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Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6–65) was divided into six successive 6–10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6–13 and adults aged 50–65 with OCD taking SRIs (Cohen's d = −0.24 to −0.74). Volumes of putamen, pallidum (d = 0.18–0.40), and ventricles (d = 0.31–0.66) were greater in patients aged 20–29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = −0.27 to −1.31). Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20–29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

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.

Acknowledgements: We thank the self-advocates and family advisors at the Azrieli Adult Neurodevelopmental Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who helped us evaluate the feasibility of the design of this study and edit the language in the informed consent form and assent form to facilitate the readability of these documents for people with IDD., Funder: Department of Psychiatry, University of Toronto, Funder: CAMH Academic Health Science Centre Alternative Funding Plan (AHSC AFP), Severe behavioral problems (SBPs) are common contributors to morbidity and reduced quality of life for adults with intellectual and developmental disabilities (IDD) and their families. Current medications for SBPs show equivocal effectiveness and are associated with a high risk of side effects. New and safe treatments are urgently needed. While preliminary studies suggest that medical cannabinoids, particularly the synthetic cannabinoid nabilone, are plausible treatment options for SBPs in adults with IDD, data on the tolerability, safety and efficacy of nabilone in this population has never been investigated. Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD, and explore changes in SBPs pre- to post-treatment. We hypothesize that nabilone has favorable tolerability and safety profile for adults with IDD. The preliminary results will inform the next-stage pilot randomized controlled trials, followed by fully powered clinical trials eventually. This research helps fill the evidence gap in the use of cannabinoids in individuals with IDD to meet the needs of patients, families, and service providers.

1.AbstractSome children that experience a concussion exhibit long-lasting emotional and behavioral problems post-injury, with greater rates of persistent problems in females. Establishing the contribution of (1) pre-existing behavioral problems and (2) disrupted maturation of the brain’s vulnerable white matter, to long-lasting behavioral problems has been a challenge due to a lack of pre-injury behavioral and imaging data. From the Adolescent Brain Cognitive Development Cohort, this study examined 204 11-12-year-old children who experienced a concussion after baseline data collection at age 9-10-years-old. Internalizing and externalizing behavioral problems were assessed with the Child Behavior Checklist. In 99 of these children with MRI data available, white matter microstructure was characterized in deep and superficial white matter by neurite density from restriction spectrum image modeling of diffusion MRI. Linear regressions modeled 1) post-concussion behavior symptoms controlling for pre-injury behavior, 2) the impact of concussion on white matter maturation, and 3) the contribution of deviations in white matter maturation to post-concussion behavior symptoms. When controlling for preinjury scores, post-injury internalizing and externalizing scores were higher in female but not male children with concussion compared to children with no concussion. Group comparisons of change in neurite density over two years reflecting white matter maturation demonstrated an age-dependent effect whereby younger female children had less change in neurite density over time than younger children with no concussion. In female children with concussion, less change in superficial white matter neurite density over time was associated with more internalizing behavior problems. These results suggest that in female children, concussions are associated with behavior problems beyond those that exist pre-injury, and injury to the brain’s vulnerable white matter may be a biological substrate underlying persistent internalizing behaviors.

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.

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.

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 (κ2 ) 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.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16–33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI− (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI− participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

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.

Oxidative stress is associated with white matter diffusion metrics in adults with bipolar disorder (BD). We examined the association of single-nucleotide polymorphisms in the oxidative stress system, superoxide dismutase-2 (SOD2) rs4880 and glutathione peroxidase-3 (GPX3) rs3792797 with fractional anisotropy (FA) and radial diffusivity (RD) in youth with BD. Participants included 104 youth (age 17.5 ± 1.7 years; 58 BD, 46 healthy controls). Saliva samples were obtained for genotyping, and diffusion tensor imaging was acquired. Voxel-wise whole-brain white matter diffusion analyses controlled for age, sex, and race. There were significant diagnosis-by-SOD2 rs4880 interaction effects for FA and RD in major white matter tracts. Within BD, the group with two copies of the G-allele (GG) showed lower FA and higher RD than A-allele carriers. Whereas within the control group, the GG group showed higher FA and lower RD than A-allele carriers. Additionally, FA was higher and RD was lower within the control GG group compared to the BD GG group. No significant findings were observed for GPX3 rs3793797. The current study revealed that, within matter tracts known to differ in BD, associations of SOD2 rs4880 GG genotype with both FA and RD differed between BD vs healthy control youth. The SOD2 enzyme encoded by the G-allele, has higher antioxidant capacity than the enzyme encoded by the A-allele. We speculate that the current findings of lower FA and higher RD of the BD GG group compared to the other groups reflects attenuation of the salutary antioxidant effects of GG genotype on white matter integrity in youth with BD, in part due to predisposition to oxidative stress. Future studies incorporating other genetic markers and oxidative stress biomarkers are warranted.

