Publications by authors named "Evdokia Anagnostou"

159 Publications

Novel treatments for autism spectrum disorder based on genomics and systems biology.

Pharmacol Ther 2021 Jun 24:107939. Epub 2021 Jun 24.

Department of Pediatrics, University of Toronto, Holland Bloorview Kids Rehabilitation Hospital, Toronto, ON, Canada. Electronic address:

Background: Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with a complex underlying genetic architecture. There are currently no known pharmacologic treatments for the core ASD symptoms of social deficits and restricted/ repetitive behavior. However, there are dozens of clinical trials currently underway that are testing the impact of novel and existing agents on core and associated symptoms in ASD.

Methods: We present a narrative synthesis of the historical and contemporary challenges to drug discovery in ASD. We then provide an overview of novel treatments currently under investigation from a genomics and systems biology perspective.

Results: Data driven network and cluster analyses suggest alterations in transcriptional regulation, chromatin remodelling, synaptic transmission, neuropeptide signalling, and/or immunological mechanisms may contribute to or underlie the development of ASD. Agents and upcoming trials targeting each of the above listed systems are reviewed.

Conclusion: Identifying effective pharmacologic treatments for the core and associated symptom domains in ASD will require further collaboration and innovation in the areas of outcome measurement, biomarker research, and genomics, as well as systematic efforts to identify and treat subgroups of individuals with ASD who may be differentially responsive to specific treatments.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107939DOI Listing
June 2021

Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions.

Eur Neuropsychopharmacol 2021 Jul 19;48:3-31. Epub 2021 Jun 19.

Department of Psychiatry, Columbia University, New York, NY, United States.

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research.
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http://dx.doi.org/10.1016/j.euroneuro.2021.05.010DOI Listing
July 2021

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

Intestinal permeability correlates with behavioural severity in very young children with ASD: A preliminary study.

J Neuroimmunol 2021 Aug 12;357:577607. Epub 2021 May 12.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada. Electronic address:

Systemic inflammation is known to alter behaviour, and since it has been reported that individuals with autism spectrum disorder (ASD) have higher levels of circulating cytokines, it has been hypothesized that systemic inflammation may exacerbate behaviours characteristic of ASD. The acute phase proteins α-2-macroglobulin, C-reactive protein, haptoglobin, serum amyloid P, serum amyloid A, ferritin and tissue plasminogen activator, as well as markers of intestinal permeability (intestinal fatty acid binding protein and lipopolysaccharide) were quantitated in the plasma of very young children with ASD. Behaviour severity was measured using the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and the Vineland Adaptive Behaviour Scale (VABS). An increase in circulating I-FABP correlated with more severe deficits in communication, communication + social interaction as well as maladaptive behaviour. The acute phase protein haptoglobin was associated with more severe social interaction and communication + social interaction. In summary, I-FABP, a marker of intestinal epithelial damage, was associated with more severe behavioural phenotypes in very young children with ASD. In addition, the acute phase protein, haptoglobin, was associated with behaviour.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577607DOI Listing
August 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

Brain and Language Associations in Autism Spectrum Disorder: A Scoping Review.

J Autism Dev Disord 2021 Mar 25. Epub 2021 Mar 25.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, ON, M4G 1R8, Canada.

Examining brain and behaviour associations for language in autism spectrum disorder (ASD) may bring us closer to identifying neural profiles that are unique to a subgroup of individuals with ASD identified as language impaired (e.g. ASD LI+). We conducted a scoping review to examine brain regions that are associated with language performance in ASD. Further, we examined methodological differences across studies in how language ability was characterized and what neuroimaging methods were used to explore brain regions. Seventeen studies met inclusion criteria. Brain regions specific to ASD LI+ groups were found, however inconsistencies in brain and language associations were evident across study findings. Participant age, age-appropriate language scores, and neuroimaging methods likely contributed to differences in associations found.
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http://dx.doi.org/10.1007/s10803-021-04975-0DOI Listing
March 2021

Multisite Comparison of MRI Defacing Software Across Multiple Cohorts.

Front Psychiatry 2021 24;12:617997. Epub 2021 Feb 24.

Rotman Research Institute, Baycrest Health Sciences Centre, Toronto, ON, Canada.

