Dissecting the heterogeneous cortical anatomy of autism spectrum disorder using normative models

International audienceBACKGROUNDThe neuroanatomical basis of autism spectrum disorder (ASD) has remained elusive, mostly owing to high biological and clinical heterogeneity among diagnosed individuals. Despite considerable effort toward understanding ASD using neuroimaging biomarkers, heterogeneity remains a barrier, partly because studies mostly employ case-control approaches, which assume that the clinical group is homogeneous.METHODS:Here, we used an innovative normative modeling approach to parse biological heterogeneity in ASD. We aimed to dissect the neuroanatomy of ASD by mapping the deviations from a typical pattern of neuroanatomical development at the level of the individual and to show the necessity to look beyond the case-control paradigm to understand the neurobiology of ASD. We first estimated a vertexwise normative model of cortical thickness development using Gaussian process regression, then mapped the deviation of each participant from the typical pattern. For this, we employed a heterogeneous cross-sectional sample of 206 typically developing individuals (127 males) and 321 individuals with ASD (232 males) (6-31 years of age).RESULTS:We found few case-control differences, but the ASD cohort showed highly individualized patterns of deviations in cortical thickness that were widespread across the brain. These deviations correlated with severity of repetitive behaviors and social communicative symptoms, although only repetitive behaviors survived corrections for multiple testing.CONCLUSIONS:Our results 1) reinforce the notion that individuals with ASD show distinct, highly individualized trajectories of brain development and 2) show that by focusing on common effects (i.e., the "average ASD participant"), the case-control approach disguises considerable interindividual variation crucial for precision medicine

Machine Learning Methods for Structural Brain MRIs: Applications for Alzheimer’s Disease and Autism Spectrum Disorder

This thesis deals with the development of novel machine learning applications to automatically detect brain disorders based on magnetic resonance imaging (MRI) data, with a particular focus on Alzheimer’s disease and the autism spectrum disorder. Machine learning approaches are used extensively in neuroimaging studies of brain disorders to investigate abnormalities in various brain regions. However, there are many technical challenges in the analysis of neuroimaging data, for example, high dimensionality, the limited amount of data, and high variance in that data due to many confounding factors. These limitations make the development of appropriate computational approaches more challenging. To deal with these existing challenges, we target multiple machine learning approaches, including supervised and semi-supervised learning, domain adaptation, and dimensionality reduction methods.In the current study, we aim to construct effective biomarkers with sufficient sensitivity and specificity that can help physicians better understand the diseases and make improved diagnoses or treatment choices. The main contributions are 1) development of a novel biomarker for predicting Alzheimer’s disease in mild cognitive impairment patients by integrating structural MRI data and neuropsychological test results and 2) the development of a new computational approach for predicting disease severity in autistic patients in agglomerative data by automatically combining structural information obtained from different brain regions.In addition, we investigate various data-driven feature selection and classification methods for whole brain, voxel-based classification analysis of structural MRI and the use of semi-supervised learning approaches to predict Alzheimer’s disease. We also analyze the relationship between disease-related structural changes and cognitive states of patients with Alzheimer’s disease.The positive results of this effort provide insights into how to construct better biomarkers based on multisource data analysis of patient and healthy cohorts that may enable early diagnosis of brain disorders, detection of brain abnormalities and understanding effective processing in patient and healthy groups. Further, the methodologies and basic principles presented in this thesis are not only suited to the studied cases, but also are applicable to other similar problems

The cingulum as a marker of individual differences in neurocognitive development.

The canonical approach to exploring brain-behaviour relationships is to group individuals according to a phenotype of interest, and then explore the neural correlates of this grouping. A limitation of this approach is that multiple aetiological pathways could result in a similar phenotype, so the role of any one brain mechanism may be substantially underestimated. Building on advances in network analysis, we used a data-driven community-clustering algorithm to identify robust subgroups based on white-matter microstructure in childhood and adolescence (total N = 313, mean age: 11.24 years). The algorithm indicated the presence of two equal-size groups that show a critical difference in fractional anisotropy (FA) of the left and right cingulum. Applying the brain-based grouping in independent samples, we find that these different 'brain types' had profoundly different cognitive abilities with higher performance in the higher FA group. Further, a connectomics analysis indicated reduced structural connectivity in the low FA subgroup that was strongly related to reduced functional activation of the default mode network. These results provide a proof-of-concept that bottom-up brain-based groupings can be identified that relate to cognitive performance. This provides a first demonstration of a complimentary approach for investigating individual differences in brain structure and function, particularly for neurodevelopmental disorders where researchers are often faced with phenotypes that are difficult to define at the cognitive or behavioural level.The Centre for Attention Learning and Memory (CALM) research clinic is based at and supported by funding from the MRC Cognition and Brain Sciences Unit, University of Cambridge

Involvement of the habenula in the pathophysiology of autism spectrum disorder.

