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Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models.

ABSTRACT: BACKGROUND:The 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.

SUBMITTER: Zabihi M

PROVIDER: S-EPMC6551348 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models.

Zabihi Mariam M Oldehinkel Marianne M Wolfers Thomas T Frouin Vincent V Goyard David D Loth Eva E Charman Tony T Tillmann Julian J Banaschewski Tobias T Dumas Guillaume G Holt Rosemary R Baron-Cohen Simon S Durston Sarah S Bölte Sven S Murphy Declan D Ecker Christine C Buitelaar Jan K JK Beckmann Christian F CF Marquand Andre F AF

Biological psychiatry. Cognitive neuroscience and neuroimaging 20181219 6

<h4>Background</h4>The 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.<h4>Methods</h4>Here, we used an innovative normative modeling approach to parse ...[more]

PMID: 30799285

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Project description:Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys (<=14 years), male adolescents (15-22 years), and adult men (> = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.

Project description:Importance:Schizophrenia and bipolar disorder are severe and complex brain disorders characterized by substantial clinical and biological heterogeneity. However, case-control studies often ignore such heterogeneity through their focus on the average patient, which may be the core reason for a lack of robust biomarkers indicative of an individual's treatment response and outcome. Objectives:To investigate the degree to which case-control analyses disguise interindividual differences in brain structure among patients with schizophrenia and bipolar disorder and to map the brain alterations linked to these disorders at the level of individual patients. Design, Setting, and Participants:This study used cross-sectional, T1-weighted magnetic resonance imaging data from participants recruited for the Thematically Organized Psychosis study from October 27, 2004, to October 17, 2012. Data were reanalyzed in 2017 and 2018. Patients were recruited from inpatient and outpatient clinics in the Oslo area of Norway, and healthy individuals from the same catchment area were drawn from the national population registry. Main Outcomes and Measures:Interindividual differences in brain structure among patients with schizophrenia and bipolar disorder. Voxel-based morphometry maps were computed, which were used for normative modeling to map the range of interindividual differences in brain structure. Results:This study included 218 patients with schizophrenia spectrum disorders (mean [SD] age, 30 [9.3] years; 126 [57.8%] male), of whom 163 had schizophrenia (mean [SD] age, 31 [8.7] years; 105 [64.4%] male) and 190 had bipolar disorder (mean [SD] age, 34 [11.3] years; 79 [41.6%] male), and 256 healthy individuals (mean [SD] age, 34?[9.5] years; 140 [54.7%] male). At the level of the individual, deviations from the normative model were frequent in both disorders but highly heterogeneous. Overlap of more than 2% among patients was observed in only a few loci, primarily in frontal, temporal, and cerebellar regions. The proportion of alterations was associated with diagnosis and cognitive and clinical characteristics within clinical groups. Patients with schizophrenia, on average, had significantly reduced gray matter in frontal regions, cerebellum, and temporal cortex. In patients with bipolar disorder, mean deviations were primarily present in cerebellar regions. Conclusions and Relevance:This study found that group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient. This study presents a workable route toward precision medicine in psychiatry.

Project description:Autism spectrum disorder is associated with an altered early brain development. However, the specific cortical structure abnormalities underlying this disorder remain largely unknown. Nonetheless, atypical cortical folding provides lingering evidence of early disruptions in neurodevelopmental processes and identifying changes in the geometry of cortical sulci is of primary interest for characterizing these structural abnormalities in autism and their evolution over the first stages of brain development. Here, we applied state-of-the-art sulcus-based morphometry methods to a large highly-selective cohort of 73 young male children of age spanning from 18 to 108 months. Moreover, such large cohort was selected through extensive behavioral assessments and stringent inclusion criteria for the group of 59 children with autism. After manual labeling of 59 different sulci in each hemisphere, we computed multiple shape descriptors for each single sulcus element, hereby separating the folding measurement into distinct factors such as the length and depth of the sulcus. We demonstrated that the central, intraparietal and frontal medial sulci showed a significant and consistent pattern of abnormalities across our different geometrical indices. We also found that autistic and control children exhibited strikingly different relationships between age and structural changes in brain morphology. Lastly, the different measures of sulcus shapes were correlated with the CARS and ADOS scores that are specific to the autistic pathology and indices of symptom severity. Inherently, these structural abnormalities are confined to regions that are functionally relevant with respect to cognitive disorders in ASD. In contrast to those previously reported in adults, it is very unlikely that these abnormalities originate from general compensatory mechanisms unrelated to the primary pathology. Rather, they most probably reflect an early disruption on developmental trajectory that could be part of the primary pathology.

Project description:Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

Project description:Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers' germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

Dataset Information

Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models.

Publications

Dissecting the Heterogeneous Cortical Anatomy of Autism Spectrum Disorder Using Normative Models.

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