With improvements to both scan quality and facial recognition software, there is an increased risk of participants being identified by a 3D render of their structural neuroimaging scans, even when all other personal information has been removed. To prevent this, facial features should be removed before data are shared or openly released, but while there are several publicly available software algorithms to do this, there has been no comprehensive review of their accuracy within the general population. To address this, we tested multiple algorithms on 300 scans from three neuroscience research projects, funded in part by the Ontario Brain Institute, to cover a wide range of ages (3-85 years) and multiple patient cohorts. While skull stripping is more thorough at removing identifiable features, we focused mainly on defacing software, as skull stripping also removes potentially useful information, which may be required for future analyses. We tested six publicly available algorithms (afni_refacer, deepdefacer, mri_deface, mridefacer, pydeface, quickshear), with one skull stripper (FreeSurfer) included for comparison. Accuracy was measured through a pass/fail system with two criteria; one, that all facial features had been removed and two, that no brain tissue was removed in the process. A subset of defaced scans were also run through several preprocessing pipelines to ensure that none of the algorithms would alter the resulting outputs. We found that the success rates varied strongly between defacers, with afni_refacer (89%) and pydeface (83%) having the highest rates, overall. In both cases, the primary source of failure came from a single dataset that the defacer appeared to struggle with - the youngest cohort (3-20 years) for afni_refacer and the oldest (44-85 years) for pydeface, demonstrating that defacer performance not only depends on the data provided, but that this effect varies between algorithms. While there were some very minor differences between the preprocessing results for defaced and original scans, none of these were significant and were within the range of variation between using different NIfTI converters, or using raw DICOM files.
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http://dx.doi.org/10.3389/fpsyt.2021.617997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943842PMC
February 2021

Quantitative and Qualitative Sex Modulations in the Brain Anatomy of Autism.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Mar 10. Epub 2021 Mar 10.

Department of Psychiatry, Hospital for Sick Children, Toronto, Ontario, Canada; Neurosciences and Mental Health Program, SickKids Research Institute, Toronto, Ontario, Canada; Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health and Azrieli Adult Neurodevelopmental Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. Electronic address:

Background: Sex-based neurobiological heterogeneity in autism is poorly understood. Research is disproportionately biased to males, leading to an unwarranted presumption that autism neurobiology is the same across sexes. Previous neuroimaging studies using amalgamated multicenter datasets to increase autistic female samples are characterized by large statistical noise.

Methods: We used a better-powered dataset of 1183 scans of 839 individuals-299 (467 scans) autistic males, 74 (102 scans) autistic females, 240 (334 scans) control males, and 226 (280 scans) control females-to test two whole-brain models of overall/global sex modulations on autism neuroanatomy, by summary measures computed across the brain: the local magnitude model, in which the same brain regions/circuitries are involved across sexes but effect sizes are larger in females, indicating quantitative sex modulation; and spatial dissimilarity model, in which the neuroanatomy differs spatially between sexes, indicating qualitative sex modulation. The male and female autism groups were matched on age, IQ, and autism symptoms. Autism brain features were defined by comparisons with same-sex control individuals.

Results: Across five metrics (cortical thickness, surface area, volume, mean absolute curvature, and subcortical volume), we found no evidence supporting the local magnitude model. We found indicators supporting the spatial dissimilarity model on cortical mean absolute curvature and subcortical volume, but not on other metrics.

Conclusions: The overall/global autism neuroanatomy in females and males does not simply differ quantitatively in the same brain regions/circuitries. They may differ qualitatively in spatial involvement in cortical curvature and subcortical volume. The neuroanatomy of autism may be partly sex specific. Sex stratification to inform autism preclinical/clinical research is needed to identify sex-informed neurodevelopmental targets.
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http://dx.doi.org/10.1016/j.bpsc.2021.03.001DOI Listing
March 2021

Assessing the validity of administrative health data for the identification of children and youth with autism spectrum disorder in Ontario.

Autism Res 2021 05 10;14(5):1037-1045. Epub 2021 Mar 10.