The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts.

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 = ameisr 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.

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.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.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.

Background: Autism is not always considered for girls and women until later along their clinical diagnostic pathways. Misdiagnosis or late diagnosis can pose significant disadvantages with respect to accessing timely health and autism-related services and supports. Understanding what contributes to roadblocks and detours along clinical pathways to an autism diagnosis can shed light on missed opportunities for earlier recognition. Objective: Our objective was to examine what contributed to roadblocks, detours, and missed opportunities for earlier recognition and clinical diagnosis of autism for girls and women. Design: We conducted a qualitative secondary analysis using data from a Canadian primary study that examined the health and healthcare experiences of autistic girls and women through interviews and focus groups. Methods: Transcript data of 22 girls and women clinically diagnosed with autism and 15 parents were analysed, drawing on reflexive thematic analysis procedures. Techniques included coding data both inductively based on descriptions of roadblocks and detours and deductively based on conceptualizations of sex and gender. Patterns of ideas were categorized into themes and the ‘story’ of each theme was refined through writing and discussing analytic memos, reflecting on sex and gender assumptions, and creating a visual map of clinical pathways. Results: Contributing factors to roadblocks, detours, and missed opportunities for earlier recognition and diagnosis were categorized as follows: (1) age of pre-diagnosis ‘red flags’ and ‘signals’; (2) ‘non-autism’ mental health diagnoses first; (3) narrow understandings of autism based on male stereotypes; and (4) unavailable and unaffordable diagnostic services. Conclusion: Professionals providing developmental, mental health, educational, and/or employment supports can be more attuned to nuanced autism presentations. Research in collaboration with autistic girls and women and their childhood caregivers can help to identify examples of nuanced autistic features and how context plays a role in how these are experienced and navigated.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool with potential for broad application in individuals with neuropsychiatric conditions. As in adults, most rTMS research in youth has focused on treatment-resistant depression. A limited number of rTMS studies have also been conducted in children and youth with primary diagnoses of Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD) or Tourette's syndrome. Across the available rTMS literature, rTMS appears to be well tolerated with few adverse effects reported when applied to child and youth research samples. However, the potential efficacy of rTMS treatment for a variety of targets in children and youth remains unclear, due in part to limitations of the current literature, including studies using diverse protocols, potential for bias in existing clinical trial designs, variability in the research samples, and the use of heterogenous outcome measures. While rTMS is unlikely to take the place of more accessible treatments (e.g., psychopharmacological, psychosocial, psychotherapeutic), rTMS may provide a valuable alternative treatment option, particularly for those individuals where conventional treatments are inaccessible, poorly tolerated, or ineffective. A more robust body of well-designed, controlled trials, is needed in order to clarify rTMS treatment efficacy across relevant neuropsychiatric conditions, optimize treatment protocols, and meet the critical need for novel mental health interventions in children and youth.La Stimulation magnétique transcrânienne répétitive (SMTr) est un instrument de stimulation du cerveau non invasif qui a le potentiel d’une application élargie chez les personnes souffrant de conditions neuropsychiatriques. Comme chez les adultes, la majorité de la recherche sur la SMTr chez les jeunes a porté sur la dépression réfractaire au traitement. Un nombre limité d’études sur la SMTr ont aussi été menées chez les enfants et les jeunes ayant des diagnostics primaires du trouble du spectre de l’autisme (TSA), du trouble de déficit de l’attention avec hyperactivité (TDAH) ou du syndrome de la Tourette. Dans la littérature disponible sur la SMTr, celle-ci semble bien tolérée et peu d’effets indésirables sont signalés lorsqu’elle est appliquée aux enfants et aux jeunes des échantillons de recherche. Cependant, l’efficacité potentielle d’un traitement par SMTr pour une variété d’objectifs chez les enfants et les jeunes demeure imprécise, partiellement en raison des limitations de la littérature actuelle, notamment des études utilisant divers protocoles, le potentiel de biais dans les méthodes d’essais cliniques existants, la variabilité des échantillons de recherche, et l’usage de mesures de résultats hétérogènes. Même si la SMTr ne prendra probablement pas la place de traitements plus accessibles (p. ex., psychopharmacologiques, psychosociaux, psychothérapeutiques), la SMTr peut procurer une option de traitement parallèle valable, chez les personnes pour qui les traitements conventionnels sont inaccessible, mal tolérés ou inefficaces. Un ensemble plus robuste d’essais contrôlés mieux conçus est nécessaire afin de clarifier l’efficacité du traitement par SMTr dans toutes les conditions neuropsychiatriques, optimiser les protocoles de traitement et répondre au besoin critique de nouvelles interventions de santé mentale chez les enfants et les jeunes.

