Publications by authors named "Russell Schachar"

155 Publications

Cross-Diagnosis Structural Correlates of Autistic-Like Social Communication Differences.

Cereb Cortex 2021 Jun 3. Epub 2021 Jun 3.

Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario M4G 1R8, Canada.

Social communication differences are seen in autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), but the brain mechanisms contributing to these differences remain largely unknown. To address this gap, we used a data-driven and diagnosis-agnostic approach to discover brain correlates of social communication differences in ASD, ADHD, and OCD, and subgroups of individuals who share similar patterns of brain-behavior associations. A machine learning pipeline (regression clustering) was used to discover the pattern of association between structural brain measures (volume, surface area, and cortical thickness) and social communication abilities. Participants (n = 416) included children with a diagnosis of ASD (n = 192, age = 12.0[5.6], 19% female), ADHD (n = 109, age = 11.1[4.1], 18% female), or OCD (n = 50, age = 12.3[4.2], 42% female), and typically developing controls (n = 65, age = 11.6[7.1], 48% female). The analyses revealed (1) associations with social communication abilities in distributed cortical and subcortical networks implicated in social behaviors, language, attention, memory, and executive functions, and (2) three data-driven, diagnosis-agnostic subgroups based on the patterns of association in the above networks. Our results suggest that different brain networks may contribute to social communication differences in subgroups that are not diagnosis-specific.
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http://dx.doi.org/10.1093/cercor/bhab142DOI Listing
June 2021

An Epigenetically Distinct Subset of Children With Autism Spectrum Disorder Resulting From Differences in Blood Cell Composition.

Front Neurol 2021 16;12:612817. Epub 2021 Apr 16.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors. ASD is extremely heterogeneous both clinically and etiologically, which represents one of the greatest challenges in studying the molecular underpinnings of ASD. While hundreds of ASD-associated genes have been identified that confer varying degrees of risk, no single gene variant accounts for >1% of ASD cases. Notably, a large number of ASD-risk genes function as epigenetic regulators, indicating potential epigenetic dysregulation in ASD. As such, we compared genome-wide DNA methylation (DNAm) in the blood of children with ASD ( = 265) to samples from age- and sex-matched, neurotypical controls ( = 122) using the Illumina Infinium HumanMethylation450 arrays. While DNAm patterns did not distinctly separate ASD cases from controls, our analysis identified an epigenetically unique subset of ASD cases ( = 32); these individuals exhibited significant differential methylation from both controls than the remaining ASD cases. The CpG sites at which this subset was differentially methylated mapped to known ASD risk genes that encode proteins of the nervous and immune systems. Moreover, the observed DNAm differences were attributable to altered blood cell composition, i.e., lower granulocyte proportion and granulocyte-to-lymphocyte ratio in the ASD subset, as compared to the remaining ASD cases and controls. This ASD subset did not differ from the rest of the ASD cases in the frequency or type of high-risk genomic variants. Within our ASD cohort, we identified a subset of individuals that exhibit differential methylation from both controls and the remaining ASD group tightly associated with shifts in immune cell type proportions. This is an important feature that should be assessed in all epigenetic studies of blood cells in ASD. This finding also builds on past reports of changes in the immune systems of children with ASD, supporting the potential role of altered immunological mechanisms in the complex pathophysiology of ASD. The discovery of significant molecular and immunological features in subgroups of individuals with ASD may allow clinicians to better stratify patients, facilitating personalized interventions and improved outcomes.
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http://dx.doi.org/10.3389/fneur.2021.612817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085304PMC
April 2021

Magnetic Resonance Imaging Findings Are Associated with Long-Term Global Neurological Function or Death after Traumatic Brain Injury in Critically Ill Children.

J Neurotrauma 2021 May 13. Epub 2021 May 13.

Neuroscience and Mental Health Research Program, Hospital for Sick Children, Toronto, Ontario, Canada.

The identification of children with traumatic brain injury (TBI) who are at risk of death or poor global neurological functional outcome remains a challenge. Magnetic resonance imaging (MRI) can detect several brain pathologies that are a result of TBI; however, the types and locations of pathology that are the most predictive remain to be determined. Forty-two critically ill children with TBI were recruited prospectively from pediatric intensive care units at five Canadian children's hospitals. Pathologies detected on subacute phase MRIs included cerebral hematoma, herniation, cerebral laceration, cerebral edema, midline shift, and the presence and location of cerebral contusion or diffuse axonal injury (DAI) in 28 regions of interest were assessed. Global functional outcome or death more than 12 months post-injury was assessed using the Pediatric Cerebral Performance Category score. Linear modeling was employed to evaluate the utility of an MRI composite score for predicting long-term global neurological function or death after injury, and nonlinear Random Forest modeling was used to identify which MRI features have the most predictive utility. A linear predictive model of favorable versus unfavorable long-term outcomes was significantly improved when an MRI composite score was added to clinical variables. Nonlinear Random Forest modeling identified five MRI variables as stable predictors of poor outcomes: presence of herniation, DAI in the parietal lobe, DAI in the subcortical white matter, DAI in the posterior corpus callosum, and cerebral contusion in the anterior temporal lobe. Clinical MRI has prognostic value to identify children with TBI at risk of long-term unfavorable outcomes.
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http://dx.doi.org/10.1089/neu.2020.7514DOI Listing
May 2021