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Population-level identification of children and youth with ASD is essential for surveillance and planning for required services. The objective of this study was to develop and validate an algorithm for the identification of children and youth with ASD using administrative health data. In this retrospective validation study, we linked an electronic medical record (EMR)-based reference standard, consisting 10,000 individuals aged 1-24 years, including 112 confirmed ASD cases to Ontario administrative health data, for the testing of multiple case-finding algorithms. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and corresponding 95% confidence intervals (CI) were calculated for each algorithm. The optimal algorithm was validated in three external cohorts representing family practice, education, and specialized clinical settings. The optimal algorithm included an ASD diagnostic code for a single hospital discharge or emergency department visit or outpatient surgery, or three ASD physician billing codes in 3 years. This algorithm's sensitivity was 50.0% (95%CI 40.7-88.7%), specificity 99.6% (99.4-99.7), PPV 56.6% (46.8-66.3), and NPV 99.4% (99.3-99.6). The results of this study illustrate limitations and need for cautious interpretation when using administrative health data alone for the identification of children and youth with ASD. LAY SUMMARY: We tested algorithms (set of rules) to identify young people with ASD using routinely collected administrative health data. Even the best algorithm misses more than half of those in Ontario with ASD. To understand this better, we tested how well the algorithm worked in different settings (family practice, education, and specialized clinics). The identification of individuals with ASD at a population level is essential for planning for support services and the allocation of resources. Autism Res 2021, 14: 1037-1045. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/aur.2491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252648PMC
May 2021

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Cereb Cortex 2021 Jun;31(7):3338-3352

Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal H4H 1R3, Canada.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.
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http://dx.doi.org/10.1093/cercor/bhab015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196259PMC
June 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

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

Am J Med Genet A 2021 04 20;185(4):1120-1130. Epub 2021 Jan 20.

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

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.
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http://dx.doi.org/10.1002/ajmg.a.62086DOI Listing
April 2021

DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders.

J Autism Dev Disord 2021 Jan 4. Epub 2021 Jan 4.

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

Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.
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http://dx.doi.org/10.1007/s10803-020-04792-xDOI Listing
January 2021

Cortical Gyrification Morphology in Individuals with ASD and ADHD across the Lifespan: A Systematic Review and Meta-Analysis.

Cereb Cortex 2021 Mar;31(5):2653-2669

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

Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are common neurodevelopmental disorders (NDDs) that may impact brain maturation. A number of studies have examined cortical gyrification morphology in both NDDs. Here we review and when possible pool their results to better understand the shared and potentially disorder-specific gyrification features. We searched MEDLINE, PsycINFO, and EMBASE databases, and 24 and 10 studies met the criteria to be included in the systematic review and meta-analysis portions, respectively. Meta-analysis of local Gyrification Index (lGI) findings across ASD studies was conducted with SDM software adapted for surface-based morphometry studies. Meta-regressions were used to explore effects of age, sex, and sample size on gyrification differences. There were no significant differences in gyrification across groups. Qualitative synthesis of remaining ASD studies highlighted heterogeneity in findings. Large-scale ADHD studies reported no differences in gyrification between cases and controls suggesting that, similar to ASD, there is currently no evidence of differences in gyrification morphology compared with controls. Larger, longitudinal studies are needed to further clarify the effects of age, sex, and IQ on cortical gyrification in these NDDs.
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http://dx.doi.org/10.1093/cercor/bhaa381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023842PMC
March 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

Alpha connectivity and inhibitory control in adults with autism spectrum disorder.

Mol Autism 2020 12 7;11(1):95. Epub 2020 Dec 7.

Department of Diagnostic Imaging, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.

Background: Individuals with autism spectrum disorder (ASD) often report difficulties with inhibition in everyday life. During inhibition tasks, adults with ASD show reduced activation of and connectivity between brain areas implicated in inhibition, suggesting impairments in inhibitory control at the neural level. Our study further investigated these differences by using magnetoencephalography (MEG) to examine the frequency band(s) in which functional connectivity underlying response inhibition occurs, as brain functions are frequency specific, and whether connectivity in certain frequency bands differs between adults with and without ASD.

Methods: We analysed MEG data from 40 adults with ASD (27 males; 26.94 ± 6.08 years old) and 39 control adults (27 males; 27.29 ± 5.94 years old) who performed a Go/No-go task. The task involved two blocks with different proportions of No-go trials: Inhibition (25% No-go) and Vigilance (75% No-go). We compared whole-brain connectivity in the two groups during correct No-go trials in the Inhibition vs. Vigilance blocks between 0 and 400 ms.

