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Objectives: Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) - which potentiates brain inhibitory mechanisms - would 'stabilize' hyperplasticity., Methods: Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS., Results: Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults., Conclusions: We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be 'stabilized' using rTMS. Such 'stabilizing' effect of rTMS on LTP was not observed, likely due to small sample size or a more specific 'attenuating' effect of rTMS on LTD, compared to LTP., Significance: These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of 'mechanism-driven' rTMS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Externalizing and internalizing behaviors contribute to clinical impairment in children with neurodevelopmental disorders (NDDs). Although associations between externalizing or internalizing behaviors and cortico-amygdalar connectivity have been found in clinical and non-clinical pediatric samples, no previous study has examined whether similar shared associations are present across children with different NDDs., Methods: Multi-modal neuroimaging and behavioral data from the Province of Ontario Neurodevelopmental Disorders (POND) Network were used. POND participants aged 6-18 years with a primary diagnosis of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD), as well as typically developing children (TDC) with T1-weighted, resting-state fMRI or diffusion weighted imaging (DWI) and parent-report Child Behavioral Checklist (CBCL) data available, were analyzed (total n = 346). Associations between externalizing or internalizing behavior and cortico-amygdalar structural and functional connectivity indices were examined using linear regressions, controlling for age, gender, and image-modality specific covariates. Behavior-by-diagnosis interaction effects were also examined., Results: No significant linear associations (or diagnosis-by-behavior interaction effects) were found between CBCL-measured externalizing or internalizing behaviors and any of the connectivity indices examined. Post-hoc bootstrapping analyses indicated stability and reliability of these null results., Conclusions: The current study provides evidence towards an absence of a shared linear relationship between internalizing or externalizing behaviors and cortico-amygdalar connectivity properties across a transdiagnostic sample of children with different primary NDD diagnoses and TDC. Different methodological approaches, including incorporation of multi-dimensional behavioral data (e.g., task-based fMRI) or clustering approaches may be needed to clarify complex brain-behavior relationships relevant to externalizing/internalizing behaviors in heterogeneous clinical NDD populations., (© 2022. The Author(s).)

Shared etiological pathways are suggested in ASD and ADHD given high rates of comorbidity, phenotypic overlap and shared genetic susceptibility. Given the peak of cortical gyrification expansion and emergence of ASD and ADHD symptomology in early development, we investigated gyrification morphology in 539 children and adolescents (6-17 years of age) with ASD (n=197) and ADHD (n=96) compared to typically developing controls (n=246) using the local Gyrification Index (lGI) to provide insight into contributing etiopathological factors in these two disorders. We also examined IQ effects and functional implications of gyrification by exploring the relation between lGI and ASD and ADHD symptomatology beyond diagnosis. General Linear Models yielded no group differences in lGI, and across groups, we identified an age-related decrease of lGI and greater lGI in females compared to males. No diagnosis-by-age interactions were found. Accounting for IQ variability in the model (n=484) yielded similar results. No significant associations were found between lGI and social communication deficits, repetitive and restricted behaviours, inattention or adaptive functioning. By examining both disorders and controls using shared methodology, we found no evidence of atypicality in gyrification as measured by the lGI in these conditions., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Executive functioning (EF) varies in children with autism spectrum disorder (ASD) and is associated with clinical symptoms, academic, and adaptive functioning. Here, we examined whether middle-childhood EF mediates associations between early-childhood autism symptoms and adolescent outcomes in children with ASD., Methods: The Pathways in ASD Cohort comprising children recruited at the time of ASD diagnosis (at 2-4 years-of-age) and followed prospectively across eight subsequent timepoints over ~10 years was used. A subset of Pathways participants (n = 250) with Behavior Rating Inventory of Executive Function (BRIEF)-Parent Form data from at least one timepoint when participants were school-aged was analyzed. A mediation framework was used to examine whether BRIEF-measured EF across age 7-10 years (middle-childhood) mediated associations between early-childhood autism symptoms (measured using the parent-report Social Responsiveness Scale across age 2-6 years) and clinical, academic, and functional outcomes, indexed at age >10-11.8 years (early-adolescence) using the Child Behavior Checklist (CBCL)-Internalizing and Externalizing Scales, Academic Performance from the Teacher's Report Form, and Vineland Adaptive Behavior Scales. Models were rerun substituting clinician-rated and teacher-rated measures, where possible., Results: Mediation models indicated a significant indirect effect of middle-childhood EF on associations between early-childhood autism symptoms and externalizing behavior, academic performance, or adaptive functioning in early adolescence; kappa squared (κ 2 ) effect sizes ranged from large to small. Model findings were stable across raters. Middle-childhood EF did not mediate associations between early-childhood autism symptoms and adolescent internalizing behavior., Conclusions: Among children with an ASD diagnosis, middle-childhood EF may be one pathway through which early-childhood autism symptoms influence a variety of outcomes in early-adolescence. An experimental study targeting middle-childhood EF to improve adolescent academic, emotional/behavioral, and adaptive functioning is needed to evaluate the clinical meaningfulness of these findings., (© 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Purpose of Review: Sex/gender-related factors contribute to contextual issues influencing the recognition of autism and attention-deficit/hyperactivity disorder (ADHD), and modulate how neurodevelopmental characteristics are manifested. This review summarizes the empirical literature to provide directions for improving clinical diagnostic practices., Recent Findings: Timing of autism and/or ADHD diagnosis, particularly in girls/women, is related to the individual's developmental characteristics and co-occurring diagnoses, and expectancy, alongside gender stereotype biases, of referral sources and clinicians. This is further compounded by sex and gender modulations of behavioural presentations. The emerging 'female autism phenotype' concept may serve as a helpful illustration of nuanced autism phenotypes, but should not be viewed as essential features of autism in a particular sex or gender. These nuanced phenotypes that can present across sexes and genders include heightened attention to socially salient stimuli, friendship and social groups, richness in language expression, and more reciprocal behaviours. The nuanced female-predominant ADHD phenotypes are characterized by subtle expressions in hyperactivity-impulsivity (e.g., hyper-verbal behaviours). Optimizing neurodevelopmental diagnoses across sexes and genders also requires an understanding of sex-related and gender-related variations in developmental trajectories, including compensation/masking efforts, and the influences of co-occurring conditions on clinical presentations., Summary: Equitable diagnoses across sexes and genders for autism and ADHD require understanding of the nuanced presentations and the Gestalt clinical-developmental profiles, and addressing contextual biases that influence diagnostic practices., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2020 Association for Child and Adolescent Mental Health.)