Funder: Fondation Brain Canada; doi: http://dx.doi.org/10.13039/100009408The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder (ASD) is characterized by social communication deficits, restricted interests, repetitive behaviors, and is frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in ASD subjects compared to controls across the entire age range studied (6-30 years). No differences were observed between sexes. Furthermore, support-vector machine modeling classified ASD with 85% accuracy (model using habenula volume, age and sex) and 64% accuracy in cross validation. The Social Responsiveness Scale (SRS) significantly differed between groups, however, it was not related to individual habenula volume. The present study is the first to provide evidence in human subjects of an involvement of the habenula in the pathophysiology of ASD

Systematic bibliometric and visualized analysis of research hotspots and trends in artificial intelligence in autism spectrum disorder

BackgroundArtificial intelligence (AI) has been the subject of studies in autism spectrum disorder (ASD) and may affect its identification, diagnosis, intervention, and other medical practices in the future. Although previous studies have used bibliometric techniques to analyze and investigate AI, there has been little research on the adoption of AI in ASD. This study aimed to explore the broad applications and research frontiers of AI used in ASD.MethodsCitation data were retrieved from the Web of Science Core Collection (WoSCC) database to assess the extent to which AI is used in ASD. CiteSpace.5.8. R3 and VOSviewer, two online tools for literature metrology analysis, were used to analyze the data.ResultsA total of 776 publications from 291 countries and regions were analyzed; of these, 256 publications were from the United States and 173 publications were from China, and England had the largest centrality of 0.33; Stanford University had the highest H-index of 17; and the largest cluster label of co-cited references was machine learning. In addition, keywords with a high number of occurrences in this field were autism spectrum disorder (295), children (255), classification (156) and diagnosis (77). The burst keywords from 2021 to 2023 were infants and feature selection, and from 2022 to 2023, the burst keyword was corpus callosum.ConclusionThis research provides a systematic analysis of the literature concerning AI used in ASD, presenting an overall demonstration in this field. In this area, the United States and China have the largest number of publications, England has the greatest influence, and Stanford University is the most influential. In addition, the research on AI used in ASD mostly focuses on classification and diagnosis, and “infants, feature selection, and corpus callosum are at the forefront, providing directions for future research. However, the use of AI technologies to identify ASD will require further research

Applications of Supervised Machine Learning in Autism Spectrum Disorder Research: A Review

Autism spectrum disorder (ASD) research has yet to leverage big data on the same scale as other fields; however, advancements in easy, affordable data collection and analysis may soon make this a reality. Indeed, there has been a notable increase in research literature evaluating the effectiveness of machine learning for diagnosing ASD, exploring its genetic underpinnings, and designing effective interventions. This paper provides a comprehensive review of 45 papers utilizing supervised machine learning in ASD, including algorithms for classification and text analysis. The goal of the paper is to identify and describe supervised machine learning trends in ASD literature as well as inform and guide researchers interested in expanding the body of clinically, computationally, and statistically sound approaches for mining ASD data

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Atypical functional connectome hierarchy in autism.

One paradox of autism is the co-occurrence of deficits in sensory and higher-order socio-cognitive processing. Here, we examined whether these phenotypical patterns may relate to an overarching system-level imbalance-specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Combining connectome gradient and stepwise connectivity analysis based on task-free functional magnetic resonance imaging (fMRI), we demonstrated atypical connectivity transitions between sensory and higher-order default mode regions in a large cohort of individuals with autism relative to typically-developing controls. Further analyses indicated that reduced differentiation related to perturbed stepwise connectivity from sensory towards transmodal areas, as well as atypical long-range rich-club connectivity. Supervised pattern learning revealed that hierarchical features predicted deficits in social cognition and low-level behavioral symptoms, but not communication-related symptoms. Our findings provide new evidence for imbalances in network hierarchy in autism, which offers a parsimonious reference frame to consolidate its diverse features