Magnetic Resonance Imaging Findings Are Associated with Long-Term Global Neurological Function or Death after Traumatic Brain Injury in Critically Ill Children.

J Neurotrauma 2021 May 13. Epub 2021 May 13.

Neuroscience and Mental Health Research Program, Hospital for Sick Children, Toronto, Ontario, Canada.

The identification of children with traumatic brain injury (TBI) who are at risk of death or poor global neurological functional outcome remains a challenge. Magnetic resonance imaging (MRI) can detect several brain pathologies that are a result of TBI; however, the types and locations of pathology that are the most predictive remain to be determined. Forty-two critically ill children with TBI were recruited prospectively from pediatric intensive care units at five Canadian children's hospitals. Pathologies detected on subacute phase MRIs included cerebral hematoma, herniation, cerebral laceration, cerebral edema, midline shift, and the presence and location of cerebral contusion or diffuse axonal injury (DAI) in 28 regions of interest were assessed. Global functional outcome or death more than 12 months post-injury was assessed using the Pediatric Cerebral Performance Category score. Linear modeling was employed to evaluate the utility of an MRI composite score for predicting long-term global neurological function or death after injury, and nonlinear Random Forest modeling was used to identify which MRI features have the most predictive utility. A linear predictive model of favorable versus unfavorable long-term outcomes was significantly improved when an MRI composite score was added to clinical variables. Nonlinear Random Forest modeling identified five MRI variables as stable predictors of poor outcomes: presence of herniation, DAI in the parietal lobe, DAI in the subcortical white matter, DAI in the posterior corpus callosum, and cerebral contusion in the anterior temporal lobe. Clinical MRI has prognostic value to identify children with TBI at risk of long-term unfavorable outcomes.
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http://dx.doi.org/10.1089/neu.2020.7514DOI Listing
May 2021

Mostly worse, occasionally better: impact of COVID-19 pandemic on the mental health of Canadian children and adolescents.

Eur Child Adolesc Psychiatry 2021 Feb 26. Epub 2021 Feb 26.

Department of Psychiatry, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, 686 Bay Street, 6th Floor, Toronto, On, M5G 0A4, Canada.

This large cross-sectional study examined the impact of COVID-19 emergency measures on child/adolescent mental health for children/adolescents with and without pre-existing psychiatric diagnoses. Using adapted measures from the CRISIS questionnaire, parents of children aged 6-18 (N = 1013; 56% male; 62% pre-existing psychiatric diagnosis) and self-reporting children/adolescents aged 10-18 (N = 385) indicated changes in mental health across six domains: depression, anxiety, irritability, attention, hyperactivity, and obsessions/compulsions. Changes in anxiety, irritability, and hyperactivity were calculated for children aged 2-5 years using the Strengths and Difficulties Questionnaire. COVID-19 exposure, compliance with emergency measures, COVID-19 economic concerns, and stress from social isolation were measured with the CRISIS questionnaire. Prevalence of change in mental health status was estimated for each domain; multinomial logistic regression was used to determine variables associated with mental health status change in each domain. Depending on the age group, 67-70% of children/adolescents experienced deterioration in at least one mental health domain; however, 19-31% of children/adolescents experienced improvement in at least one domain. Children/adolescents without and with psychiatric diagnoses tended to experience deterioration during the first wave of COVID-19. Rates of deterioration were higher in those with a pre-exiting diagnosis. The rate of deterioration was variable across different age groups and pre-existing psychiatric diagnostic groups: depression 37-56%, anxiety 31-50%, irritability 40-66%, attention 40-56%, hyperactivity 23-56%, obsessions/compulsions 13-30%. Greater stress from social isolation was associated with deterioration in all mental health domains (all ORs 11.12-55.24). The impact of pre-existing psychiatric diagnosis was heterogenous, associated with deterioration in depression, irritability, hyperactivity, obsession/compulsions for some children (ORs 1.96-2.23) but also with improvement in depression, anxiety, and irritability for other children (ORs 2.13-3.12). Economic concerns were associated with improvement in anxiety, attention, and obsessions/compulsions (ORs 3.97-5.57). Children/adolescents with and without pre-existing psychiatric diagnoses reported deterioration. Deterioration was associated with increased stress from social isolation. Enhancing social interactions for children/adolescents will be an important mitigation strategy for current and future COVID-19 waves.
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http://dx.doi.org/10.1007/s00787-021-01744-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909377PMC
February 2021

ADHD severity as a predictor of cognitive task performance in children with Autism Spectrum Disorder (ASD).