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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Schizophrenia spectrum disorders (SSDs) and autism spectrum disorder (ASD) both feature social cognitive deficits; however, these disorders historically have been examined separately using a range of tests and subdomain focus and at different time points in the life span. Moving beyond diagnostic categories and characterizing social cognitive deficits can enhance understanding of shared pathways across these disorders., Objective: To investigate how deficits in social cognitive domains diverge or overlap between SSDs and ASD based on the extant literature., Data Sources: Literature searches were conducted in MEDLINE, PsycInfo, Embase, and Web of Science from database inception until July 26, 2020., Study Selection: Original research articles were selected that reported performance-based measures of social cognition in both SSDs and ASD samples. Selected articles also had to be published in English and use International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, DSM-IV, or more recent diagnostic criteria., Data Extraction and Synthesis: This systematic review and meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines, including data extraction and quality assessment using a modified version of the Newcastle-Ottawa Scale. Data were pooled using a random-effects model., Main Outcomes and Measures: Effect sizes were calculated as Hedges g (SSDs vs ASD). The primary outcomes were performance on emotion processing tasks, theory of mind (ToM) tasks, and the Reading the Mind in the Eyes Test (RMET) in SSDs compared with ASD. Meta-regressions were performed for age difference, publication year, quality assessment scores, and antipsychotic medication use., Results: Of the 4175 screened articles, 36 studies directly comparing social cognitive performance in individuals with SSDs vs ASD were included in the qualitative analysis (n = 1212 for SSDs groups and n = 1109 for ASD groups), and 33 studies were included in the quantitative analyses (n = 1113 for SSDs groups and n = 1015 for ASD groups). Most study participants were male (number of studies [k] = 36, 72% [878 of 1212] in SSDs groups and 82% [907 of 1109] in ASD groups), and age (k = 35) was older in SSDs groups (mean [SD], 28.4 [9.5] years) than in ASD groups (mean [SD], 23.3 [7.6] years). Included studies highlighted the prevalence of small, male-predominant samples and a paucity of cross-disorder clinical measures. The meta-analyses revealed no statistically significant differences between SSDs and ASD on emotion processing measures (k = 15; g = 0.12 [95% CI, -0.07 to 0.30]; P = .21; I2 = 51.0%; 1 outlier excluded), ToM measures (k = 17; g = -0.01 [95% CI, -0.21 to 0.19]; P = .92; I2 = 56.5%; 1 outlier excluded), or the RMET (k = 13; g = 0.25 [95% CI, -0.04 to 0.53]; P = .10; I2 = 75.3%). However, SSDs vs ASD performance differences between studies were statistically significantly heterogeneous, which was only minimally explained by potential moderators., Conclusions and Relevance: In this analysis, similar levels of social cognitive impairment were present, on average, in individuals with SSDs and ASD. Cross-disorder studies of social cognition, including larger samples, consensus batteries, and consistent reporting of measures, as well as data across multiple levels of analysis, are needed to help identify subgroups within and across disorders that may be more homogeneous in etiology and treatment response.