Results: Despite comparable performance on the Go/No-go task, adults with ASD showed reduced connectivity compared to controls in the alpha band (8-14 Hz) in a network with a main hub in the right inferior frontal gyrus. Decreased connectivity in this network predicted more self-reported difficulties on a measure of inhibition in everyday life.

Limitations: Measures of everyday inhibitory control were not available for all participants, so this relationship between reduced network connectivity and inhibitory control abilities may not be necessarily representative of all adults with ASD or the larger ASD population. Further research with independent samples of adults with ASD, including those with a wider range of cognitive abilities, would be valuable.

Conclusions: Our findings demonstrate reduced functional brain connectivity during response inhibition in adults with ASD. As alpha-band synchrony has been linked to top-down control mechanisms, we propose that the lack of alpha synchrony observed in our ASD group may reflect difficulties in suppressing task-irrelevant information, interfering with inhibition in real-life situations.
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http://dx.doi.org/10.1186/s13229-020-00400-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722440PMC
December 2020

Changing Faces: Dynamic Emotional Face Processing in Autism Spectrum Disorder Across Childhood and Adulthood.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Sep 12. Epub 2020 Sep 12.

Department of Diagnostic Imaging, Hospital for Sick Children, Toronto, Ontario, Canada; Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada; Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.

Background: Autism spectrum disorder (ASD) is classically associated with poor emotional face processing. Few studies, however, have used more ecological dynamic stimuli. We contrasted functional magnetic resonance imaging measures of dynamic emotional face processing in ASD and typically developing (TD) cohorts across a wide age range to determine if the processing and age-related trajectories differed between participants with and without ASD.

Methods: Functional magnetic resonance imaging data collected from 200 participants (5-42 years old; 107 in ASD cohort, 93 in TD cohort) during the presentation of dynamic emotional faces (neutral-to-happy, neutral-to-angry) and dynamic flowers (closed-to-open) were analyzed. Group differences and group-by-age interactions in the faces versus flowers and between emotion contrasts were investigated.

Results: Differences in activation between dynamic faces and flowers in occipital regions, including the fusiform gyri, were reduced in the ASD group. Contrasting the two emotions, ASD compared with TD participants showed increased engagement of the precentral, postcentral, and superior temporal gyri to happy faces and increased activation to angry faces occipitally. Emotion processing regions, such as insula, temporal pole, and frontal regions, showed increased recruitment with age to happy faces compared with both angry faces and flowers in the TD group, but decreased recruitment with age in the ASD group.

Conclusions: Using dynamic stimuli, we demonstrated that participants with ASD processed faces similarly to nonface stimuli, and age-related atypicalities were more pronounced to happy faces in participants with ASD. We demonstrated emotion-specific atypicalities in a large group of participants with ASD that underscore persistent difficulties from childhood into mid-adulthood.
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http://dx.doi.org/10.1016/j.bpsc.2020.09.006DOI Listing
September 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

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

Procedural Sequence Learning in Attention Deficit Hyperactivity Disorder: A Meta-Analysis.

Front Psychol 2020 28;11:560064. Epub 2020 Oct 28.

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

Previous literature proposes that the motor deficits in Attention Deficit Hyperactivity Disorder (ADHD) may be attributed to impairments of the procedural memory network, a long-term memory system involved in sensorimotor and cognitive skill development. A handful of studies have explored procedural sequence learning in ADHD, but findings have been inconsistent. A meta-analysis was conducted to begin to establish whether procedural sequence learning deficits exist in ADHD. The results of seven studies comprising 213 participants with ADHD and 257 participants with typical development (TD) generated an average standardized mean difference of 0.02 (CI -0.35, 0.39) that was not significant. Heterogeneity was significant across studies and could be partially attributed to the age of participants. We argue that procedural sequence learning appears to be preserved in ADHD and discuss potential explanations for and against this finding.
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http://dx.doi.org/10.3389/fpsyg.2020.560064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655644PMC
October 2020

Characterizing Inscapes and resting-state in MEG: Effects in typical and atypical development.

