a significant increase in depression symptoms relative to pre-pandemic levels was observed; children and adolescents experienced elevated and sustained levels of depression and anxiety during the two-year period. Findings have direct policy implications in the prioritization and of maintenance of educational, recreational, and social activities with added MH supports in the face of future events.

Altered Error Monitoring and Decreased Flanker Task Accuracy in Pediatric Obsessive-Compulsive Disorder.

The error-related negativity (ERN) and error positivity (Pe) are components of the event-related potential following an error that are potential mechanistic biomarkers of obsessive-compulsive disorder (OCD). The study examined the ERN, Pe, flanker task accuracy, and clinical measures in 105 OCD cases and 105 matched healthy controls (HC) ages 8-18 years. Higher flanker task accuracy in all participants was associated with an increased ERN amplitude and increased difference between Pe and correct positivity amplitudes (ΔPe). Compared to HC, OCD cases had an increased ERN but decreased ΔPe and flanker task accuracy. Those differences were also significant in tic-related and non-tic-related OCD cases compared to HC. A lower ΔPe was associated in cases with an earlier age at OCD symptom onset. The results support the hypothesis that OCD involves defects in an error monitoring system and suggest a reduced ΔPe may compromise error signaling and cause uncertainty about the correctness of a response.

Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

OBJECTIVES: Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. METHODS: Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. RESULTS: Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P  = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. CONCLUSION: Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population.

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Racial/Ethnic Disparities in Psychiatric Traits and Diagnoses within a Community-based Sample of Children and Youth: Disparités raciales/ethniques dans les traits et diagnostics psychiatriques au sein d'un échantillon communautaire d'enfants et de jeunes.

OBJECTIVE: Racial/ethnic disparities in the prevalence of psychiatric disorders have been reported, but have not accounted for the prevalence of the traits that underlie these disorders. Examining rates of diagnoses in relation to traits may yield a clearer understanding of the degree to which racial/ethnic minority youth in Canada differ in their access to care. We sought to examine differences in self/parent-reported rates of diagnoses for obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders after adjusting for differences in trait levels between youth from three racial/ethnic groups: White, South Asian and East Asian. METHOD: We collected parent or self-reported ratings of OCD, ADHD and anxiety traits and diagnoses for 6- to 17-year-olds from a Canadian general population sample (Spit for Science). We examined racial/ethnic differences in trait levels and the odds of reporting a diagnosis using mixed-effects linear models and logistic regression models. RESULTS: East Asian (N = 1301) and South Asian (N = 730) youth reported significantly higher levels of OCD and anxiety traits than White youth (N = 6896). East Asian and South Asian youth had significantly lower odds of reporting a diagnosis for OCD (odds ratio [OR]East Asian = 0.08 [0.02, 0.41]; ORSouth Asian = 0.05 [0.00, 0.81]), ADHD (OREast Asian = 0.27 [0.16, 0.45]; ORSouth Asian = 0.09 [0.03, 0.30]) and anxiety (OREast Asian = 0.21 [0.11, 0.39]; ORSouth Asian = 0.12 [0.05, 0.32]) than White youth after accounting for psychiatric trait levels. CONCLUSIONS: These results suggest a discrepancy between trait levels of OCD, ADHD and anxiety and rates of diagnoses for East Asian and South Asian youth. This discrepancy may be due to increased barriers for ethnically diverse youth to access mental health care. Efforts to understand and mitigate these barriers in Canada are needed.

We know that there is there are differences in the prevalence of childhood mental illnesses by race/ethnic group, which may be related to disproportionate access to mental health care. What is unknown is whether there this difference in prevalence is related to differences in the presence of symptoms for mental illness or whether children and youth from marginalized racial/ethnic groups have symptoms but are not getting diagnosed. This information is needed to understand the degree to which children and youth from marginalized race/ethnicity groups are accessing mental health care in Canada. We tested the differences in reported symptoms and diagnosis of three common and impairing childhood-onset disorders (obsessive-compulsive disorder­OCD), attention-deficit/hyperactivity disorder­ADHD and anxiety disorders) in children and youth (6­17 years of age) living in Canada that were from three racial/ethnic groups: White, South Asian and East Asian. East Asian and South Asian youth reported significantly higher levels of OCD and anxiety traits than White youth. However, East Asian and South Asian youth were significantly less likely than White youth to have a reported diagnosis of OCD, ADHD or anxiety even after accounting for symptom levels for each disorder. Our findings suggest that East and South Asian children are less likely than White children to get a diagnosis for common mental illness even if they have symptoms of that mental illness. This gap in receiving a diagnosis might be because of more barriers to mental health care for children and youth from marginalized racial/ethnic groups but we need more research to pinpoint the cause.

Using a Rapid Learning Health System for Stratified Care in Emerging Adult Mental Health Services: Protocol for the Implementation of Patient-Reported Outcome Measures.

