Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

Family accommodation in obsessive-compulsive disorder: An updated systematic review and meta-analysis.

Family accommodation might play a crucial role in obsessive-compulsive disorder (OCD). Previous systematic reviews on family accommodation in OCD have focused on specific populations or variables or are outdated. We conducted a preregistered systematic review and meta-analysis on family accommodation in adults, children, and adolescents with OCD (CRD42021264461). We searched PubMed, Scopus, and Web of Science using the keywords "family accommodation" and "obsessive-compulsive disorder. One hundred-eight studies involving 8928 individuals with OCD were included. Our results indicate that levels of family accommodation in OCD are moderate, that there is a significant positive correlation between family accommodation and OCD severity (r = 0.42), that baseline family accommodation does not predict pre- to post-treatment change in OCD severity (g = -0.03), and that family accommodation decreases as a result of both individual and family-focused cognitive behavioral therapy for OCD (g = 2.00 and g = 1.17, respectively). Our findings highlight the relevance of family accommodation in OCD and may help guide assessment and treatment.

Accuracy of estimating self and other body size among adolescent girls with anorexia nervosa.

This study aimed to analyze body size estimates of others by patients with anorexia nervosa (AN) and to identify any differences with the perception of their own body size. Adolescent females (age, 13-17 years) were enrolled into AN (n = 30) and control(n = 23) groups. The Subjective Body Dimensions Apparatus (SBDA) was used to evaluate body size estimates for oneself (self-estimation) and others (other-estimation). Participants also completed questionnaires assessing eating disorders and depressive symptoms. The AN and control groups scored significantly higher in self-estimation than in other-estimation. However, the AN group showed higher self-estimation scores than the control group for all the body parts and for the global silhouette (p < .001). Patients with more severe eating disorder symptomatology showed more distorted self-estimation (p < .05). No statistically significant differences were found in the other-estimation scores between the groups (p = .714), indicating that AN and control patients estimate the body sizes of others similarly. Eating disorder symptomatology correlates with self-estimation scores but not with other-estimation scores in adolescents with AN. No correlations existed between clinical symptomatology and other-estimation.

Delusional beliefs in adolescents with anorexia nervosa, obsessive-compulsive disorder, or first-episode psychosis: A comparative study.

Delusional thinking is a key symptom of first-episode psychosis (FEP), but it has also been studied in obsessive-compulsive disorder (OCD) and anorexia nervosa (AN). This study aimed to analyze the psychometric properties of the Brown Assessment of Beliefs Scale (BABS) in a sample of adolescents diagnosed with a FEP, AN, or OCD, and to compare delusional thinking among the three samples. The sample comprised 60 patients in three groups of 20 diagnosed with OCD, AN, or FEP. Participants underwent assessment by diagnostic interview, the BABS scale, and a measure of depressive symptomatology. Specific instruments were also used to assess the main symptomatology of each disorder. The BABS had good internal consistency, and high validity and reliability. The OCD group scored significantly lower than the other two groups in all scale items except for items 4 (fixation of ideas), 6 (insight), and 7 (delusions of reference). A significant difference only existed between the AN and FEP groups for item 7 (delusions of reference). The BABS scale is a valid and reliable tool for assessing delusionality in adolescents diagnosed with OCD, AN, or FEP, with evidence of marked differences between the disorders. Assessing these symptoms could influence management, helping to improve treatment adherence and prognosis.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Right Prefrontal Cortical Thickness Is Associated With Response to Cognitive-Behavioral Therapy in Children With Obsessive-Compulsive Disorder.