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.

Our current understanding of autism is largely based on clinical experiences and research involving male individuals given the male-predominance in prevalence and the under-inclusion of female individuals due to small samples, co-occurring conditions, or simply being missed for diagnosis. There is a significantly biased 'male lens' in this field with autistic females insufficiently understood. We therefore conducted a systematic review to examine how sex and gender modulate brain structure and function in autistic individuals. Findings from the past 20 years are yet to converge on specific brain regions/networks with consistent sex/gender-modulating effects. Despite at least three well-powered studies identifying specific patterns of significant sex/gender-modulation of autism-control differences, many other studies are likely underpowered, suggesting a critical need for future investigation into sex/gender-based heterogeneity with better-powered designs. Future research should also formally investigate the effects of gender, beyond biological sex, which is mostly absent in the current literature. Understanding the roles of sex and gender in the development of autism is an imperative step to extend beyond the 'male lens' in this field., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Postmortem studies reveal that individuals with major neuropsychiatric disorders such as schizophrenia and autism spectrum disorder have gray matter microstructural abnormalities. These include abnormalities in neuropil organization, expression of proteins supporting neuritic and synaptic integrity, and myelination. Genetic and postmortem studies suggest that these changes may be causally linked to the pathogenesis of these disorders. Advances in diffusion-weighted magnetic resonance image (dMRI) acquisition techniques and biophysical modeling allow for the quantification of gray matter microstructure in vivo. While several biophysical models for imaging microstructural properties are available, one in particular, neurite orientation dispersion and density imaging (NODDI), holds great promise for clinical applications. NODDI can be applied to both gray and white matter and requires only a single extra shell beyond a standard dMRI acquisition. Since its development only a few years ago, the NODDI algorithm has been used to characterize gray matter microstructure in schizophrenia, Alzheimer's disease, healthy aging, and development. These investigations have shown that microstructural findings in vivo, using NODDI, align with postmortem findings. Not only do NODDI and other advanced dMRI-based modeling methods provide a window into the brain previously only available postmortem, but they may be more sensitive to certain brain changes than conventional magnetic resonance imaging approaches. This opens up exciting new possibilities for clinicians to more rapidly detect disease signatures and allows earlier intervention in the course of the disease. Given that neurites and gray matter microstructure have the capacity to rapidly remodel, these novel dMRI-based methods represent an opportunity to noninvasively monitor neuroplastic changes posttherapy within much shorter time scales., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data., Methods: Structural T 1 -weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures)., Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood., Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.