BACKGROUND: Mental illness among emerging adults is often difficult to ameliorate due to fluctuating symptoms and heterogeneity. Recently, innovative approaches have been developed to improve mental health care for emerging adults, including (1) implementing patient-reported outcome measures (PROMs) to assess illness severity and inform stratified care to assign emerging adults to a treatment modality commensurate with their level of impairment and (2) implementing a rapid learning health system in which data are continuously collected and analyzed to generate new insights, which are then translated to clinical practice, including collaboration among clients, health care providers, and researchers to co-design and coevaluate assessment and treatment strategies. OBJECTIVE: The aim of the study is to determine the feasibility and acceptability of implementing a rapid learning health system to enable a measurement-based, stratified care treatment strategy for emerging adults. METHODS: This study takes place at a specialty clinic serving emerging adults (age 16-24 years) in Calgary, Canada, and involves extensive collaboration among researchers, providers, and youth. The study design includes six phases: (1) developing a transdiagnostic platform for PROMs, (2) designing an initial stratified care model, (3) combining the implementation of PROMs with stratified care, (4) evaluating outcomes and disseminating results, (5) modification of stratified care based on data derived from PROMs, and (6) spread and scale to new sites. Qualitative and quantitative feedback will be collected from health care providers and youth throughout the implementation process. These data will be analyzed at regular intervals and used to modify the way future services are delivered. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework is used to organize and evaluate implementation according to 3 key objectives: improving treatment selection, reducing average wait time and treatment duration, and increasing the value of services. RESULTS: This project was funded through a program grant running from 2021 to 2026. Ethics approval for this study was received in February 2023. Presently, we have developed a system of PROMs and organized clinical services into strata of care. We will soon begin using PROMs to assign clients to a stratum of care and using feedback from youth and clinicians to understand how to improve experiences and outcomes. CONCLUSIONS: This study has key implications for researchers and clinicians looking to understand how to customize emerging adult mental health services to improve the quality of care and satisfaction with care. This study has significant implications for mental health care systems as part of a movement toward value-based health care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/51667.

Impact of Cytochrome P450 Genetic Variation on Patient-Reported Symptom Improvement and Side Effects Among Children and Adolescents Treated with Fluoxetine.

Background: Clinical practice guidelines recommend the use of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), as a first-line pharmacotherapy for major depressive disorder (MDD) and obsessive compulsive disorder (OCD) in children and adolescents. However, response and tolerability to fluoxetine varies from child to child, which may in part, be a result of interindividual differences in fluoxetine metabolism. In this study, we examined whether genotype-predicted activity scores of cytochrome P450 enzymes were associated with patient-reported symptom improvement and side effects in children and adolescents treated with fluoxetine. Methods: Ninety children and adolescents aged 7-18 with a MDD or OCD diagnosis and a history of fluoxetine treatment were recruited from Western Canada. For each participant, fluoxetine dose and duration information were collected, as well as questions about adherence, side effects, and symptom improvement. DNA was extracted from a saliva sample and genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. Logistic regression models were fitted to assess the impact of activity scores on symptom improvement and side effects. Results: Increased CYP2D6 activity score was significantly associated with reduced odds of symptom improvement (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.23-0.91, p = 0.028) as well as a trend association with reduced side effects (OR = 0.49, 95% CI = 0.22-1.07, p = 0.072), after adjusting for age, sex, diagnosis, dose, duration, adherence, and activity scores of the other assessed CYP enzymes. No associations with symptom improvement or side effects were detected for the other CYP enzymes examined. Conclusions: Our results suggest that an increase in the genotype-predicted CYP2D6 activity score was associated with a decrease in the odds of reporting symptom improvement among children and adolescents treated with fluoxetine. These findings will contribute to future updates of pharmacogenetic-based SSRI prescribing guidelines and if replicated, could inform fluoxetine treatment in children and adolescents with MDD or OCD. Clinical Trial Registration: NCT04797364.

White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

The genetic architecture of youth anxiety: a study protocol.

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.

Is irritability multidimensional: Psychometrics of The Irritability and Dysregulation of Emotion Scale (TIDES-13).

