Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.

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Sex differences in brain structure: An autism twin study on restricted and repetitive behaviors

10.1101/334367 ◽

2018 ◽

Cited By ~ 3

Author(s):

Annelies van’t Westeinde ◽

Élodie Cauvet ◽

Roberto Toro ◽

Ralf Kuja-Halkola ◽

Janina Neufeld ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Sex Differences ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Brain Anatomy ◽

Social Responsiveness ◽

Autism Symptoms ◽

Twin Design ◽

Restricted And Repetitive Behaviors

AbstractFemales with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. In 75 twin pairs (n=150, 62 females, 88 males) enriched for autism spectrum disorder (n=32), and other neurodevelopmental disorders (n =32), we explored the association of restricted and repetitive behaviors and interests – operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale), with cortical volume, surface area and thickness of neocortical, sub-cortical and cerebellar networks. Cotwin control analyses revealed within-pair associations between RRBI symptoms and the right intraparietal sulcus and right orbital gyrus in females only. These findings endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.

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Adoptees’ responses to separation from, and reunion with, their adoptive parent at age 4 years is associated with long-term persistence of autism symptoms following early severe institutional deprivation

Development and Psychopathology ◽

10.1017/s0954579419000506 ◽

2019 ◽

Vol 32 (2) ◽

pp. 631-640 ◽

Cited By ~ 1

Author(s):

Edmund Sonuga-Barke ◽

Mark Kennedy ◽

Dennis Golm ◽

Nicky Knights ◽

Hanna Kovshoff ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Cognitive Impairment ◽

Social Engagement ◽

Developmental Trajectories ◽

Autism Spectrum ◽

Adoptive Parents ◽

Developmental Trajectory ◽

Spectrum Disorder ◽

Adoptive Parent ◽

Autism Symptoms

AbstractInstitutionally deprived young children often display distinctive patterns of attachment, classified as insecure/other (INS/OTH), with their adoptive parents. The associations between INS/OTH and developmental trajectories of mental health and neurodevelopmental symptoms were examined. Age 4 attachment status was determined for 97 Romanian adoptees exposed to up to 24 months of deprivation in Romanian orphanages and 49 nondeprived UK adoptees. Autism, inattention/overactivity and disinhibited-social-engagement symptoms, emotional problems, and IQ were measured at 4, 6, 11, and 15 years and in young adulthood. Romanian adoptees with over 6 months deprivation (Rom>6) were more often classified as INS/OTH than UK and Romanian adoptees with less than 6 months deprivation combined. INS/OTH was associated with cognitive impairment at age 4 years. The interaction between deprivation, attachment status, and age for autism spectrum disorder assessment was significant, with greater symptom persistence in Rom>6 INS/OTH(+) than other groups. This effect was reduced when IQ at age 4 was controlled for. Age 4 INS/OTH in Rom>6 was associated with worse autism spectrum disorder outcomes up to two decades later. Its association with cognitive impairment at age 4 is consistent with INS/OTH being an early marker of this negative developmental trajectory, rather than its cause.

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Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10120951 ◽

2020 ◽

Vol 10 (12) ◽

pp. 951

Author(s):

Alma Y. Galvez-Contreras ◽

David Zarate-Lopez ◽

Ana L. Torres-Chavez ◽

Oscar Gonzalez-Perez

Keyword(s):

Autism Spectrum Disorder ◽

Interpersonal Communication ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Abnormal Development ◽

Matter Production

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

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Altered Gray-White Matter Boundary Contrast in Toddlers at Risk for Autism Relates to Later Diagnosis of Autism Spectrum Disorder

Frontiers in Neuroscience ◽

10.3389/fnins.2021.669194 ◽

2021 ◽

Vol 15 ◽

Author(s):

Michel Godel ◽

Derek S. Andrews ◽

David G. Amaral ◽

Sally Ozonoff ◽

Gregory S. Young ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

High Risk ◽

Early Onset ◽

Brain Regions ◽

Autism Spectrum ◽

Developmental Trajectory ◽

Spectrum Disorder ◽

Typical Development ◽

Diagnostic Outcome

BackgroundRecent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD.Materials and MethodsWe used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n = 20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at 3 years of age for diagnostic outcome. Three outcome groups were defined (ASD, n = 9; typical development, n = 8; non-typical development, n = 3).ResultsASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e., prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.LimitationsOur study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples.ConclusionThese preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.

