The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression

Floris, Dorothea L.; Han, Peng; Warrier, Varun; Lombardo, Michael V.; Pretzsch, Charlotte M.; Moreau, Clara; Tsompanidis, Alex; Gong, Weikang; Mennes, Maarten; Llera, Alberto; Rooij, Daan van; Oldehinkel, Marianne; Forde, Natalie J.; Charman, Tony; Tillmann, Julian; Banaschewski, Tobias; Moessnang, Carolin; Durston, Sarah; Holt, Rosemary; Ecker, Christine; Dell’Acqua, Flavio; Loth, Eva; Bourgeron, Thomas; Murphy, Declan; Marquand, André F.; Lai, Meng‐Chuan; Buitelaar, Jan K.; Baron‐Cohen, Simon; Beckmann, Christian F.

doi:10.1176/appi.ajp.20220194

Cited by 21 publications

(13 citation statements)

References 121 publications

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“…Longitudinal design and/or high-risk autism models may help to highlight the neurodevelopmental foundations of functional asymmetry in autism and guide implications for support. Finally, we excluded autistic females, however, research shows that brain lateralization differs by sex (Kong et al, 2018;Liang et al, 2021;McGlone, 1978McGlone, , 1980 and autism shows sex and gender differences in prevalence, behavior and brain (Floris et al, 2023;Fombonne, 2003;Hull et al, 2017;Lai et al, 2015;Xu et al, 2018). Future studies should investigate whether there exist sex and gender-differential patterns of atypical asymmetry in autism.…”

Section: Discussionmentioning

confidence: 99%

Diverging asymmetry of intrinsic functional organization in autism

Wan

Hong

Bethlehem

et al. 2023

Preprint

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Autism is a neurodevelopmental condition involving atypical sensory-perceptual functions together with language and socio-cognitive deficits. Previous work has reported subtle alterations in the asymmetry of brain structure and reduced laterality of functional activation in individuals with autism relative to non-autistic individuals (NAI). However, whether functional asymmetries show altered intrinsic systematic organization in autism remains unclear. Here, we computed inter- and intra-hemispheric asymmetry of intrinsic functional gradients capturing connectome organization along three axes, stretching between sensory-default, somatomotor-visual, and default-multiple demand networks, to study system-level hemispheric imbalances in autism. We observed decreased leftward functional asymmetry of language network organization in individuals with autism, relative to NAI. Whereas language network asymmetry varied across age groups in NAI, this was not the case in autism, suggesting atypical functional laterality in autism may result from altered developmental trajectories. Finally, we observed that intra- but not inter-hemispheric features were predictive of the severity of autistic traits. In sum, our findings illustrate how regional and patterned functional lateralization is altered in autism at the system level. Such differences may be rooted in altered developmental trajectories of functional organization asymmetry in autism.

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Section: Discussionmentioning

confidence: 99%

Diverging asymmetry of intrinsic functional organization in autism

Wan

Hong

Bethlehem

et al. 2023

Preprint

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“…see refs. [20,28,39,40]). Therefore, to better understand the neurobiological correlates of adaptive behaviour and outcome, here we examined them both cross-sectionally and longitudinally, i.e.…”

Section: Discussionmentioning

confidence: 99%

Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

et al. 2023

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Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals’ adaptive skills naturally improve or remain stable, while others’ decrease. To pave the way for ‘precision-medicine’ approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6–30 years), with two assessment time points separated by ~12–24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful “Increasers”, “No-changers”, and “Decreasers” in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup’s neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences’ potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

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“…Further limitations have to be taken into account. Due to limited power, we excluded all females, however, sex-differential factors in the manifestations of autism phenotypes are increasingly being recognized (Braden et al, 2021; Floris et al, 2023). Particularly, the expression and nature of RRBs differ between autistic males and females (McFayden et al, 2020) which also extends to their neural underpinnings (Supekar & Menon, 2015) and highlights the importance of including autistic females into studies.…”

Section: Discussionmentioning

confidence: 99%

Towards Understanding Autism Heterogeneity: Identifying Clinical Subgroups and Neuroanatomical Deviations

Meijer,

Vieira,

Elleaume

et al. 2023

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Autism Spectrum Disorder ('autism') is a neurodevelopmental condition characterized by substantial behavioural and neuroanatomical heterogeneity. This poses significant challenges to understanding its neurobiological mechanisms and developing effective interventions. Identifying phenotypically more homogeneous subgroups and shifting the focus from average group differences to individuals is a promising approach to addressing heterogeneity. In the present study, we aimed to parse clinical and neuroanatomical heterogeneity in autism by combining clustering of clinical features with normative modeling based on neuroanatomical measures (cortical thickness [CT] and subcortical volume) within the ABIDE datasets (N autism=861, N neurotypical=886, age-range 5-64). First, model-based clustering was applied to autistic symptoms as measured by the Autism Diagnostic Observation Schedule to identify clinical subgroups of autism. Next, we examined whether clinical subgrouping resulted in increased neurobiological homogeneity within the subgroups compared to the entire autism group by comparing their spatial overlap of neuroanatomical deviations. We further investigated whether the identified subgroups improved the accuracy of autism classification based on the neuroanatomical deviations using supervised machine learning with cross-validation. Results yielded two clinical subgroups primarily differing in restrictive and repetitive behaviours (RRB). Both subgroups showed increased homogeneity in localized deviations with the high-RRB subgroup showing increased volume deviations in cerebellum and the low-RRB subgroup showing decreased CT deviations predominantly in the postcentral gyrus and fusiform cortex. Nevertheless, substantial within-group heterogeneity remained highlighted by the failure of the classifier to distinguish between the subgroups. Identifying subgroups of autism has substantial clinical implications opening the potential for more tailored behavioural interventions and improving clinical outcomes.

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The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression

Cited by 21 publications

References 121 publications

Diverging asymmetry of intrinsic functional organization in autism

Diverging asymmetry of intrinsic functional organization in autism

Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

Towards Understanding Autism Heterogeneity: Identifying Clinical Subgroups and Neuroanatomical Deviations

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