Res Dev Disabil 2021 Apr 3;111:103882. Epub 2021 Feb 3.

McGovern Medical School, University of Texas Health Science Center at Houston, United States. Electronic address:

Background: In recent years, a number of studies have begun to explore the nature of Attention-Deficit/Hyperactivity Disorder (ADHD) in children with Autism Spectrum Disorder (ASD). In this study, we examined the relationship between both symptoms of ADHD and symptoms of ASD on cognitive task performance in a sample of higher-functioning children and adolescents with ASD. Participants completed cognitive tasks tapping aspects of attention, impulsivity/inhibition, and immediate memory.

Aims: We hypothesized that children with ASD who had higher levels of ADHD symptom severity would be at higher risk for poorer sustained attention and selective attention, greater impulsivity/disinhibition, and weaker memory.

Methods And Procedures: The sample included 92 children (73 males) diagnosed with ASD (Mean Age = 9.41 years; Mean Full Scale IQ = 84.2).

Outcomes And Results: Using regression analyses, more severe ADHD symptomatology was found to be significantly related to weaker performance on tasks measuring attention, immediate memory, and response inhibition. In contrast, increasing severity of ASD symptomatology was not associated with higher risk of poorer performance on any of the cognitive tasks assessed.

Conclusions And Implications: These results suggest that children with ASD who have more severe ADHD symptoms are at higher risk for impairments in tasks assessing attention, immediate memory, and response inhibition-similar to ADHD-related impairments seen in the general pediatric population. As such, clinicians should assess various aspects of cognition in pediatric patients with ASD in order to facilitate optimal interventional and educational planning.
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http://dx.doi.org/10.1016/j.ridd.2021.103882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987770PMC
April 2021

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder.

Transl Psychiatry 2021 02 2;11(1):91. Epub 2021 Feb 2.

Genetics and Genome Biology Hospital for Sick Children, Toronto, Canada.

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). 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 = 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.
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http://dx.doi.org/10.1038/s41398-020-01121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870035PMC
February 2021

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

Psychol Med 2021 Feb 3:1-9. Epub 2021 Feb 3.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).

Methods: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.

Results: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).

Conclusions: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.
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http://dx.doi.org/10.1017/S0033291720005218DOI Listing
February 2021

Exploring the Neural Structures Underlying the Procedural Memory Network as Predictors of Language Ability in Children and Adolescents With Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Front Hum Neurosci 2020 10;14:587019. Epub 2020 Dec 10.

Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada.

: There is significant overlap in the type of structural language impairments exhibited by children with autism spectrum disorder (ASD) and children with attention deficit hyperactivity disorder (ADHD). This similarity suggests that the cognitive impairment(s) contributing to the structural language deficits in ASD and ADHD may be shared. Previous studies have speculated that procedural memory deficits may be the shared cognitive impairment. The procedural deficit hypothesis (PDH) argues that language deficits can be explained by differences in the neural structures underlying the procedural memory network. This hypothesis is based on the premise that the neural structures comprising the procedural network support language learning. In this study, we aimed to test the PDH in children with ASD, ADHD, and typical development (TD). : One hundred and sixty-three participants (ages 10-21): 91 with ASD, 26 with ADHD, and 46 with TD, completed standardized measures of cognitive and language ability as well as structural magnetic resonance imaging. We compared the structural language abilities, the neural structures underlying the procedural memory network, and the relationship between structural language and neural structure across diagnostic groups. : Our analyses revealed that while the structural language abilities differed across ASD, ADHD, and TD groups, the thickness, area, and volume of the structures supporting the procedural memory network were not significantly different between diagnostic groups. Also, several neural structures were associated with structural language abilities across diagnostic groups. Only two of these structures, the inferior frontal gyrus, and the left superior parietal gyrus, are known to be linked to the procedural memory network. : The inferior frontal gyrus and the left superior parietal gyrus, have well-established roles in language learning independent of their role as part of the procedural memory system. Other structures such as the caudate and cerebellum, with critical roles in the procedural memory network, were not associated with structural language abilities across diagnostic groups. It is unclear whether the procedural memory network plays a fundamental role in language learning in ASD, ADHD, and TD.
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http://dx.doi.org/10.3389/fnhum.2020.587019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759764PMC
December 2020

Tracking Inhibitory Control in Youth With ADHD: A Multi-Modal Neuroimaging Approach.

