Meng-Chuan Lai | University of Toronto (original) (raw)

Papers by Meng-Chuan Lai

Human Brain Mapping, 2020

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompani... more Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompanied by neuroanatomical differences on the macroscopic and microscopic level. Findings from histological, genetic, and more recently in vivo neuroimaging studies converge in suggesting that neuroanatomical abnormalities, specifically around the gray-white matter (GWM) boundary, represent a crucial feature of ASD. However, no research has yet characterized the GWM boundary in ASD based on measures of diffusion. Here, we registered diffusion tensor imaging data to the structural T1-weighted images of 92 adults with ASD and 92 matched neurotypical controls in order to examine between-group differences and group-by-sex interactions in fractional anisotropy and mean diffusivity sampled at the GWM boundary, and at different sampling depths within the superficial white and into the gray matter. As hypothesized, we observed atypical diffusion at and around the GWM boundary in ASD, with between-group differences and group-by-sex interactions depending on tissue class and sampling depth. Furthermore, we identified that altered diffusion at

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

BackgroundReward processing has been proposed to underpin atypical social behavior, a core featur... more BackgroundReward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.MethodsFunctional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).ResultsAcross social and monetary reward anticipation, whole-brain analyses (p<0.05, family-wise error-corrected) showed hypoactivation of the right ventral striatum (VS) in ASD. Further, region of interest (ROI) analysis across both reward types yielded hypoactivation in ASD in both the left and right VS. Across delivery...

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenot... more Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multi-center magnetic resonance structural imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male) and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferio...

Background: There is a growing recognition of sex and gender influences in autism. Increasingly, ... more Background: There is a growing recognition of sex and gender influences in autism. Increasingly, studies include comparisons between sexes or genders, but few have focused on clarifying the characteristics of autistic girls' and women's physical health. Methods: A scoping review was conducted to determine what is currently known about the physical health of autistic girls and women. We screened 1,112 unique articles, with 40 studies meeting the inclusion criteria. We used a convergent iterative process to synthesize this content into broad thematic areas. Results: Overall, autistic girls and women experience more physical health challenges compared to non-autistic girls and women, and to autistic boys and men. Preliminary evidence suggests increased neurological conditions (e.g., epilepsy) in autistic girls and women compared to autistic boys and men. As well, the literature suggests increased endocrine/reproductive conditions in autistic girls and women compared to non-auti...

BackgroundMarked sex differences in autism prevalence accentuate the need to understand the role ... more BackgroundMarked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.MethodsWe addressed this gap by using the largest sample of male and female autistic and neurotypical (NT) control individuals, to date (ABIDE; Autism: 362 males, 82 females; NT: 410 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics.Secondary analyses assessed the robustness of primary results to different pre-processing approaches and their replicability in two independent samples, the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).ResultsDiscovery analyses in ABIDE revealed significant ma...

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperac... more 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 determin...

Imbalance between neurophysiological excitation versus inhibition (E:I) has been theorized as a p... more Imbalance between neurophysiological excitation versus inhibition (E:I) has been theorized as a pathophysiological mechanism of autism. However, a majority of the evidence behind the E:I theory comes from animal models of rare genetic mutations that account for only a small fraction of the autistic population. Scale-free metrics of neural time-series data could represent biomarkers for E:I imbalance and could enable a greater understanding of how E:I imbalance affects different types of autistic individuals and how such mechanisms relate to behavior. Here we show that a measure of scale-free dynamics, the Hurst exponent (H), measured in-vivo in resting state fMRI (rsfMRI) data, is a surrogate marker of E:I imbalance and differentially affects autistic males versus females. In-silico modeling of local field potentials (LFP) from recurrent networks of interacting excitatory and inhibitory neurons shows that increasing the E:I ratio by specifically enhancing excitation attenuates H and...

Brain Stimulation, 2020

Background: In youth and young adults with autism spectrum disorder (ASD), executive function (EF... more 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 16e35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n ¼ 20 active/n ¼ 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.

Autism is both a medical condition that can give rise to disability and an example of human neuro... more Autism is both a medical condition that can give rise to disability and an example of human neurological variation (‘neurodiversity’) that contributes to identity, with cognitive assets and challenges. We refer to this as the dual nature of autism. Enhancing adaptation and wellbeing is the ultimate goal for intervention/support. Evidence-based support for autistic people across the lifespan is emerging. Support should be collaborative between autistic individuals, their families, and service providers, taking a shared decision-making approach. To maximize the individual’s potential, comprehensive early intervention and parent-mediated intervention, ideally taking a naturalistic approach, may help support the early development of adaptive, cognitive and language skills. Targeted intervention of social skills and aspects of cognition may help but challenges remain for behavioural flexibility and generalisation to different contexts. To minimize barriers for an individual’s development...