Neuroimage 2021 01 2;225:117524. Epub 2020 Nov 2.

Department of Diagnostic Imaging, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada; Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada; Department of Medical Imaging, University of Toronto, Toronto, Canada; Department of Psychology, University of Toronto, Toronto, Canada.

Examining the brain at rest is a powerful approach used to understand the intrinsic properties of typical and disordered human brain function, yet task-free paradigms are associated with greater head motion, particularly in young and/or clinical populations such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Inscapes, a non-social and non-verbal movie paradigm, has been introduced to increase attention, thus mitigating head motion, while reducing the task-induced activations found during typical movie watching. Inscapes has not yet been validated for use in magnetoencephalography (MEG), and it has yet to be shown whether its effects are stable in clinical populations. Across typically developing (N = 32) children and adolescents and those with ASD (N = 46) and ADHD (N = 42), we demonstrate that head motion is reduced during Inscapes. Due to the task state evoked by movie paradigms, we also expectedly observed concomitant modulations in local neural activity (oscillatory power) and functional connectivity (phase and envelope coupling) in intrinsic resting-state networks and across the frequency spectra compared to a fixation cross resting-state. Increases in local activity were accompanied by decreases in low-frequency connectivity within and between resting-state networks, primarily the visual network, suggesting that task-state evoked by Inscapes moderates ongoing and spontaneous cortical inhibition that forms the idling intrinsic networks found during a fixation cross resting-state. Importantly, these effects were similar in ASD and ADHD, making Inscapes a well-suited advancement for investigations of resting brain function in young and clinical populations.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117524DOI Listing
January 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

Sex Differences in Age of Diagnosis and First Concern among Children with Autism Spectrum Disorder.

J Clin Child Adolesc Psychol 2020 Nov 2:1-11. Epub 2020 Nov 2.

Department of Psychiatry, Western University.

Objective: Early identification of autism spectrum disorder (ASD) is an essential healthcare priority. Girls may be at risk for late diagnosis, although research is equivocal regarding how sex and other factors relate to ASD identification. The goals of the current investigation were to (1) identify how child sex, cognitive abilities, and demographic factors relate to age of first concern (AOC) and age of diagnosis (AOD), (2) evaluate trends in AOC/AOD over time, and (3) consider whether main effects of sex on AOC/AOD are moderated by cognitive abilities or time.

Method: Children (N = 365; 20% female; 85.6% identified as White) with ASD participated through the Province of Ontario Neurodevelopmental Disorders (POND) Network. Study records included AOD, date/timing of diagnosis (between 1996 and 2017), age of first parent concern, demographics, and standardized cognitive testing results (24.7% of children had IQ scores below standard scores of 70).

Results: Average AOC occurred before 2 years of age whereas average AOD occurred after 5 years of age. Girls did not differ on AOC but had a later AOD than boys. Higher verbal IQ was associated with later AOD more strongly in girls than boys. Regarding time-related changes, average AOC and AOD increased across the study period, more strongly for girls.

Conclusions: Results support that sex is a key factor underlying delays in ASD identification and highlight the urgent need to improve diagnostic practices among girls. Limitations and implications for improving the diagnostic process are discussed.

ASD=autism spectrum disorder; IQ=intelligence quotient; AOC=parental report of age of first concern; AOD=age of diagnosis.
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http://dx.doi.org/10.1080/15374416.2020.1823850DOI Listing
November 2020

Identifying Children and Youth With Autism Spectrum Disorder in Electronic Medical Records: Examining Health System Utilization and Comorbidities.

Autism Res 2021 02 24;14(2):400-410. Epub 2020 Oct 24.

