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  • 1
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    Online Resource
    Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry
    Springer Science and Business Media LLC ; 2021
    In:  Communications Biology Vol. 4, No. 1 ( 2021-05-14)
    Details
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2021-05-14)
    Abstract: Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC  〉  RRB, and RRB  〉  SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset ( n  = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC  〉  RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    URL: Article
    DOI: 10.1038/s42003-021-02015-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 2
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    Altered Connectivity Between Cerebellum, Visual, and Sensory-Motor Networks in Autism Spectrum Disorder: Results from the EU-AIMS Longitudinal European Autism Project
    Elsevier BV ; 2019
    In:  Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Vol. 4, No. 3 ( 2019-03), p. 260-270
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    In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Elsevier BV, Vol. 4, No. 3 ( 2019-03), p. 260-270
    Type of Medium: Online Resource
    ISSN: 2451-9022
    URL: Article
    DOI: 10.1016/j.bpsc.2018.11.010
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2879089-3
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  • 3
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    Dissecting the phenotypic heterogeneity in sensory features in autism spectrum disorder: a factor mixture modelling approach
    Springer Science and Business Media LLC ; 2020
    In:  Molecular Autism Vol. 11, No. 1 ( 2020-12)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-12)
    Abstract: Heterogeneity in the phenotypic presentation of autism spectrum disorder (ASD) is apparent in the profile and the severity of sensory features. Here, we applied factor mixture modelling (FMM) to test a multidimensional factor model of sensory processing in ASD. We aimed to identify homogeneous sensory subgroups in ASD that differ intrinsically in their severity along continuous factor scores. We also investigated sensory subgroups in relation to clinical variables: sex, age, IQ, social-communication symptoms, restricted and repetitive behaviours, adaptive functioning and symptoms of anxiety and attention-deficit/hyperactivity disorder. Methods Three hundred thirty-two children and adults with ASD between the ages of 6 and 30 years with IQs varying between 40 and 148 were included. First, three different confirmatory factor models were fit to the 38 items of the Short Sensory Profile (SSP). Then, latent class models (with two-to-six subgroups) were evaluated. The best performing factor model, the 7-factor structure, was subsequently used in two FMMs that varied in the number of subgroups: a two-subgroup, seven-factor model and a three-subgroup and seven-factor model. Results The ‘three-subgroup/seven-factor’ FMM was superior to all other models based on different fit criteria. Identified subgroups differed in sensory severity from severe, moderate to low. Accounting for the potential confounding effects of age and IQ, participants in these sensory subgroups had different levels of social-communicative symptoms, restricted and repetitive behaviours, adaptive functioning skills and symptoms of inattention and anxiety. Limitations Results were derived using a single parent-report measure of sensory features, the SSP, which limits the generalisability of findings. Conclusion Sensory features can be best described by three homogeneous sensory subgroups that differ in sensory severity gradients along seven continuous factor scores. Identified sensory subgroups were further differentiated by the severity of core and co-occurring symptoms, and level of adaptive functioning, providing novel evidence on the associated clinical correlates of sensory subgroups. These sensory subgroups provide a platform to further interrogate the neurobiological and genetic correlates of altered sensory processing in ASD.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-020-00367-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 4
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    Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers
    Springer Science and Business Media LLC ; 2021
    In:  Molecular Autism Vol. 12, No. 1 ( 2021-12)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-12)
    Abstract: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. Methods Eye-tracking data were collected from 486 6-to-30-year-old autistic ( N  = 282) and non-autistic control ( N  = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). Results The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. Limitations The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. Conclusions Biological motion preference elicits small-to-medium-sized case–control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-021-00476-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 5
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    Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis
    Springer Science and Business Media LLC ; 2022
    In:  Molecular Autism Vol. 13, No. 1 ( 2022-12)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-12)
    Abstract: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. Methods We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2–32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults ( n  = 212 ASD, n  = 199 neurotypicals [NT], all with IQ  〉  75). We performed analyses in source-space using individual head models derived from the participants’ MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%–30% split). Results In the training dataset, we found an interaction between age and group for the reactivity to eye opening ( p  = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52–0.62, specificity 0.59–0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. Limitations The statistical power to detect weak effects—of the magnitude of those found in the training dataset—in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset’s effects. Conclusions This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-022-00500-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 6
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    Sensory salience processing moderates attenuated gazes on faces in autism spectrum disorder: a case–control study
    Springer Science and Business Media LLC ; 2023
    In:  Molecular Autism Vol. 14, No. 1 ( 2023-02-09)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-02-09)