Background: In youth and young adults with autism spectrum disorder (ASD), executive function (EF) deficits may be a promising treatment target with potential impact on everyday functioning., Objective: To conduct a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for EF deficits in ASD., Method: In Toronto, Ontario (November 2014 to June 2017), a 20-session, 4-week course of 20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) (90%RMT) was compared to sham stimulation in 16-35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n = 20 active/n = 20 sham). Outcome measures evaluated protocol feasibility and clinical effects of active vs. sham rTMS on EF performance. The moderating effect of baseline functioning was explored., Results: Of eligible participants, 95% were enrolled and 95% of randomized participants completed the protocol. Adverse events across treatment arms were mild-to-moderate. There was no significant difference between active vs. sham rTMS on EF performance. Baseline adaptive functioning moderated the effect of rTMS, such that participants with lower baseline functioning experienced significant EF improvement in the active vs. sham group., Conclusions: Our pilot RCT demonstrated the feasibility and acceptability of using high frequency rTMS targeting DLPFC in youth and young adults with autism. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, we found promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits. Future work could focus on examining efficacy of rTMS in this higher-need population., Clinical Trial Registration: Repetitive Transcranial Magnetic Stimulation (rTMS) for Executive Function Deficits in Autism Spectrum Disorder and Effects on Brain Structure: A Pilot Study; https://clinicaltrials.gov/ct2/show/NCT02311751?term = ameis&rank = 1; NCT02311751. The trial was funded by: an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award, the Innovation Fund from the Alternate Funding Plan of the Academic Health Sciences Centres of Ontario, and an Ontario Mental Health Foundation (OMHF) Project A Grant and New Investigator Fellowship., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Objective: Evidence-based guidance of clinical decision-making for the management of Autism Spectrum Disorder (ASD) is lacking, particularly for co-occurring psychiatric symptoms. This review evaluates treatment evidence for six common symptom targets in children/adolescents with ASD and provides a resource to facilitate application of the evidence to clinical practice., Method: A systematic search identified randomized controlled trials (RCTs) and high-quality systematic reviews published between 2007 and 2016, focused on: social interaction/communication impairment, stereotypic/repetitive behaviours, irritability/agitation, attention-deficit/hyperactivity disorder symptoms, mood or anxiety symptoms, and sleep difficulties. We then completed qualitative evaluation of high-quality systematic reviews/meta-analyses and quantitative evaluation of recently published RCTs not covered by prior comprehensive systematic reviews., Results: Recently published RCTs focused on social interaction and communication impairment (trials = 32) using psychosocial interventions. Interventions for irritability/agitation (trials = 16) were mainly pharmacological. Few RCTs focused on other symptom targets (trials = 2-5/target). Integration of these results with our qualitative review indicated that few established treatment modalities exist, and available evidence is limited by small studies with high risk of bias., Conclusion: Given the current evidence-base, treatment targets must be clearly defined, and a systematic approach to intervention trials in children/adolescents with ASD must be undertaken with careful consideration of the limitations of safety/efficacy data., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recent advances in techniques using functional magnetic resonance imaging data demonstrate individually specific variation in brain architecture in healthy individuals. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported., Methods: We developed a novel approach (Personalized Intrinsic Network Topography, PINT) for localizing individually specific resting-state networks using conventional resting-state functional magnetic resonance imaging scans. Using cross-sectional data from participants with autism spectrum disorder (ASD; n = 393) and typically developing (TD) control participants (n = 496) across 15 sites, we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in persons with ASD compared with TD persons remain after PINT application., Results: We found greater variability in the spatial locations of resting-state networks within individuals with ASD compared with those in TD individuals. For TD persons, variability decreased from childhood into adulthood and increased in late life, following a U-shaped pattern that was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypoconnected regions in ASD., Conclusions: Our results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

There is considerable heterogeneity in social cognitive and neurocognitive performance among people with schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), bipolar disorder (BD), and healthy individuals. This study used Similarity Network Fusion (SNF), a novel data-driven approach, to identify participant similarity networks based on relationships among demographic, brain imaging, and behavioral data. T1-weighted and diffusion-weighted magnetic resonance images were obtained for 174 adolescents and young adults (aged 16-35 years) with an SSD (n=51), an ASD without intellectual disability (n=38), euthymic BD (n=34), and healthy controls (n=51). A battery of social cognitive and neurocognitive tasks were administered. Data integration, cluster determination, and biological group formation were then obtained using SNF. We identified four new groups of individuals, each with distinct neural circuit-cognitive profiles. The most influential variables driving the formation of the new groups were robustly reliable across embedded resampling techniques. The data-driven groups showed considerably greater differentiation on key social and neurocognitive circuit nodes than groups generated by diagnostic analyses or dimensional social cognitive analyses. The data-driven groups were validated through functional outcome and brain network property measures not included in the SNF model. Cutting across diagnostic boundaries, our approach can effectively identify new groups of people based on a profile of neuroimaging and behavioral data. Our findings bring us closer to disease subtyping that can be leveraged toward the targeting of specific neural circuitry among participant subgroups to ameliorate social cognitive and neurocognitive deficits.

Objective: Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented., Methods: An ongoing protocol will enroll participants aged 16-35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing., Conclusions: EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD.