Autism : the international journal of research and practice, Jan 24, 2018

Prior work has revealed sex/gender-dependent autistic characteristics across behavioural and neur... more Prior work has revealed sex/gender-dependent autistic characteristics across behavioural and neural/biological domains. It remains unclear whether and how neural sex/gender differences are related to behavioural sex/gender differences in autism. Here, we examined whether atypical neural responses during mentalizing and self-representation are sex/gender-dependent in autistic adults and explored whether 'camouflaging' (acting as if behaviourally neurotypical) is associated with sex/gender-dependent neural responses. In total, N = 119 adults (33 typically developing males, 29 autistic males, 29 typically developing females and 28 autistic females) participated in a task-related functional magnetic resonance imaging paradigm to assess neural activation within right temporo-parietal junction and ventromedial prefrontal cortex during mentalizing and self-representation. Camouflaging in autism was quantified as the discrepancy between extrinsic behaviour in social-interpersonal co...

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2018

Background: Resting-state fMRI-based studies on functional connectivity in autism spectrum disord... more Background: Resting-state fMRI-based studies on functional connectivity in autism spectrum disorder (ASD) have generated inconsistent results. Interpretation of findings is further hampered by small samples and a focus on a limited number of networks, with networks underlying sensory processing largely under-examined. We aimed to comprehensively characterize ASD-related alterations within and between 20 well-characterized resting-state networks using baseline-data from the EU-AIMS Longitudinal European Autism Project. Methods: Resting-state fMRI data was available for 265 individuals with ASD (7.5-30.3 years; 73.2% male) and 218 typically developing (TD) individuals (6.9-29.8 years; 64.2% male), all with IQ>70. We compared functional connectivity within 20 networks-obtained using independent component analysis-between the ASD and TD group, and related functional connectivity within these networks to continuous (overall) autism trait severity scores derived from the Social Responsiveness Scale-2 across all participants. Furthermore, we investigated case-control differences and autism trait-related alterations in between-network connectivity. Results: Higher autism traits were associated with increased connectivity within salience, medial motor, and orbitofrontal networks. However, we did not replicate previously reported case-control differences within these networks. The between-network analysis did reveal case-control differences showing on average 1) decreased connectivity of the visual association network with somatosensory, medial and lateral motor networks, and 2) increased connectivity of the cerebellum with these sensory and motor networks in ASD compared to TD. Conclusions: We demonstrate ASD-related alterations in within and between-network connectivity. The between-network alterations broadly affect connectivity between cerebellum, visual, and sensorymotor networks, potentially underlying impairments in multisensory and visual-motor integration frequently observed in ASD.

Journal of autism and developmental disorders, Jan 25, 2018

There currently exist no self-report measures of social camouflaging behaviours (strategies used ... more There currently exist no self-report measures of social camouflaging behaviours (strategies used to compensate for or mask autistic characteristics during social interactions). The Camouflaging Autistic Traits Questionnaire (CAT-Q) was developed from autistic adults' experiences of camouflaging, and was administered online to 354 autistic and 478 non-autistic adults. Exploratory factor analysis suggested three factors, comprising of 25 items in total. Good model fit was demonstrated through confirmatory factor analysis, with measurement invariance analyses demonstrating equivalent factor structures across gender and diagnostic group. Internal consistency (α = 0.94) and preliminary test-retest reliability (r = 0.77) were acceptable. Convergent validity was demonstrated through comparison with measures of autistic traits, wellbeing, anxiety, and depression. The present study provides robust psychometric support for the CAT-Q.

Molecular autism, 2018

The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research ... more The male predominance in the prevalence of autism spectrum disorder (ASD) has motivated research on sex differentiation in ASD. Multiple sources of evidence have suggested a neurophenotypic convergence of ASD-related characteristics and typical sex differences. Two existing, albeit competing, models provide predictions on such neurophenotypic convergence. These two models are testable with neuroimaging. Specifically, the Extreme Male Brain (EMB) model predicts that ASD is associated with enhanced brain maleness in both males and females with ASD (i.e., a shift-towards-maleness). In contrast, the Gender Incoherence (GI) model predicts a shift-towards-maleness in females, yet a shift-towards-femaleness in males with ASD. To clarify whether either model applies to the intrinsic functional properties of the brain in males with ASD, we measured the statistical overlap between typical sex differences and ASD-related atypicalities in resting-state fMRI (R-fMRI) datasets largely available i...