    Abstract: Attenuated social attention is a key marker of autism spectrum disorder (ASD). Recent neuroimaging findings also emphasize an altered processing of sensory salience in ASD. The locus coeruleus–norepinephrine system (LC-NE) has been established as a modulator of this sensory salience processing (SSP). We tested the hypothesis that altered LC-NE functioning contributes to different SSP and results in diverging social attention in ASD. Methods We analyzed the baseline eye-tracking data of the EU-AIMS Longitudinal European Autism Project (LEAP) for subgroups of autistic participants ( n  = 166, age = 6–30 years, IQ = 61–138, gender [female/male] = 41/125) or neurotypical development (TD; n  = 166, age = 6–30 years, IQ = 63–138, gender [female/male] = 49/117) that were matched for demographic variables and data quality. Participants watched brief movie scenes ( k  = 85) depicting humans in social situations (human) or without humans (non-human). SSP was estimated by gazes on physical and motion salience and a corresponding pupillary response that indexes phasic activity of the LC-NE. Social attention is estimated by gazes on faces via manual areas of interest definition. SSP is compared between groups and related to social attention by linear mixed models that consider temporal dynamics within scenes. Models are controlled for comorbid psychopathology, gaze behavior, and luminance. Results We found no group differences in gazes on salience, whereas pupillary responses were associated with altered gazes on physical and motion salience. In ASD compared to TD, we observed pupillary responses that were higher for non-human scenes and lower for human scenes. In ASD, we observed lower gazes on faces across the duration of the scenes. Crucially, this different social attention was influenced by gazes on physical salience and moderated by pupillary responses. Limitations The naturalistic study design precluded experimental manipulations and stimulus control, while effect sizes were small to moderate. Covariate effects of age and IQ indicate that the findings differ between age and developmental subgroups. Conclusions Pupillary responses as a proxy of LC-NE phasic activity during visual attention are suggested to modulate sensory salience processing and contribute to attenuated social attention in ASD.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-023-00537-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 7
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    Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project
    Springer Science and Business Media LLC ; 2020
    In:  Molecular Autism Vol. 11, No. 1 ( 2020-12)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-12)
    Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the “social brain,” a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD. Methods As part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD ( N = 205) and typically developing (TD) individuals ( N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits. Results We observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders. Conclusions Contrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-020-0317-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 8
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    Patterns of connectome variability in autism across five functional activation tasks: findings from the LEAP project
    Springer Science and Business Media LLC ; 2022
    In:  Molecular Autism Vol. 13, No. 1 ( 2022-12-27)
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    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-12-27)
    Abstract: Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioral, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterize heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with a varied array of cognitive tasks. Methods All analyses were based on the EU-AIMS/AIMS-2-TRIALS multisite Longitudinal European Autism Project (LEAP) with participants with autism ( n  = 282) and typically developing (TD) controls ( n  = 221) between 6 and 30 years of age. We employed a novel task potency approach which combines the unique aspects of both resting state fMRI and task-fMRI to quantify task-induced variations in the functional connectome. Normative modelling was used to map atypicality of features on an individual basis with respect to their distribution in neurotypical control participants. We applied robust out-of-sample canonical correlation analysis (CCA) to relate connectome data to behavioral data. Results Deviation from the normative ranges of global functional connectivity was greater for individuals with autism compared to TD in each fMRI task paradigm (all tasks p   〈  0.001). The similarity across individuals of the deviation pattern was significantly increased in autistic relative to TD individuals ( p   〈  0.002). The CCA identified significant and robust brain-behavior covariation between functional connectivity atypicality and autism-related behavioral features. Conclusions Individuals with autism engage with tasks in a globally atypical way, but the particular spatial pattern of this atypicality is nevertheless similar across tasks. Atypicalities in the tasks originate mostly from prefrontal cortex and default mode network regions, but also speech and auditory networks. We show how sophisticated modeling methods such as task potency and normative modeling can be used toward unravelling complex heterogeneous conditions like autism.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-022-00529-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 9
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    Atypical Brain Asymmetry in Autism—A Candidate for Clinically Meaningful Stratification
    Elsevier BV ; 2021
    In:  Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Vol. 6, No. 8 ( 2021-08), p. 802-812
    Details
    In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Elsevier BV, Vol. 6, No. 8 ( 2021-08), p. 802-812
    Type of Medium: Online Resource
    ISSN: 2451-9022
    URL: Article
    DOI: 10.1016/j.bpsc.2020.08.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2879089-3
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  • 10
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    Linking functional and structural brain organisation with behaviour in autism: a multimodal EU-AIMS Longitudinal European Autism Project (LEAP) study
    Springer Science and Business Media LLC ; 2023
    In:  Molecular Autism Vol. 14, No. 1 ( 2023-08-31)
    Details
    In: Molecular Autism, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2023-08-31)
    Abstract: Neuroimaging analyses of brain structure and function in autism have typically been conducted in isolation, missing the sensitivity gains of linking data across modalities. Here we focus on the integration of structural and functional organisational properties of brain regions. We aim to identify novel brain-organisation phenotypes of autism. We utilised multimodal MRI (T1-, diffusion-weighted and resting state functional), behavioural and clinical data from the EU AIMS Longitudinal European Autism Project (LEAP) from autistic ( n  = 206) and non-autistic ( n  = 196) participants. Of these, 97 had data from 2 timepoints resulting in a total scan number of 466. Grey matter density maps, probabilistic tractography connectivity matrices and connectopic maps were extracted from respective MRI modalities and were then integrated with Linked Independent Component Analysis. Linear mixed-effects models were used to evaluate the relationship between components and group while accounting for covariates and non-independence of participants with longitudinal data. Additional models were run to investigate associations with dimensional measures of behaviour. We identified one component that differed significantly between groups (coefficient = 0.33, p adj  = 0.02). This was driven (99%) by variance of the right fusiform gyrus connectopic map 2. While there were multiple nominal (uncorrected p   〈  0.05) associations with behavioural measures, none were significant following multiple comparison correction. Our analysis considered the relative contributions of both structural and functional brain phenotypes simultaneously, finding that functional phenotypes drive associations with autism. These findings expanded on previous unimodal studies by revealing the topographic organisation of functional connectivity patterns specific to autism and warrant further investigation.
    Type of Medium: Online Resource
    ISSN: 2040-2392
    URL: Article
    DOI: 10.1186/s13229-023-00564-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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