Structural and functional cortico-striatal–thalamic–cortical (CSTC) circuit abnormalities have been observed in schizophrenia and the clinical high-risk state. However, this circuit is sexually dimorphic and changes across neurodevelopment. We examined effects of sex and age on structural and functional properties of the CSTC circuit in a large sample of youth with and without psychosis spectrum symptoms (PSS) from the Philadelphia Neurodevelopmental Cohort. T1-weighted and resting-state functional MRI scans were collected on a 3T Siemens scanner, in addition to participants’ cognitive and psychopathology data. After quality control, the total sample (aged 11–21) was n = 1095 (males = 485, females = 610). Structural subdivisions of the striatum and thalamus were identified using the MAGeT Brain segmentation tool. Functional seeds were segmented based on brain network connectivity. Interaction effects among PSS group, sex, and age on striatum, thalamus, and subdivision volumes were examined. A similar model was used to test effects on functional connectivity of the CSTC circuit. A sex by PSS group interaction was identified, whereby PSS males had higher volumes and PSS females had lower volumes in striatal and thalamic subdivisions. Reduced functional striato-cortical connectivity was found in PSS youth, primarily driven by males, whereby younger male PSS youth also exhibited thalamo-cortical hypo-connectivity (compared to non-PSS youth), vs. striato-cortical hyper-connectivity in older male PSS youth (compared to non-PSS youth). Youth with PSS demonstrate sex and age-dependent differences in striatal and thalamic subdivision structure and functional connectivity. Further efforts at biomarker discovery and early therapeutic intervention targeting the CSTC circuit in psychosis should consider effects of sex and age.

Background Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI. Methods Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata. Results Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI. Conclusions The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.

Background: Response inhibition engages the cortico-striato-thalamo-cortical (CSTC) circuit, which has been implicated in children, and youth with obsessive compulsive disorder (OCD). This study explored whether CSTC engagement during response inhibition, measured using magnetoencephalography (MEG), differed in a sample of medication-naïve youth with OCD, compared to typically developing controls (TDC).Methods: Data was analyzed in 17 medication-naïve children and youth with OCD (11.7 ± 2.2 SD years) and 13 TDC (12.6 ± 2.2 SD years). MEG was used to localize and characterize neural activity during a Go/No-Go task. Task performance on Go/No-Go conditions and regional differences in amplitude of activity during Go and No-Go condition between OCD vs. TDC were examined using two-sample t-tests. Post-hoc analysis with Bayesian t-tests was used to estimate the certainty of outcomes.Results: No differences in Go/No-Go performance were found between OCD and TDC groups. In response to the visual cue presented during the Go condition, participants with OCD showed significantly increased amplitude of activity in the primary motor (MI) cortex compared to TDC. In addition, significantly reduced amplitude of PCu was found following successful stopping to No-Go cues in OCD vs. TDC during No-Go task performance. Bayesian t-tests indicated high probability and large effect sizes for the differences in MI and PCu amplitude found between groups.Conclusion: Our preliminary study in a small medication-naïve sample extends previous work indicating intact response inhibition in pediatric OCD. While altered neural response in the current study was found during response inhibition performance in OCD, differences localized to regions outside of the CSTC. Our findings suggest that additional imaging research in medication-naïve samples is needed to clarify regional differences associated with OCD vs. influenced by medication effects, and suggest that MEG may be sensitive to detecting such differences.

BackgroundExternalizing and internalizing behaviors are common and contribute to impairment in children with neurodevelopmental disorders (NDDs). Associations between externalizing or internalizing behaviors and cortico-amygdalar connectivity have been found in children with and without clinically significant internalizing/externalizing behaviors. This study examined whether such associations are present across children with different NDDs.MethodsMulti-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 and parent-report Child Behavioral Checklist (CBCL) data available, were analyzed (n range=157-346). 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.ResultsNo 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.ConclusionsThe current study provides evidence in favour of the absence of a shared linear relationship between internalizing or externalizing behaviors and cortico-amygdalar connectivity properties across a transdiagnostic sample of children with various NDDs and TDC. Detecting shared brain-behavior relationships in children with NDDs may benefit from the use of different methodological approaches, including incorporation of multi-dimensional behavioral data (i.e. behavioral assessments, neurocognitive tasks, task-based fMRI) or clustering approaches to delineate whether subgroups of individuals with different brain-behavior profiles are present within heterogeneous cross-disorder samples.