Journal of autism and developmental disorders, Jan 7, 2017

We developed a brief, informant-report interview for assessing autism spectrum conditions (ASC) i... more We developed a brief, informant-report interview for assessing autism spectrum conditions (ASC) in adults, called the Developmental, Dimensional and Diagnostic Interview-Adult Version (3Di-Adult); and completed a preliminary evaluation. Informant reports were collected for participants with ASC (n = 39), a non-clinical comparison group (n = 29) and a clinical comparison group (n = 20) who had non-autistic mental health conditions. Mean administration time was 38 min (50 min for ASC). Internal consistency (αs ≥ 0.93) and inter-rater agreement (ICCs ≥ 0.99) were high. When discriminating ASC from non-ASC, the 3Di-Adult showed excellent sensitivity (95%) and specificity (92%). The 3Di-Adult shows promise as a psychometrically sound and time-efficient interview for collecting standardised informant reports for DSM-5 assessments of ASC in adults, in research and clinical practice.

Molecular autism, 2017

The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, mult... more The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on...

Journal of autism and developmental disorders, Aug 19, 2017

Camouflaging of autistic characteristics in social situations is hypothesised as a common social ... more Camouflaging of autistic characteristics in social situations is hypothesised as a common social coping strategy for adults with autism spectrum conditions (ASC). Camouflaging may impact diagnosis, quality of life, and long-term outcomes, but little is known about it. This qualitative study examined camouflaging experiences in 92 adults with ASC, with questions focusing on the nature, motivations, and consequences of camouflaging. Thematic analysis was used to identify key elements of camouflaging, which informed development of a three-stage model of the camouflaging process. First, motivations for camouflaging included fitting in and increasing connections with others. Second, camouflaging itself comprised a combination of masking and compensation techniques. Third, short- and long-term consequences of camouflaging included exhaustion, challenging stereotypes, and threats to self-perception.

JAMA psychiatry, Apr 1, 2017

Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female ind... more Autism spectrum disorder (ASD) is 2 to 5 times more common in male individuals than in female individuals. While the male preponderant prevalence of ASD might partially be explained by sex differences in clinical symptoms, etiological models suggest that the biological male phenotype carries a higher intrinsic risk for ASD than the female phenotype. To our knowledge, this hypothesis has never been tested directly, and the neurobiological mechanisms that modulate ASD risk in male individuals and female individuals remain elusive. To examine the probability of ASD as a function of normative sex-related phenotypic diversity in brain structure and to identify the patterns of sex-related neuroanatomical variability associated with low or high probability of ASD. This study examined a cross-sectional sample of 98 right-handed, high-functioning adults with ASD and 98 matched neurotypical control individuals aged 18 to 42 years. A multivariate probabilistic classification approach was used ...

Cerebral cortex (New York, N.Y. : 1991), Feb 4, 2017

Atypical cortical organization and reduced integrity of the gray-white matter boundary have been ... more Atypical cortical organization and reduced integrity of the gray-white matter boundary have been reported by postmortem studies in individuals with autism spectrum disorder (ASD). However, there are no in vivo studies that examine these particular features of cortical organization in ASD. Hence, we used structural magnetic resonance imaging to examine differences in tissue contrast between gray and white matter in 98 adults with ASD and 98 typically developing controls, to test the hypothesis that individuals with ASD have significantly reduced tissue contrast. More specifically, we examined contrast as a percentage between gray and white matter tissue signal intensities (GWPC) sampled at the gray-white matter boundary, and across different cortical layers. We found that individuals with ASD had significantly reduced GWPC in several clusters throughout the cortex (cluster, P < 0.05). As expected, these reductions were greatest when tissue intensities were sampled close to gray-wh...

Autism : the international journal of research and practice, Aug 29, 2016

Autobiographical descriptions and clinician observations suggest that some individuals with autis... more Autobiographical descriptions and clinician observations suggest that some individuals with autism, particularly females, 'camouflage' their social communication difficulties, which may require considerable cognitive effort and lead to increased stress, anxiety and depression. Using data from 60 age- and IQ-matched men and women with autism (without intellectual disability), we operationalized camouflaging in adults with autism for the first time as the quantitative discrepancy between the person's 'external' behavioural presentation in social-interpersonal contexts (measured by the Autism Diagnostic Observation Schedule) and the person's 'internal' status (dispositional traits measured by the Autism Spectrum Quotient and social cognitive capability measured by the 'Reading the Mind in the Eyes' Test). We found that the operationalized camouflaging measure was not significantly correlated with age or IQ. On average, women with autism had highe...