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder requiring significant health and educational resources for affected individuals. A reference standard for ASD was generated from an existing population-based cohort of 10,000 children and youth aged 1-24 years who were randomly selected for chart abstraction from 29,256 patients from 119 family physicians. We developed and validated an algorithm to identify children and youth with ASD within an electronic medical record system (N = 80,237, aged 1-24 years) in order to examine the prevalence of comorbidities and quantify health system utilization within the cohort. We identified 1,062 children and youth with ASD representing a prevalence of 1.32%. Compared to individuals without ASD, those with ASD had a higher prevalence of asthma, were more likely to visit a specialist, undergo surgery, and be hospitalized for psychiatric reasons. Children and youth with ASD in Ontario have complex health system needs, illustrated through a significant burden of comorbidities and increased health system utilization. LAY SUMMARY: Our paper generates population-based estimates of health system use by children and youth with ASD, who have a higher burden of comorbidities than the general population. We developed a case-finding algorithm and applied it in electronic medical records to create a cohort of children and youth with ASD, thereby generating an important resource to further study the health care needs of individuals with ASD.
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http://dx.doi.org/10.1002/aur.2419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894325PMC
February 2021

Frontoparietal Network Connectivity During an -Back Task in Adults With Autism Spectrum Disorder.

Front Psychiatry 2020 9;11:551808. Epub 2020 Sep 9.

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

Background: Short-term and working memory (STM and WM) deficits have been demonstrated in individuals with autism spectrum disorder (ASD) and may emerge through atypical functional activity and connectivity of the frontoparietal network, which exerts top-down control necessary for successful STM and WM processes. Little is known regarding the spectral properties of the frontoparietal network during STM or WM processes in ASD, although certain neural frequencies have been linked to specific neural mechanisms.

Methods: We analysed magnetoencephalographic data from 39 control adults (26 males; 27.15 ± 5.91 years old) and 40 adults with ASD (26 males; 27.17 ± 6.27 years old) during a 1-back condition (STM) of an -back task, and from a subset of this sample during a 2-back condition (WM). We performed seed-based connectivity analyses using regions of the frontoparietal network. Interregional synchrony in theta, alpha, and beta bands was assessed with the phase difference derivative and compared between groups during periods of maintenance and recognition.

Results: During maintenance of newly presented vs. repeated stimuli, the two groups did not differ significantly in theta, alpha, or beta phase synchrony for either condition. Adults with ASD showed alpha-band synchrony in a network containing the right dorsolateral prefrontal cortex, bilateral inferior parietal lobules (IPL), and precuneus in both 1- and 2-back tasks, whereas controls demonstrated alpha-band synchrony in a sparser set of regions, including the left insula and IPL, in only the 1-back task. During recognition of repeated vs. newly presented stimuli, adults with ASD exhibited decreased theta-band connectivity compared to controls in a network with hubs in the right inferior frontal gyrus and left IPL in the 1-back condition. Whilst there were no group differences in connectivity in the 2-back condition, adults with ASD showed no frontoparietal network recruitment during recognition, whilst controls activated networks in the theta and beta bands.

Conclusions: Our findings suggest that since adults with ASD performed well on the -back task, their appropriate, but effortful recruitment of alpha-band mechanisms in the frontoparietal network to maintain items in STM and WM may compensate for atypical modulation of this network in the theta band to recognise previously presented items in STM.
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http://dx.doi.org/10.3389/fpsyt.2020.551808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509600PMC
September 2020

Physical activity participation among adolescents with autism spectrum disorder.

Autism 2021 04 14;25(3):613-626. Epub 2020 Sep 14.

Rehabilitation Sciences Institute, University of Toronto, Canada.

Lay Abstract: Adolescents with autism spectrum disorder are less likely to be physically active compared to their age-related peers. Despite the lower levels of physical activity observed among adolescents with autism spectrum disorder, it is unknown why they are predominantly inactive. Much of the research so far has focused on understanding how biological aspects influence physical activity participation. But there is little research that has examined how social and cultural components influence their physical activity participation. There is also little research that has sought the perspectives and experiences of adolescents with autism spectrum disorder. In this study, 10 adolescent boys with autism spectrum disorder created a digital story, and also participated in two face-to-face interviews. The purpose of the study was to examine how individual, social, and cultural forces influenced physical activity participation. Analysis of the data highlight that bullying, challenges in community programs, and the prioritization of therapeutic interventions limited participation. On the contrary, participants were more likely to be active when physical activity generated meaning, purpose, a sense of identity, and affective pleasures. The findings add new knowledge suggesting that adolescents with autism spectrum disorder are not simply unmotivated. Rather, physical activity participation was shaped by wider social experiences, norms, values, and practices in which they were immersed. The findings suggest a need for directed efforts to create policies and practices which are individualized and reflective of the needs and abilities of adolescents with autism spectrum disorder to promote physical activity participation and potentially enhance physical health and wellbeing.
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http://dx.doi.org/10.1177/1362361320949344DOI Listing
April 2021

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Brief Report: Parent Perspectives on Sensory-Based Interventions for Children with Autism Spectrum Disorder.