Front Psychiatry 2020 19;11:00831. Epub 2020 Nov 19.

Department of Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.3389/fpsyt.2020.00831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710692PMC
November 2020

Factor Structure of Repetitive Behaviors Across Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

J Autism Dev Disord 2020 Nov 24. Epub 2020 Nov 24.

Department of Psychology, Western University, London, ON, Canada.

Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in attention-deficit/hyperactivity disorder (ADHD). Little is known about how RRBs manifest in ADHD. We quantified and compared factor structures of RRBs in children with ASD (n = 634) or ADHD (n = 448), and related factors to sex and IQ. A four-factor solution emerged, including Stereotypy, Self-Injury, Compulsions, and Ritualistic/Sameness. Factor structures were equivalent across diagnoses, though symptoms were more severe in ASD. IQ negatively correlated with Stereotypy, Self-Injury, and Compulsions in ASD, and negatively correlated with Compulsions and Ritualistic/Sameness behaviors in ADHD. In ASD only, females exhibited higher Self-Injury. Thus, patterns of RRBs are preserved across ASD and ADHD, but severity and relationship with IQ differed.
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http://dx.doi.org/10.1007/s10803-020-04800-0DOI Listing
November 2020

Cognitive and behavioral risk factors for low quality of life in survivors of childhood acute lymphoblastic leukemia.

Pediatr Res 2020 Nov 17. Epub 2020 Nov 17.

Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada.

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). 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.
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http://dx.doi.org/10.1038/s41390-020-01230-7DOI Listing
November 2020

Beyond diagnosis: Cross-diagnostic features in canonical resting-state networks in children with neurodevelopmental disorders.

Neuroimage Clin 2020 27;28:102476. Epub 2020 Oct 27.

Autism Research Centre, Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1016/j.nicl.2020.102476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649647PMC
June 2021

Integration of brain and behavior measures for identification of data-driven groups cutting across children with ASD, ADHD, or OCD.

Neuropsychopharmacology 2021 02 9;46(3):643-653. Epub 2020 Nov 9.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network was used including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Future work is needed to build on this early attempt through replication of the current findings in independent samples and testing longitudinally for prognostic value.
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http://dx.doi.org/10.1038/s41386-020-00902-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027842PMC
February 2021

Emotional face processing across neurodevelopmental disorders: a dynamic faces study in children with autism spectrum disorder, attention deficit hyperactivity disorder and obsessive-compulsive disorder.

Transl Psychiatry 2020 11 2;10(1):375. Epub 2020 Nov 2.

Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Canada.

Autism spectrum disorder (ASD) is classically associated with poor face processing skills, yet evidence suggests that those with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) also have difficulties understanding emotions. We determined the neural underpinnings of dynamic emotional face processing across these three clinical paediatric groups, including developmental trajectories, compared with typically developing (TD) controls. We studied 279 children, 5-19 years of age but 57 were excluded due to excessive motion in fMRI, leaving 222: 87 ASD, 44 ADHD, 42 OCD and 49 TD. Groups were sex- and age-matched. Dynamic faces (happy, angry) and dynamic flowers were presented in 18 pseudo-randomized blocks while fMRI data were collected with a 3T MRI. Group-by-age interactions and group difference contrasts were analysed for the faces vs. flowers and between happy and angry faces. TD children demonstrated different activity patterns across the four contrasts; these patterns were more limited and distinct for the NDDs. Processing happy and angry faces compared to flowers yielded similar activation in occipital regions in the NDDs compared to TDs. Processing happy compared to angry faces showed an age by group interaction in the superior frontal gyrus, increasing with age for ASD and OCD, decreasing for TDs. Children with ASD, ADHD and OCD differentiated less between dynamic faces and dynamic flowers, with most of the effects seen in the occipital and temporal regions, suggesting that emotional difficulties shared in NDDs may be partly attributed to shared atypical visual information processing.
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http://dx.doi.org/10.1038/s41398-020-01063-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608673PMC
November 2020

Quantitative MRI outcomes in child and adolescent leukemia survivors: Evidence for global alterations in gray and white matter.

Neuroimage Clin 2020 15;28:102428. Epub 2020 Sep 15.

Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address:

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), 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.
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http://dx.doi.org/10.1016/j.nicl.2020.102428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522853PMC
June 2021

A Time Series-Based Point Estimation of Stop Signal Reaction Times: More Evidence on the Role of Reactive Inhibition-Proactive Inhibition Interplay on the SSRT Estimations.

Brain Sci 2020 Aug 29;10(9). Epub 2020 Aug 29.

Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, 620, 155 College Street, Toronto, ON M5T 3M7, Canada.

The Stop Signal Reaction Time (SSRT) is a latency measurement for the unobservable human brain stopping process, and was formulated by Logan (1994) without consideration of the nature (go/stop) of trials that precede the stop trials. Two asymptotically equivalent and larger indices of mixture SSRT and weighted SSRT were proposed in 2017 to address this issue from time in task longitudinal perspective, but estimation based on the time series perspective has still been missing in the literature. A time series-based state space estimation of SSRT was presented and it was compared with Logan 1994 SSRT over two samples of real Stop Signal Task (SST) data and the simulated SST data. The results showed that time series-based SSRT is significantly larger than Logan's 1994 SSRT consistent with former Longitudinal-based findings. As a conclusion, SSRT indices considering the after effects of inhibition in their estimation process are larger yielding to hypothesize a larger estimates of SSRT using information on the reactive inhibition, proactive inhibition and their interplay in the SST data.
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http://dx.doi.org/10.3390/brainsci10090598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563621PMC
August 2020

Obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: distinct associations with DNA methylation and genetic variation.

J Neurodev Disord 2020 08 16;12(1):23. Epub 2020 Aug 16.

Genetics and Genome Biology, SickKids Hospital, Toronto, ON, Canada.

Background: A growing body of research has demonstrated associations between specific neurodevelopmental disorders and variation in DNA methylation (DNAm), implicating this molecular mark as a possible contributor to the molecular etiology of these disorders and/or as a novel disease biomarker. Furthermore, genetic risk variants of neurodevelopmental disorders have been found to be enriched at loci associated with DNAm patterns, referred to as methylation quantitative trait loci (mQTLs).

Methods: We conducted two epigenome-wide association studies in individuals with attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) (aged 4-18 years) using DNA extracted from saliva. DNAm data generated on the Illumina Human Methylation 450 K array were used to examine the interaction between genetic variation and DNAm patterns associated with these disorders.

Results: Using linear regression followed by principal component analysis, individuals with the most endorsed symptoms of ADHD or OCD were found to have significantly more distinct DNAm patterns from controls, as compared to all cases. This suggested that the phenotypic heterogeneity of these disorders is reflected in altered DNAm at specific sites. Further investigations of the DNAm sites associated with each disorder revealed that despite little overlap of these DNAm sites across the two disorders, both disorders were significantly enriched for mQTLs within our sample.

Conclusions: Our DNAm data provide insights into the regulatory changes associated with genetic variation, highlighting their potential utility both in directing GWAS and in elucidating the pathophysiology of neurodevelopmental disorders.
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http://dx.doi.org/10.1186/s11689-020-09324-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429807PMC
August 2020

Concurrent Validity of the ABAS-II Questionnaire with the Vineland II Interview for Adaptive Behavior in a Pediatric ASD Sample: High Correspondence Despite Systematically Lower Scores.

J Autism Dev Disord 2021 May;51(5):1417-1427

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

We examined the correlation between interviewer-administered Vineland Adaptive Behavior Scale II (VABS-II) and the parent-rated Adaptive Behavior Assessment System II (ABAS-II) questionnaire in 352 participants (ages 1.5-20.8 years) with autism spectrum disorder (ASD) to determine if ABAS could be used as a screen to reduce the number of VABS interviews. Corresponding domain scores between the two measures were highly correlated but scores were significantly lower on the ABAS-II. Screening with ABAS-II significantly reduced the number of VABS-II interviews required with little cost to overall accuracy. The ABAS-II provides a cost- and time-saving alternative to the VABS-II to rule out functional impairment; however, scores are not strictly comparable between the two measures.
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http://dx.doi.org/10.1007/s10803-020-04597-yDOI Listing
May 2021

Effects of Extended-Release Methylphenidate Treatment on Cognitive Task Performance in Children with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

J Child Adolesc Psychopharmacol 2020 09 9;30(7):414-426. Epub 2020 Jul 9.

Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.

To examine the effectiveness of four doses of psychostimulant medication, combining extended-release methylphenidate (ER-MPH) in the morning with immediate-release MPH (IR-MPH) in the afternoon, on cognitive task performance. The sample comprised 24 children (19 boys and 5 girls) who met the (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the and the , and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age = 8.8 years, SD = 1.7; mean intelligence quotient = 85; SD = 16.8). Effects of placebo and three dose levels of ER-MPH (containing 0.21, 0.35, and 0.48 mg/kg equivalent of IR-MPH) on cognitive task performance were compared using a within-subject, crossover, placebo-controlled design. Each of the four MPH dosing regimens (placebo, low-dose MPH, medium-dose MPH, and high-dose MPH) was administered for 1 week; the dosing order was counterbalanced across children. MPH treatment was associated with significant performance gains on cognitive tasks tapping sustained attention, selective attention, and impulsivity/inhibition. Dose/response was generally linear in the dose range studied, with no evidence of deterioration in performance at higher MPH doses in the dose range studied. The results of this study suggest that MPH formulations are associated with significant improvements on cognitive task performance in children with ASD and ADHD.
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http://dx.doi.org/10.1089/cap.2020.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475091PMC
September 2020

Shared genetic etiology between obsessive-compulsive disorder, obsessive-compulsive symptoms in the population, and insulin signaling.