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F(1,19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t(18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD.Clinical Trial Registration:Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

Highlights • Male-based understanding of autism leads to poor understanding of autistic females. • We used a uniquely unbiased search strategy and quantitative evaluation of studies. • At least 3 well-powered studies identified sex/gender-modulation of autism effects. • No specific brain regions or networks show consistent sex/gender-modulating effects. • Future studies require larger sample sizes with more autistic female participants., 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.

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; I(2) = 51.0%; 1 outlier excluded), ToM measures (k = 17; g = –0.01 [95% CI, –0.21 to 0.19]; P = .92; I(2) = 56.5%; 1 outlier excluded), or the RMET (k = 13; g = 0.25 [95% CI, –0.04 to 0.53]; P = .10; I(2) = 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.

Fombonne's (2020) editorial is a thought-provoking appraisal of the literature on 'camouflaging', whereby some autistic people mask or compensate for their autistic characteristics as an attempt to fit in and to cope with disabilities under neurotypical social norms. Fombonne (2020) highlights three issues of contention: (a) construct validity and measurement of camouflaging; (b) camouflaging as a reason for late autism diagnosis in adolescence/adulthood; and (c) camouflaging as a feature of the 'female autism phenotype'. Here, we argue that (a) establishing construct validity and measurement of different aspects of camouflaging is warranted; (b) subjective experiences are important for the differential diagnosis of autism in adolescence/adulthood; and (c) camouflaging is not necessarily a feature of autism in female individuals - nevertheless, taking into account sex and gender influences in development is crucial to understand behavioural manifestations of autism. Future research and clinical directions should involve clarification of associated constructs and measurements, demography, mechanisms, impact (including harms and benefits) and tailored support.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

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.

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.MethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and 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. We examined subcortical volume, cortical thickness and 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 ICV for subcortical and surface area measures).ResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.ConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

Accepted Manuscript, BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD.METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status.RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -20.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets.CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

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.

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 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 was used. 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 (NMI) 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. Such new groups can be evaluated longitudinally for prognostic utility and could be stratified for clinical trials targeted toward each group’s unique brain and behavioral profiles.

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.

Although awareness of the substantial need for appropriate wellness efforts for adults with autism is growing, females with autism may have been under-identified in the past, and consequently, the research to date is largely based in a male-centric conceptualization of autism. The purpose of this narrative review was to ascertain what is known about wellness efforts for women with autism. Beyond the shared challenges as experienced by autistic men, autistic women may have unique and differing social, physical, and psychological wellness needs; however, there remains limited research to date in many areas of lifespan wellness concerns. We emphasize the need for future autism and disability research to acknowledge and account for potential sex and gender impact across areas of study. Further acknowledgement of sex and gender impact will play an important role in improving clinicians’ capacity to identify autism in girls and women, which is a foundational component of many wellness efforts.

ImportanceMicrostructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities.ObjectiveTo investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date.Design, Setting, and ParticipantsIn this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group.Main Outcomes and MeasuresWe extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics.ResultsAdult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, pConclusions and RelevanceMicrostructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD.KEY POINTSQuestionDo patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features?FindingsData from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features.MeaningMicrostructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

Several brain disorders exhibit sex differences in onset, presentation, and prevalence. Increased understanding of the neurobiology of sex-based differences across the lifespan can provide insight into potential disease risk and protective mechanisms. We focused on sex-related differences in variability, which may be indicative of both disease vulnerability and resilience. In n=3,069 participants, from 8-95 years of age, we first analyzed the variance ratio in females vs. males of cortical surface area and global and subcortical volumes for discrete brain regions, and found widespread greater variability in males. In contrast, variance in cortical thickness was similar for males and females. Multivariate analysis that accounts for structural covariance supported variance ratio findings. Findings were present from early life and stable with age. We then examined variability among brain regions by sex. We found significant age-by-sex interactions across neuroimaging metrics, whereby in very early life males had reduced among-region variability compared to females, while in very late life this was reversed. Overall, our findings of greater regional variability but less among-region variability in males in early life may aid our understanding of sex-based risk for neurodevelopmental disorders. In contrast, our findings in late life may provide a potential sex-based risk mechanism for dementia.