J Autism Dev Disord 2021 Jun;51(6):2109-2114

Holland Bloorview Kids Rehabilitation Hospital, 150 Kilgour Road, Toronto, ON, Canada.

Sensory-Based Interventions (SBIs) are often recommended to enable function/participation in children with ASD. Still, there are limited studies to evaluate their effectiveness. Acceptability studies are an important step towards establishing effective interventions. We examined parents' perceptions of the uptake and acceptability of such interventions. An online survey was sent to 399 families; response rate was 39%. The most frequently therapist-recommended interventions were trampoline (54.6%), massage (47.8%), and oral-motor tools (43.8%). Highest use was reported for massage (96.3%), trampoline (89.2%) and joint compressions and brushing (89.2%). The majority of parents viewed these interventions to be very important /important, (74.8%) but barriers to their use were identified. High acceptability of SBIs was reported by parents of children with ASD.
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http://dx.doi.org/10.1007/s10803-020-04644-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124036PMC
June 2021

Practitioner Review: Pharmacological treatment of attention-deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta-analysis.

J Child Psychol Psychiatry 2021 Jun 26;62(6):680-700. Epub 2020 Aug 26.

The Margaret and Wallace McCain Centre for Child, Youth and Family Mental Health, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Clinically significant attention-deficit/hyperactivity disorder (ADHD) symptoms are common and impairing in children and youth with autism spectrum disorder(ASD). The aim of this systematic review and meta-analysis was to (a) evaluate the efficacy and safety of pharmacotherapy for the treatment of ADHD symptoms in ASD and (b) distil findings for clinical translation.

Methods: We searched electronic databases and clinical trial registries (1992 onwards). We selected randomized controlled trials conducted in participants <25 years of age, diagnosed with ASD that evaluated ADHD outcomes (hyperactivity/impulsivity and inattention) following treatment with stimulants (methylphenidate or amphetamines), atomoxetine, alpha-2 adrenergic receptor agonists, antipsychotics, tricyclic antidepressants, bupropion, modafinil, venlafaxine, or a combination, in comparison with placebo, any of the listed medications, or behavioral therapies. Data were pooled using a random-effects model.

Results: Twenty-five studies (4 methylphenidate, 4 atomoxetine, 1 guanfacine, 14 antipsychotic, 1 venlafaxine, and 1 tianeptine) were included. Methylphenidate reduced hyperactivity (parent-rated: standardized mean difference [SMD] = -.63, 95%CI = -.95,-.30; teacher-rated: SMD = -.81, 95%CI = -1.43,-.19) and inattention (parent-rated: SMD = -.36, 95%CI = -.64,-.07; teacher-rated: SMD = -.30, 95%CI = -.49,-.11). Atomoxetine reduced inattention (parent-rated: SMD = -.54, 95%CI = -.98,-.09; teacher/investigator-rated: SMD = -0.38, 95%CI = -0.75, -0.01) and parent-rated hyperactivity (parent-rated: SMD = -.49, 95%CI = -.76,-.23; teacher-rated: SMD = -.43, 95%CI = -.92, .06). Indirect evidence for significant reductions in hyperactivity with second-generation antipsychotics was also found. Quality of evidence for all interventions was low/very low. Methylphenidate was associated with a nonsignificant elevated risk of dropout due to adverse events.

Conclusions: Direct pooled evidence supports the efficacy and tolerability of methylphenidate or atomoxetine for treatment of ADHD symptoms in children and youth with ASD. The current review highlights the efficacy of standard ADHD pharmacotherapy for treatment of ADHD symptoms in children and youth with ASD. Consideration of the benefits weighed against the limitations of safety/efficacy data and lack of data evaluating long-term continuation is undertaken to help guide clinical decision-making regarding treatment of co-occurring ADHD symptoms in children and youth with ASD.
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http://dx.doi.org/10.1111/jcpp.13305DOI Listing
June 2021
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