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The Causes of Individual Differences in Autism Spectrum Disorder

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v5i5.2526 ◽

2021 ◽

Vol 5 (5) ◽

pp. 86-89

Author(s):

Yufei Jin

Keyword(s):

Autism Spectrum Disorder ◽

Individual Differences ◽

Study Design ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Restricted Interests ◽

Twin Design ◽

Classical Twin Design ◽

Clinical Profiles

Autism spectrum disorder (ASD) is characterized by various symptoms including impaired social interactions, unusually repetitive behaviors, and highly restricted interests etc. People with ASD differ significantly on their clinical profiles and the causes of such individual differences are not yet fully understood. The present paper provides an overview of the causes of individual differences in ASD from three different perspectives: genetic, environmental, and neurobiological perspectives. The present paper also describes one study design in detail within each perspective (i.e., classical twin design, epidemiological case-control design, and magnetic resonance imaging), and explains how each study design is informative about the causes of ASD.

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Examining the boundary sharpness coefficient as an index of cortical microstructure and its relationship to age and sex in autism spectrum disorder

10.1101/2020.07.09.196212 ◽

2020 ◽

Author(s):

Emily Olafson ◽

Saashi Bedford ◽

Gabriel A. Devenyi ◽

Raihaan Patel ◽

Stephanie Tullo ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

Cortical Thickness ◽

Meta Analysis ◽

Inferior Frontal Gyrus ◽

Superior Temporal Gyrus ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Sharpness Coefficient

AbstractAutism 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 inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Increases were observed in different brain regions in males and females, with larger effect sizes in females. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. BSC correlated with ADOS-2 CSS in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared to cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

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Transcriptional subtyping explains phenotypic variability in genetic subtypes of autism spectrum disorder

Development and Psychopathology ◽

10.1017/s0954579420000784 ◽

2020 ◽

Vol 32 (4) ◽

pp. 1353-1361

Author(s):

Sandy Trinh ◽

Anne Arnett ◽

Evangeline Kurtz-Nelson ◽

Jennifer Beighley ◽

Marta Picoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Communication ◽

Phenotypic Variability ◽

Expression Patterns ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Phenotypic Heterogeneity ◽

Spectrum Disorder ◽

Genetic Subtypes

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication and presence of restricted, repetitive behaviors, and interests. However, individuals with ASD vary significantly in their challenges and abilities in these and other developmental domains. Gene discovery in ASD has accelerated in the past decade, and genetic subtyping has yielded preliminary evidence of utility in parsing phenotypic heterogeneity through genomic subtypes. Recent advances in transcriptomics have provided additional dimensions with which to refine genetic subtyping efforts. In the current study, we investigate phenotypic differences among transcriptional subtypes defined by neurobiological spatiotemporal co-expression patterns. Of the four transcriptional subtypes examined, participants with mutations to genes typically expressed highly in all brain regions prenatally, and those with differential postnatal cerebellar expression relative to other brain regions, showed lower cognitive and adaptive skills, higher severity of social communication deficits, and later acquisition of speech and motor milestones, compared to those with mutations to genes highly expressed during the postnatal period across brain regions. These findings suggest higher-order characterization of genetic subtypes based on neurobiological expression patterns may be a promising approach to parsing phenotypic heterogeneity among those with ASD and related neurodevelopmental disorders.

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The Parvalbumin Hypothesis of Autism Spectrum Disorder

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.577525 ◽

2020 ◽

Vol 14 ◽

Author(s):

Federica Filice ◽

Lucia Janickova ◽

Thomas Henzi ◽

Alessandro Bilella ◽

Beat Schwaller

Keyword(s):

Autism Spectrum Disorder ◽

Messenger Rna ◽

Energy Requirement ◽

Neurodevelopmental Disorder ◽

High Energy ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Supporting Evidence

The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

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Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

Nature Communications ◽

10.1038/s41467-019-13005-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 23

Author(s):

Merel C. Postema ◽

Daan van Rooij ◽

Evdokia Anagnostou ◽

Celso Arango ◽

Guillaume Auzias ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Cortical Thickness ◽

Large Scale ◽

Brain Regions ◽

Autism Spectrum ◽

Brain Asymmetry ◽

Spectrum Disorder ◽

Data Sets ◽

Control Effect ◽

Structural Brain

Abstract Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’s d = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

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Altered Gray-White Matter Boundary Contrast in Toddlers at Risk for Autism Relates to Later Diagnosis of Autism Spectrum Disorder.

10.21203/rs.3.rs-118792/v3 ◽

2021 ◽

Author(s):

Michel Godel ◽

Derek Sayre Andrews ◽

David Gil Amaral ◽

Sally Ozonoff ◽

Gregory S. Young ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

White Matter ◽

High Risk ◽

Early Onset ◽

Brain Regions ◽

Autism Spectrum ◽

Developmental Trajectory ◽

Spectrum Disorder ◽

Typical Development ◽

Diagnostic Outcome

Abstract Background: Recent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD. Methods: We used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n=20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at three years of age for diagnostic outcome. Three outcome groups were defined (ASD, n=9; typical development, n=8; non-typical development, n=3).Results: ASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e. prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.Limitations: Our study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples. Conclusion: These preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.

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