OBJECTIVE: Cognitive-behavioral therapy (CBT) is considered a first-line treatment for obsessive-compulsive disorder (OCD) in pediatric and adult populations. Nevertheless, some patients show partial or null response. The identification of predictors of CBT response may improve clinical management of patients with OCD. Here, we aimed to identify structural magnetic resonance imaging (MRI) predictors of CBT response in 2 large series of children and adults with OCD from the worldwide ENIGMA-OCD consortium. METHOD: Data from 16 datasets from 13 international sites were included in the study. We assessed which variations in baseline cortical thickness, cortical surface area, and subcortical volume predicted response to CBT (percentage of baseline to post-treatment symptom reduction) in 2 samples totaling 168 children and adolescents (age range 5-17.5 years) and 318 adult patients (age range 18-63 years) with OCD. Mixed linear models with random intercept were used to account for potential cross-site differences in imaging values. RESULTS: Significant results were observed exclusively in the pediatric sample. Right prefrontal cortex thickness was positively associated with the percentage of CBT response. In a post hoc analysis, we observed that the specific changes accounting for this relationship were a higher thickness of the frontal pole and the rostral middle frontal gyrus. We observed no significant effects of age, sex, or medication on our findings. CONCLUSION: Higher cortical thickness in specific right prefrontal cortex regions may be important for CBT response in children with OCD. Our findings suggest that the right prefrontal cortex plays a relevant role in the mechanisms of action of CBT in children.

Longitudinal study in adolescent anorexia nervosa: evaluation of cortico-striatal and default mode network resting-state brain circuits.

Anorexia nervosa (AN) typically emerges in adolescence. The cortico-striatal system (CSTS) and the default mode network (DMN) are brain circuits with a crucial development during this period. These circuits underlie cognitive functions that are impaired in AN, such as cognitive flexibility and inhibition, among others. Little is known about their involvement in adolescent AN and how weight and symptom improvement might modulate potential alterations in these circuits. Forty-seven adolescent females (30 AN, 17 healthy control) were clinically/neuropsychologically evaluated and scanned during a 3T-MRI resting-state session on two occasions, before and after a 6-month multidisciplinary treatment of the AN patients. Baseline and baseline-to-follow-up between-group differences in CSTS and DMN resting-state connectivity were evaluated, as well as their association with clinical/neuropsychological variables. Increased connectivity between the left dorsal putamen and the left precuneus was found in AN at baseline. At follow-up, body mass index and clinical symptoms had improved in the AN group. An interaction effect was found in the connectivity between the right dorsal caudate to right mid-anterior insular cortex, with lower baseline AN connectivity that improved at follow-up; this improvement was weakly associated with changes in neuropsychological (Stroop test) performance. These results support the presence of CSTS connectivity alterations in adolescents with AN, which improve with weight and symptom improvement. In addition, at the level of caudate-insula connectivity, they might be associated with inhibitory processing performance. Alterations in CSTS pathways might be involved in AN from the early stages of the disorder.

Symptom Dimension Breakpoints for the Obsessive-Compulsive Inventory-Child Version (OCI-CV).

Pediatric obsessive-compulsive disorder (OCD) clusters around three major symptom dimensions: contamination/cleaning, symmetry/ordering, and disturbing thoughts/checking. The Obsessive-Compulsive Inventory-Child Version (OCI-CV) is a self-report questionnaire that provides scores along six theory-based OCD dimensions, but no study has evaluated how well OCI-CV identifies clinically significant symptoms within each of the three major symptom dimensions of OCD. We examined this question using data from 197 Swedish and Spanish youth with OCD. All youth completed the OCI-CV and clinically significant symptom severity within each major OCD dimension was established with a validated interview-based measure. Results showed that a score ≥ 3 on the OCI-CV washing scale excellently captured those with clinically significant contamination/cleaning symptoms (AUC = 0.85 [0.80-0.90], 79% accuracy). A score ≥ 4 on the obsessing scale adequately captured those with disturbing thoughts/checking symptoms (AUC = 0.71 [0.64-0.78], 67% accuracy) and a score ≥ 3 on the ordering scale adequately captured those with symmetry/ordering symptoms (AUC = 0.72 [0.65-0.79], 70% accuracy). Similar accuracy of the breakpoints was found in the Swedish and Spanish samples. OCI-CV works well to identify youth with pediatric OCD that have clinically significant contamination/cleaning symptoms. The measure can also with adequate precision identify those with clinically significant disturbing thoughts/checking and symmetry/ordering symptoms. The breakpoints provided in this study can be used to examine differences in clinical presentation and treatment outcome for youth with different types of OCD.

Upward trends in eating disorders, self-harm, and suicide attempt emergency admissions in female adolescents after COVID-19 lockdown.