Irritability is a common, impairing, and potentially multifaceted manifestation of psychopathology. We designed The Irritability and Dysregulation of Emotion Scale (TIDES-13) to determine whether various expressions of irritability in children and youth form multiple subdimensions with distinct correlates. We administered parent-report (n = 3875, mean age = 8.9) and youth self-report (n = 579, mean age = 15.1) versions of TIDES-13 in a population and community-based sample. We conducted exploratory/confirmatory factor analyses and regression analyses to examine the dimensionality of TIDES-13 and the associations of the scale with age, gender, anxiety, depression, ODD, ADHD traits, and the Affective Reactivity Index (ARI). A higher-order model with a global irritability dimension and four subdimensions, including proneness to anger (PA), internalized negative emotional reactivity (iNER), externalized negative emotional reactivity (eNER), and reactive aggression (RA), showed good to excellent fit in both parent-report and self-report. The global irritability dimension showed excellent internal reliability (⍵Total; parent-report = 0.97, ⍵Total; self-report = 0.95), explained a majority of the item variance (⍵Hierarchical; parent-report = 0.94, ⍵Hierarchical; self-report = 0.90), and was moderately correlated with the ARI (rparent = 0.68, rself = 0.77). Subdimensions PA, eNER, and RA were negatively associated with age in males, whereas iNER was positively associated with age in females. Traits of ODD and ADHD were associated primarily with the global irritability dimension, whereas iNER was strongly associated with anxiety and depression traits over and above the global irritability dimension. Our results support a unidimensional interpretation of irritability in a population sample. However, limited evidence of specific behavioral, age, and sex correlates with particular irritability subdimensions may warrant further investigation.

Dorsal Striatal Functional Connectivity and Repetitive Behavior Dimensions in Children and Youths With Neurodevelopmental Disorders.

BACKGROUND: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs). METHODS: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions]). RESULTS: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity. CONCLUSIONS: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed.

A statistical method for image-mediated association studies discovers genes and pathways associated with four brain disorders.

Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. By leveraging the UK Biobank image-derived phenotypes (IDPs), the IMAS discovered genetic bases underlying four neuropsychiatric disorders and verified them by analyzing annotations, pathways, and expression quantitative trait loci (eQTLs). A cerebellar-mediated mechanism was identified to be common to the four disorders. Simulations show that, if the goal is identifying genetic risk, our IMAS is more powerful than a hypothetical protocol in which the imaging results were available in the GWAS dataset. This implies the feasibility of reanalyzing legacy GWAS datasets without conducting additional imaging, yielding cost savings for integrated analysis of genetics and imaging.

Brain-charting autism and attention deficit hyperactivity disorder reveals distinct and overlapping neurobiology.

Background: Autism and attention deficit hyperactivity disorder (ADHD) are heterogeneous neurodevelopmental conditions with complex underlying neurobiology. Despite overlapping presentation and sex-biased prevalence, autism and ADHD are rarely studied together, and sex differences are often overlooked. Normative modelling provides a unified framework for studying age-specific and sex-specific divergences in neurodivergent brain development. Methods: Here we use normative modelling and a large, multi-site neuroimaging dataset to characterise cortical anatomy associated with autism and ADHD, benchmarked against models of typical brain development based on a sample of over 75,000 individuals. We also examined sex and age differences, relationship with autistic traits, and explored the co-occurrence of autism and ADHD (autism+ADHD). Results: We observed robust neuroanatomical signatures of both autism and ADHD. Overall, autistic individuals showed greater cortical thickness and volume localised to the superior temporal cortex, whereas individuals with ADHD showed more global effects of cortical thickness increases but lower cortical volume and surface area across much of the cortex. The autism+ADHD group displayed a unique pattern of widespread increases in cortical thickness, and certain decreases in surface area. We also found evidence that sex modulates the neuroanatomy of autism but not ADHD, and an age-by-diagnosis interaction for ADHD only. Conclusions: These results indicate distinct cortical differences in autism and ADHD that are differentially impacted by age, sex, and potentially unique patterns related to their co-occurrence.

Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity.

A qualitative study on the implementation of a transdiagnostic cognitive behavioral therapy for children in a child welfare residential treatment program.

BACKGROUND: Youth with severe emotional or behavioral issues who are involved with child welfare authorities are sometimes placed in intensive care services in a residential treatment program. Evidence-based psychotherapies are often used in residential treatments, but there is very little research on how to adapt psychotherapy for residential treatment. OBJECTIVE: To describe the implementation of a transdiagnostic cognitive behavioral therapy (the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders in Children) in a residential treatment program for children. PARTICIPANTS AND SETTING: Staff (n = 20) at a residential facility in Calgary, Canada. METHODS: A combination of qualitative interviews and focus groups were conducted before and after therapy to identify barriers and facilitators to implementation. Data were analyzed and reported using the Consolidated Framework for Implementation Research and the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies. RESULTS: Modifications were made to the program including creating inclusive language, integrating relevant content targeting pediatric irritability, delivering sessions online for caregivers, and using additional staff to support youth to learn and practice the application of the content and behavioral interventions. Key barriers to implementation of the Unified Protocol included staff turnover and the difficulty of sustaining a critical mass of knowledge surrounding the Unified Protocol. The major facilitators to implementation were the perceived quality of the program and advantages of the program to children and their caregivers. CONCLUSIONS: This study supports the feasibility and acceptability of providing transdiagnostic cognitive behavioral therapies for children in residential treatment and provides a template for how to implement evidence-based practice in residential treatment.

Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies.

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I2 statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.