Objective: Neurodevelopmental disorders (NDDs) (attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) share genetic vulnerability and symptom domains. The authors present direct comparison of structural brain circuitry in children and adolescents with NDDs and control subjects and examine brain circuit-behavior relationships across NDDs using dimensional measures related to each disorder., Method: Diffusion imaging and behavioral measures were acquired in 200 children and adolescents (ADHD: N=31; OCD: N=36; ASD: N=71; controls: N=62; mean age range: 10.3-12.6 years). Following Tract-Based Spatial Statistics, multigroup comparison of white matter indices was conducted, followed by pairwise comparisons. Relationships of fractional anisotropy with dimensional measures of inattention, social deficits, obsessive-compulsive symptoms, and general adaptive functioning were conducted across the NDD sample., Results: Lower fractional anisotropy within the splenium of the corpus callosum was found in each NDD group, compared with the control group. Lower fractional anisotropy in additional white matter tracts was found in the ASD and ADHD groups, compared with the control group, but not in the OCD group. Fractional anisotropy was lower in the ASD and ADHD groups compared with the OCD group but was not different in ADHD participants compared with ASD participants. A positive relation between fractional anisotropy (across much of the brain) and general adaptive functioning across NDDs was shown., Conclusions: This study identified disruption in interhemispheric circuitry (i.e., fractional anisotropy alterations in the corpus callosum) as a shared feature of ASD, ADHD, and OCD. However, fractional anisotropy alterations may be more widespread and severe in ASD and ADHD than in OCD. Higher fractional anisotropy throughout the brain appears to be related to better adaptive function across NDDs.

Purpose: This review article summarizes original scientific research published to date on interoception in individuals with Autism Spectrum Disorder (ASD). Sensory processing has been shown to be atypical in ASD, yet physiological processing and subjective experience of internal sensation processing, namely interoception, has not been reported sufficiently in research or clinical settings., Background: There is a small but growing body of scientific research on interoception in ASD, which is relevant to understanding the behavioral and cognitive characteristics inherent in this condition, and may provide a foundation for clinical interventions such as biofeedback, pain management, and brain stimulation techniques., Methods: A literature review of original research was performed using major scientific databases., Results: Interoception, which occurs due to multisensory connections and integration of internal afferents in cortical and subcortical areas, is atypical in ASD, but the degree and directionality of this abnormality is not yet clear due to the heterogeneity of the condition. Between-group interoceptive differences in individuals with and without ASD have been repeatedly demonstrated, with a slight tendency towards hyporeactivity in interoceptive awareness in individuals with ASD., Significance: Multidimensional research combining neuroimaging with psychophysiological and self-report measures guided by a clear theoretical model is necessary to understand how interoceptive differences link to the behavioral and cognitive characteristics of ASD. Sensory processing models and autism theory should also be updated to incorporate these recent findings., (Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.)

Objective: Although irritability and aggression are relevant treatment targets in autism spectrum disorders (ASDs) and intellectual disability (ID) that may prompt antipsychotic use, antipsychotic prescribing patterns in such youth have not been systematically reviewed., Method: We systematically searched PubMed/MEDLINE/PsycInfo until March 2015 for studies reporting data on the frequency of youth diagnosed with ASDs and/or ID among antipsychotic-treated youth, as well as antipsychotic use in youth with ASD/ID, conducting a meta-analysis and meta-regression analysis of potential moderators, including publication year, study time point, country, setting, sample size, age, sex, and race/ethnicity., Results: A total of 39 studies were meta-analyzed (n = 365,449, age = 11.4 ± 6.2 years, males = 70.0% ± 10.0%). Among 27 studies (n = 273,139, age = 11.9 ± 8.0 years, males = 67.0% ± 12.9%) reporting on antipsychotic-treated youth, 9.5% (95% CI = 7.8%-11.5%) were diagnosed with ASD/ID. In 20 studies (n = 209,756) reporting data separately for ASD, 7.9% (95% CI = 6.2%-9.9%) had an ASD diagnosis. In 5 longitudinal studies, the proportion of antipsychotic-treated youth with ASD did not change significantly from 1996 to 2011 (6.7% to 5.8%, odds ratio = 0.9, 95% CI = 0.8-1.0, p =.17). However, later study time point moderated greater ASD/ID proportions (β = 0.12, p < .00001). In 13 studies (n = 96,688, age = 9.8 ± 1.2 years, males = 78.6% ± 2.0%) reporting on antipsychotic use in ASD samples, 17.5% (95% CI = 13.7%-22.1%) received antipsychotics. Again, later study time point moderated higher antipsychotic use among patients with ASD (β = 0.10, p = .004)., Conclusion: Almost 1 in 10 antipsychotic-treated youth were diagnosed with ASD and/or ID, and 1 in 6 youth with ASD received antipsychotics. Both proportions increased in later years; however, clinical reasons and outcomes of antipsychotic use in ASD/ID require further study., (Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)