INTRODUCTION: Increased mental health problems have been reported in children and adolescents related to the COVID-19 lockdown and its immediate aftermath, especially among adolescent females. However, the longer-term impact of persistent quarantine measures and social restrictions on this population is yet to be further explored. MATERIALS AND METHODS: We compared the number of children/adolescents admissions to the psychiatric emergency department (ED) of Hospital Clínic de Barcelona during the COVID-19 lockdown and the following year with the numbers of admissions the year before lockdown, adjusting for variations in the population. We also conducted separate analyses by gender, age group, and diagnostic categories. Finally, we also repeated the analyses considering the cumulated deficit/excess since the start of the lockdown. Statistical significance was estimated using binomial tests with Bonferroni correction. RESULTS: A total of 2425 admissions were recorded. Globally, admission rates decreased during the lockdown (46%) and progressively increased during the one-year aftermath (43% by spring 2021). This increase was particularly high in adolescent females (85%) while unclear in children and/or males. The main diagnostic categories involved were anxiety, depressive, and eating disorders, as well as self-harm behavior, suicidal ideation, and suicide attempts. The increase in eating disorders, self-harm behavior, and suicide attempts admissions in female adolescents remained statistically significant when considering the cumulated deficit/excess. CONCLUSIONS: We found increased ED admissions during the aftermath of the COVID-19 lockdown among adolescent females. We recommend strengthening the attention to this population to provide adequate specialized care and prevention strategies.

Psychopathology and mental health service use among youth in foster care admitted to a psychiatric inpatient unit: a 4-year retrospective controlled study.

Youth in foster care (FC) are at increased risk of poor psychosocial outcomes. The aim of this study was to assess psychopathology and mental health service use among youth living in FC who require psychiatric hospitalisation. All individuals admitted to our Children and Adolescent Inpatient Psychiatry Unit between 2014 and 2017 who were in FC were systematically reviewed. The control group was defined as all youth living with their immediate family and hospitalised in our unit throughout 2016. We identified 89 patients placed in FC and 247 controls. Socio-demographic and clinical data were retrospectively collected from computerised charts. A survival analysis of emergency department visits and readmission to the hospital was conducted. Compared to controls, the FC group presented significantly higher rates of conduct disorder (78.7% vs 14.6%; p < 0.001) and substance use disorder (49.4% vs 27.5%; p < 0.001), mainly cannabis use (34.8% vs 16.6%; p < 0.001); higher rates of comorbidity (96.6% vs 55.9%; p < 0.001) and mean number of comorbid diagnoses (3.3 ± 1.1 vs 2.3 ± 0.5; p < 0.001). The FC group had a higher number of emergency room visits before and after admission than controls. FC youth were also 2.77 times more likely to visit the emergency department after discharge, and in a shorter time period, than controls (p = 0.004). Disruptive behaviours, substance use disorder, and comorbid psychopathology were all more prevalent among FC youth than controls. Specific strategies are needed to optimize community mental health resources and address the increased use of emergency services by these youth before and after hospitalisation.

Radiological findings in brain MRI scans in youth with early-onset psychosis: A controlled study.

There is a lack of consensus on whether routine brain magnetic resonance imaging (MRI) should be recommended as part of the initial assessment in patients with psychosis. No study so far has qualitatively assessed brain MRI in patients with early-onset psychosis (EOP), in whom neurodevelopmental factors may play a stronger role. We aimed to determine the prevalence of brain MRI findings in patients with EOP compared to healthy controls, and assess whether these findings were clinically relevant. Retrospective clinical chart review of all patients with EOP in whom a brain MRI scan was acquired during admission to an inpatient child and adolescent psychiatry unit during January 2013-December 2017, compared to age and biologically assigned gender matched healthy controls. Between group analyses tested differences in rates of qualitatively abnormal MRI scans and changes in clinical management as a result of radiological findings. A total of 256 individuals were included (128 patients with EOP and 128 healthy controls). Patients with EOP presented with a significantly higher rate of abnormal MRI scans relative to healthy controls (21.9% vs 11.7%, p = .030; OR = 2.11, [95% CI:1.06-4.17]). Radiological findings in the EOP group triggered clinical referral for further evaluation or management more often than in the healthy control group (7.0% vs 1.6%, p = .030; OR = 4.76, [95% CI:1.01-22.50]). MRI scans in youth with EOP may be characterized by an increased number of radiological abnormalities than in controls. The rates of MRI findings requiring clinical referral suggests that routine MRI acquisition may need to be considered in patients with EOP.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

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.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

NRN1 Gene as a Potential Marker of Early-Onset Schizophrenia: Evidence from Genetic and Neuroimaging Approaches.