Transl Psychiatry 2020 04 27;10(1):121. Epub 2020 Apr 27.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Obsessive-compulsive symptoms (OCS) in the population have been linked to obsessive-compulsive disorder (OCD) in genetic and epidemiological studies. Insulin signaling has been implicated in OCD. We extend previous work by assessing genetic overlap between OCD, population-based OCS, and central nervous system (CNS) and peripheral insulin signaling. We conducted genome-wide association studies (GWASs) in the population-based Philadelphia Neurodevelopmental Cohort (PNC, 650 children and adolescents) of the total OCS score and six OCS factors from an exploratory factor analysis of 22 questions. Subsequently, we performed polygenic risk score (PRS)-based analysis to assess shared genetic etiologies between clinical OCD (using GWAS data from the Psychiatric Genomics Consortium), the total OCS score and OCS factors. We then performed gene-set analyses with a set of OCD-linked genes centered around CNS insulin-regulated synaptic function and PRS-based analyses for five peripheral insulin signaling-related traits. For validation purposes, we explored data from the independent Spit for Science population cohort (5,047 children and adolescents). In the PNC, we found a significant shared genetic etiology between OCD and 'guilty taboo thoughts'. In the Spit for Science cohort, we additionally observed genetic sharing between 'symmetry/counting/ordering' and 'contamination/cleaning'. The CNS insulin-linked gene-set also associated with 'symmetry/counting/ordering' in the PNC. Further, we identified genetic sharing between peripheral insulin signaling-related traits: type 2 diabetes with 'aggressive taboo thoughts', and levels of fasting insulin and 2 h glucose with OCD. In conclusion, OCD, OCS in the population and insulin-related traits share genetic risk factors, indicating a common etiological mechanism underlying somatic and psychiatric disorders.
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http://dx.doi.org/10.1038/s41398-020-0793-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186226PMC
April 2020

Inattention and hyperactive/impulsive component scores do not differentiate between autism spectrum disorder and attention-deficit/hyperactivity disorder in a clinical sample.

Mol Autism 2020 04 25;11(1):28. Epub 2020 Apr 25.

Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8, Canada.

Background: Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD.

Methods: Participants included children and youth (aged 3-20 years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender.

Results: PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group.

Limitations: We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians.

Conclusions: ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions.
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http://dx.doi.org/10.1186/s13229-020-00338-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183643PMC
April 2020

Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study.

Depress Anxiety 2020 08 24;37(8):760-770. Epub 2020 Feb 24.

Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Hoarding, originally only considered a symptom of obsessive-compulsive disorder (OCD), is now categorized as a separate disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We studied candidate serotonergic genes and the distinctness of hoarding in children and adolescents and hypothesized that unique gene variants would be associated with hoarding alone.

Methods: We examined obsessive-compulsive (OC) traits, including hoarding, in a total of 5,213 pediatric participants in the community. We genotyped candidate serotonin genes (5-HTTLPR polymorphism in SLC6A4 for 2,018 individuals and single nucleotide polymorphisms [SNPs] across genes SLC6A4, HTR2A, and HTR1B for 4,711 individuals). In a previous study conducted by our group in the same sample, we identified a significant association between 5-HTTLPR and hoarding in males. In this study, we examined hoarding more closely by testing the association between serotonin gene variants and hoarding traits with and without other accompanying OC traits.

Results: The [L +S] variant in 5-HTTLPR was significantly associated with hoarding alone in males (p-value of 0.009). There were no significant findings for 5-HTTLPR in females. There were no significant findings after correction for multiple comparisons using SNP array data, but top SNP findings suggested that variation downstream of HTR1B may be implicated in hoarding alone in females.

Conclusions: Our results suggest specific serotonin gene variants are associated with hoarding traits alone, differing between sexes. Top findings are in line with our former study, suggesting that individuals with hoarding alone were driving previous results. Our paper supports hoarding disorder's new designation.
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http://dx.doi.org/10.1002/da.22996DOI Listing
August 2020

Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study.

Depress Anxiety 2020 08 24;37(8):760-770. Epub 2020 Feb 24.

Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Hoarding, originally only considered a symptom of obsessive-compulsive disorder (OCD), is now categorized as a separate disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We studied candidate serotonergic genes and the distinctness of hoarding in children and adolescents and hypothesized that unique gene variants would be associated with hoarding alone.

Methods: We examined obsessive-compulsive (OC) traits, including hoarding, in a total of 5,213 pediatric participants in the community. We genotyped candidate serotonin genes (5-HTTLPR polymorphism in SLC6A4 for 2,018 individuals and single nucleotide polymorphisms [SNPs] across genes SLC6A4, HTR2A, and HTR1B for 4,711 individuals). In a previous study conducted by our group in the same sample, we identified a significant association between 5-HTTLPR and hoarding in males. In this study, we examined hoarding more closely by testing the association between serotonin gene variants and hoarding traits with and without other accompanying OC traits.

Results: The [L +S] variant in 5-HTTLPR was significantly associated with hoarding alone in males (p-value of 0.009). There were no significant findings for 5-HTTLPR in females. There were no significant findings after correction for multiple comparisons using SNP array data, but top SNP findings suggested that variation downstream of HTR1B may be implicated in hoarding alone in females.

Conclusions: Our results suggest specific serotonin gene variants are associated with hoarding traits alone, differing between sexes. Top findings are in line with our former study, suggesting that individuals with hoarding alone were driving previous results. Our paper supports hoarding disorder's new designation.
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http://dx.doi.org/10.1002/da.22996DOI Listing
August 2020

BOLD differences normally attributed to inhibitory control predict symptoms, not task-directed inhibitory control in ADHD.

J Neurodev Disord 2020 02 21;12(1). Epub 2020 Feb 21.

Department of Psychiatry, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

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.
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http://dx.doi.org/10.1186/s11689-020-09311-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035717PMC
February 2020

Opposing effects of cortisol on learning and memory in children using spatial versus response-dependent navigation strategies.

Neurobiol Learn Mem 2020 03 21;169:107172. Epub 2020 Jan 21.

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Verdun, QC, Canada. Electronic address:

Previous studies showed that healthy young adults who spontaneously use caudate nucleus-dependent strategies on a virtual navigation task, have significantly lower basal levels of cortisol compared with adults who use hippocampus-dependent spatial navigation strategies. In the current paper, we assessed the relation between basal cortisol levels and learning using a virtual navigation task in children. We show that basal cortisol level has a differential effect on learning and memory between children using spatial and response navigation strategies. Specifically, cortisol was found to be beneficial for learning performance in children using spatial strategies, such that higher levels of cortisol were associated with more efficient learning in a virtual maze. In contrast, cortisol had a deleterious effect on learning the virtual maze in children using response strategies, such that higher cortisol levels were associated with increased spatial working memory errors. Based on these results, individual differences in navigation strategy could help explain contradictory results in the literature showing that cortisol can have either a positive or negative association with learning and memory performance.
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http://dx.doi.org/10.1016/j.nlm.2020.107172DOI Listing
March 2020

Examining overlap and homogeneity in ASD, ADHD, and OCD: a data-driven, diagnosis-agnostic approach.

Transl Psychiatry 2019 11 26;9(1):318. Epub 2019 Nov 26.

Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada.

The validity of diagnostic labels of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) is an open question given the mounting evidence that these categories may not correspond to conditions with distinct etiologies, biologies, or phenotypes. The objective of this study was to determine the agreement between existing diagnostic labels and groups discovered based on a data-driven, diagnosis-agnostic approach integrating cortical neuroanatomy and core-domain phenotype features. A machine learning pipeline, called bagged-multiview clustering, was designed to discover homogeneous subgroups by integrating cortical thickness data and measures of core-domain phenotypic features of ASD, ADHD, and OCD. This study was conducted using data from the Province of Ontario Neurodevelopmental Disorders (POND) Network, a multi-center study in Ontario, Canada. Participants (n = 226) included children between the ages of 6 and 18 with a diagnosis of ASD (n = 112, median [IQR] age = 11.7[4.8], 21% female), ADHD (n = 58, median [IQR] age = 10.2[3.3], 14% female), or OCD (n = 34, median [IQR] age = 12.1[4.2], 38% female), as well as typically developing controls (n = 22, median [IQR] age = 11.0[3.8], 55% female). The diagnosis-agnostic groups were significantly different than each other in phenotypic characteristics (SCQ: χ(9) = 111.21, p < 0.0001; SWAN: χ(9) = 142.44, p < 0.0001) as well as cortical thickness in 75 regions of the brain. The analyses revealed disagreement between existing diagnostic labels and the diagnosis-agnostic homogeneous groups (normalized mutual information < 0.20). Our results did not support the validity of existing diagnostic labels of ASD, ADHD, and OCD as distinct entities with respect to phenotype and cortical morphology.
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http://dx.doi.org/10.1038/s41398-019-0631-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880188PMC
November 2019

A large data resource of genomic copy number variation across neurodevelopmental disorders.