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.

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.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.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: structural brain imaging studies in obsessive compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta and mega-analyses of data from OCD sites worldwide. Method: T-1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. Results: the meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohen's d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. Conclusions: the results indicate different patterns of sub cortical abnormalities in pediatric and adult OCD patients. The patlidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Background Schizophrenia spectrum disorders (SSDs) and autism spectrum disorder (ASD) both feature social cognitive deficits, which are highly debilitating. These include lower-level processes (e.g. emotion recognition), thought to be subserved by a frontoparietal mirroring network, and higher-level mentalizing processes (e.g. theory of mind), involving cortical midline and lateral temporal brain regions. Across both disorders, impairments in social cognition persist over time, drive disability, and predict functional outcome. Overlapping symptoms in SSDs and ASD have long been recognized, particularly in the realm of social deficits. However, despite some studies including both individuals with SSDs and ASD showing similar levels of social cognitive impairment, including lower-level and higher-level deficits, results are mixed. Thus, our objective was to determine based on the extant literature how deficits in social cognition diverge or overlap between individuals with SSDs and ASD by conducting a systematic review and meta-analysis of studies directly comparing these groups on behavioural social cognitive measures. Methods Literature searches were conducted in MEDLINE, Embase, PsycINFO, and Web of Science to identify articles that utilized behavioural measures to assess social cognition in both SSD and ASD samples. Of 3682 articles identified, 28 met all inclusion criteria. Across the accepted articles, lower-level (e.g. facial and/or context-embedded emotion recognition) and higher-level (e.g. intention understanding, perspective taking) social cognitive measures were identified, and random-effects meta-analyses were conducted for each category. A separate meta-analysis was also conducted for the Reading the Mind in the Eyes test given that it was the most commonly used social cognitive metric. Effect sizes were estimated using Hedges’ g. Homogeneity of effects and publication bias were also assessed for each meta-analysis. Results A significant difference in lower-level social cognitive performance was found between individuals with SSDs and ASD, with the SSD group performing better than the ASD group (Hedges’ g = 0.30, 95% CI [0.05, 0.56], p = .018). In contrast, there was no significant difference in higher-level social cognitive performance between SSD and ASD groups (Hedges’ g = -0.14, 95% CI [-0.52, 0.24], p = .46). Similarly, the Reading the Mind in the Eyes test meta-analysis revealed no significant difference in effect sizes between disorders (Hedges’ g = 0.24, 95% CI [-0.07, 0.55], p = .14). Effect size distributions were significantly heterogeneous in all three cases (all p < .001). Discussion Based on meta-analyses of the extant literature, both shared and differential social cognitive deficits may be present between individuals with SSDs and ASD. Though no differences were detected between SSD and ASD groups on higher-level social cognitive tasks or the Reading the Mind in the Eyes test, lower-level social cognitive deficits were found to be more severe in individuals with ASD than SSDs. Notably, the majority of studies included in the meta-analyses had small sample sizes, and heterogeneity of effect sizes was apparent. Thus, studies including larger sample sizes and validated measures of social cognition in conjunction with other methodologies are needed to substantiate these results, and better understand the shared and unique behavioural underpinnings and associated neural circuit abnormalities underlying social cognitive deficits in SSDs and ASD.

Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) are psychiatric disorders with abnormalities in white matter structure. These disorders share high comorbidity and family history of OCD is a risk factor for SCZ which suggests some shared neurobiology. White matter was examined using diffusion tensor imaging in relativity large samples of SCZ (N = 48), OCD (N = 38) and non-psychiatric controls (N = 45). Fractional anisotropy (FA) was calculated and tract based spatial statistics were used to compare groups. In a whole brain analysis, SCZ and OCD both showed small FA reductions relative to controls in the corpus callosum. Both SCZ and OCD showed accelerated reductions in FA with age; specifically in the left superior longitudinal fasciculus in OCD, while the SCZ group demonstrated a more widespread pattern of FA reduction. Patient groups did not differ from each other in total FA or age effects in any regions. A general linear model using 13 a-priori regions of interest showed marginal group, group*gender, and group*age interactions. When OCD and SCZ groups were analyzed together, these marginal effects became significant (p