Included in the neurotrophins family, the Neuritin 1 gene (NRN1) has emerged as an attractive candidate gene for schizophrenia (SZ) since it has been associated with the risk for the disorder and general cognitive performance. In this work, we aimed to further investigate the association of NRN1 with SZ by exploring its role on age at onset and its brain activity correlates. First, we developed two genetic association analyses using a family-based sample (80 early-onset (EO) trios (offspring onset ≤ 18 years) and 71 adult-onset (AO) trios) and an independent case-control sample (120 healthy subjects (HS), 87 EO and 138 AO patients). Second, we explored the effect of NRN1 on brain activity during a working memory task (N-back task; 39 HS, 39 EO and 39 AO; matched by age, sex and estimated IQ). Different haplotypes encompassing the same three Single Nucleotide Polymorphisms(SNPs, rs3763180-rs10484320-rs4960155) were associated with EO in the two samples (GCT, TCC and GTT). Besides, the GTT haplotype was associated with worse N-back task performance in EO and was linked to an inefficient dorsolateral prefrontal cortex activity in subjects with EO compared to HS. Our results show convergent evidence on the NRN1 association with EO both from genetic and neuroimaging approaches, highlighting the role of neurotrophins in the pathophysiology of SZ.

Functional impairment in a Spanish Sample of Children and Adolescents with Obsessive-Compulsive Disorder.

The Child Obsessive-Compulsive Impact Scale (COIS-R) is a parent- and self-report measure of the impairment related to Obsessive-Compulsive Disorder (OCD) symptoms. Previous research has demonstrated the reliability and validity of the original version of the COIS-R; to date, however, the scale has not been validated for use in Spanish samples of pediatric OCD. The present study aimed to assess the psychometric properties of this in a clinical sample of pediatric OCD (n = 91). Analyses of internal consistency, convergent and divergent validity were conducted. For both the COIS-R report scales estimates similar to those in the original instrument were obtained for internal consistency, test-retest reliability, and convergent validity. Thus, the Spanish version of the COIS-R seems to retain sound psychometric properties of its original version; it appears to be a reliable instrument for the assessment of obsessive-compulsive impairment and the effects of treatment, and can be used in other cultural contexts.

Gene expression study in monocytes: evidence of inflammatory dysregulation in early-onset obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) has a complex etiology that seems to include immune dysfunction and alterations in circulating monocytes. To investigate the immune basis and the functional dysregulation of monocytes in this disease, we analyzed gene expression in the peripheral monocytes of pediatric patients with OCD (N = 102) compared to controls (N = 47). We examined gene expression in primary cultures of peripheral monocytes from participants, under basal conditions and under exposure to lipopolysaccharide (LPS) to stimulate immune response. Whole-genome expression was assessed in 8 patients and 8 controls. Differentially expressed genes were identified followed by protein-protein interaction network construction and functional annotation analysis to identify the genes and biological processes that are altered in the monocytes of OCD patients. We also explored the expression levels of selected genes in monocytes from the other participants using qPCR. Several changes in gene expression were observed in the monocytes of OCD patients, with several immune processes involved under basal conditions (antigen processing and presentation, regulation of immune system and leukocyte cell adhesion) and after LPS stimulation (immune and inflammatory response, cytokine production and leukocyte activation). Despite the qPCR analysis provided no significant differences between patients and controls, high correlations were observed between the expression levels of some of the genes and inflammatory markers (i.e., T helper 17 and regulatory T cell levels, total monocyte and proinflammatory monocyte subset levels, and the cytokine production by resting and stimulated monocytes) of the study participants. Our findings provide more evidence of the involvement of monocyte dysregulation in early-onset OCD, indicating a proinflammatory predisposition and an enhanced immune response to environmental triggers.

The thalamus and its subnuclei-a gateway to obsessive-compulsive disorder.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.