NPJ Genom Med 2019 7;4:26. Epub 2019 Oct 7.

Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are , , , , , , , , , , and long non-coding RNAs: and . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
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http://dx.doi.org/10.1038/s41525-019-0098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779875PMC
October 2019

Sex Differences in Social Adaptive Function in Autism Spectrum Disorder and Attention-Deficit Hyperactivity Disorder.

Front Psychiatry 2019 12;10:607. Epub 2019 Sep 12.

Autism Research Centre, Bloorview Research Institute, Toronto, ON, Canada.

Social-communication difficulties, a hallmark of ASD, autism spectrum disorder (ASD) are often observed in attention - deficit/ hyperactivity disorder (ADHD), although are not part of its diagnostic criteria. Despite sex differences in the prevalence of ASD and ADHD, research examining how sex differences manifest in social and communication functions in these disorders remains limited, and findings are mixed. This study investigated potential sex differences with age in social adaptive function across these disorders, relative to controls. One hundred fifteen youth with ASD, 172 youth with ADHD, and 63 typically developing controls (age range 7-13 years, 75% males) were recruited from the Province of Ontario Neurodevelopmental Disorder (POND) Network. Social adaptive function was assessed using the Adaptive Behavior Assessment System-Second Edition (ABAS-II). The proportions of adaptive behaviors present in each skill area were analyzed as a binomial outcome using logistic regression, controlling for age, and testing for an age-by-sex interaction. In an exploratory analysis, we examined the impact of controlling for core symptom severity on the sex effect. Significant sex-by-age interactions were seen within ASD in the communication (p = 0.005), leisure (p = 0.003), and social skill areas (p < 0.0001). In all three areas, lower scores (indicating poorer function) were found in females compared to males at older ages despite females performing better at younger ages. There were significant differences in the sex-by-age interactions in the social and leisure domains between those with ASD and typically developing controls, with typically developing females showing better scores at older, compared to younger, ages. There were also significant differences in the sex-by-age interactions between ASD and ADHD on the social and leisure domains, as females with ADHD consistently scored higher on social skills than males across all ages, unlike those with ASD. Sex differences across age in the social domains for ADHD were similar to those in the typically developing group. Sex differences in social and communication skill areas were observed between ASD and ADHD, and typically developing controls, with females with ASD performing worse than males at older ages, despite an earlier advantage. These findings reinforce the need to take a developmental approach to understanding sex differences which may have diagnostic, prognostic, and treatment implications.
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http://dx.doi.org/10.3389/fpsyt.2019.00607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751776PMC
September 2019

Magnetoencephalographic (MEG) brain activity during a mental flexibility task suggests some shared neurobiology in children with neurodevelopmental disorders.

J Neurodev Disord 2019 08 19;11(1):19. Epub 2019 Aug 19.

Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.

Background: Children with neurodevelopmental disorders (NDDs) exhibit a shared phenotype that involves executive dysfunctions including impairments in mental flexibility (MF). It is of interest to understand if this phenotype stems from some shared neurobiology.

Methods: To investigate this possibility, we used magnetoencephalography (MEG) neuroimaging to compare brain activity in children (n = 88; 8-15 years) with autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), as they completed a set-shifting/mental flexibility task.

Results: Neuroimaging results revealed a similar parietal activation profile across the NDD, groups suggesting a link to their shared phenotype. Differences in frontal activity differentiated the three clinical groups. Brain-behaviour analyses showed a link with repetitive behaviours suggesting shared dysfunction in the associative loop of the corticostriatal system.

Conclusion: Our study supports the notion that NDDs may exist along a complex phenotypic/biological continuum. All NDD groups showed a sustained parietal activity profile suggesting that they share a strong reliance on the posterior parietal cortices to complete the mental flexibility task; future studies could elucidate whether this is due to delayed brain development or compensatory functioning. The differences in frontal activity may play a role in differentiating the NDDs. The OCD group showed sustained prefrontal activity that may be reflective of hyperfrontality. The ASD group showed reduced frontal activation suggestive of frontal dysfunction and the ADHD group showed an extensive hypoactivity that included frontal and parietal regions. Brain-behaviour analyses showed a significant correlation with repetitive behaviours which may reflect dysfunction in the associative loop of the corticostriatal system, linked to inflexible behaviours.
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http://dx.doi.org/10.1186/s11689-019-9280-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701152PMC
August 2019
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