Heterogeneity in symptom presentation, outcomes, and treatment response has long been problematic for researchers aiming to identify biological markers of schizophrenia or psychosis. However, there is increasing recognition that there may likely be no such general illness markers, which is consistent with the notion of a group of schizophrenia(s) that may have both shared and unique neurobiological pathways. Instead, strategies aiming to capitalize on or leverage such heterogeneity may help uncover neurobiological pathways that may then be used to stratify groups of patients for prognostic purposes or for therapeutic trials. A shift toward larger sample sizes with adequate statistical power to overcome small effect sizes and disentangle the shared variance among different brain-imaging or behavioral variables has become a priority for the field. In addition, recognition that two individuals with the same clinical diagnosis may be more different from each other (at brain, genetic, and behavioral levels) than from another individual in a different disorder or nonclinical control group—coupled with computational advances—has catapulted data-driven efforts forward. Emerging challenges for this new approach include longitudinal stability of new subgroups, demonstration of validity, and replicability. The “litmus test” will be whether computational approaches that are successfully identifying groups of patients who share features in common, more than current DSM diagnostic constructs, also provide better prognostic accuracy over time and in addition lead to enhancements in treatment response and outcomes. These are the factors that matter most to patients, families, providers, and payers.

Highlights • Executive function deficit impairs functional outcome in Autism spectrum (ASD) • ASD showed normal brain activity in a working memory task but abnormal connectivity • A sub-set of the ASD group had highly variable patterns of activity • This may have implications for treatment targeting or diagnostic biotypes, Background Individuals with autism spectrum disorder (ASD) often present with executive functioning (EF) deficits, including spatial working memory (SWM) impairment, which impedes real-world functioning. The present study examined task-related brain activity, connectivity and individual variability in fMRI-measured neural response during an SWM task in older youth and young adults with autism and clinically significant EF impairment. Methods Neuroimaging was analyzed in 29 individuals with ASD without intellectual disability who had clinically significant EF impairment on the Behavior Rating Inventory of Executive Function, and 20 typically developing controls (participant age range=16-34). An SWM N-Back task was performed during fMRI. SWM activity (2-Back vs. 0-Back) and task-related dorsolateral prefrontal cortex (DLPFC) connectivity was examined within and between groups. Variability of neural response during SWM was also examined. Results During SWM performance both groups activated the expected networks, and no group differences in network activation or task-related DLPFC-connectivity were found. However, greater individual variability in the pattern of SWM activity was found in the ASD versus the typically developing control group. Conclusions While there were no group differences in SWM task-evoked activity or connectivity, fronto-parietal network engagement was found to be more variable/idiosyncratic in ASD. Our results suggest that the fronto-parietal network may be shifted or sub-optimally engaged during SWM performance in participants with ASD with clinically significant EF impairment, with implications for developing targeted interventions for this subgroup.

Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses. Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods. Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models. Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging data.

Highlights • Deep and superficial white matter structure was altered in youths with mild TBI. • Slower processing speed was associated with superficial white matter structure in TBI. • Some abnormalities were more pronounced in superficial compared to deep white matter., Background Diffusion Tensor Imaging (DTI) studies of traumatic brain injury (TBI) have focused on alterations in microstructural features of deep white matter fibers (DWM), though post-mortem studies have demonstrated that injured axons are often observed at the gray-white matter interface where superficial white matter fibers (SWM) mediate local connectivity. Objectives To examine microstructural alterations in SWM and DWM in youths with a history of mild TBI and examine the relationship between white matter alterations and attention. Methods Using DTIDWM fractional anisotropy (FA) and SWM FA in youths with mild TBI (TBI, n=63) were compared to typically developing and psychopathology matched control groups (n=63 each). Following tract-based spatial statistics, SWM FA was assessed by applying a probabilistic tractography derived SWM mask, and DWM FA was captured with a white matter fiber tract mask. Voxel-wise z-score calculations were used to derive a count of voxels with abnormally high and low FA for each participant. Analyses examined DWM and SWM FA differences between TBI and control groups, the relationship between attention and DWM and SWM FA and the relative susceptibility of SWM compared to DWM FA to alterations associated with mild TBI. Results Case-based comparisons revealed more voxels with low FA and fewer voxels with high FA in SWM in youths with mild TBI compared to both control groups. Equivalent comparisons in DWM revealed a similar pattern of results, however, no group differences for low FA in DWM were found between mild TBI and the control group with matched psychopathology. Slower processing speed on the attention task was correlated with the number of voxels with low FA in SWM in youths with mild TBI. Conclusions Within a sample of youths with a history of mild TBI, this study identified abnormalities in SWM microstructure associated with processing speed. The majority of DTI studies of TBI have focused on long-range DWM fiber tracts, often overlooking the SWM fiber type.