Patterns of connectome variability in autism across five functional activation tasks: findings from the LEAP project
Authors: Looden Tristan , Floris Dorothea L. , Llera Alberto , Chauvin Roselyne J. , Charman Tony , Banaschewski Tobias , Murphy Declan , Marquand Andre. F. , Buitelaar Jan K. , Beckmann Christian F. ,   the AIMS-2-TRIALS group, Ahmad Jumana , Ambrosino Sara , Auyeung Bonnie , Banaschewski Tobias , Baron-Cohen Simon , Baumeister Sarah , Beckmann Christian F. , Bölte Sven , Bourgeron Thomas , Bours Carsten , Brammer Michael , Brandeis Daniel , Brogna Claudia , de Bruijn Yvette , Buitelaar Jan K. , Chakrabarti Bhismadev , Charman Tony , Cornelissen Ineke , Crawley Daisy , Acqua Flavio Dell’ , Dumas Guillaume , Durston Sarah , Ecker Christine , Faulkner Jessica , Frouin Vincent , Garcés Pilar , Goyard David , Ham Lindsay , Hayward Hannah , Hipp Joerg , Holt Rosemary , Johnson Mark H. , Jones Emily J. H. , Kundu Prantik , Lai Meng-Chuan , D’ardhuy Xavier Liogier , Lombardo Michael V. , Loth Eva , Lythgoe David J. , Mandl René , Marquand Andre , Mason Luke , Mennes Maarten , Meyer-Lindenberg Andreas , Moessnang Carolin , Mueller Nico , Murphy Declan G. M. , Oakley Bethany , O’Dwyer Laurence , Oldehinkel Marianne , Oranje Bob , Pandina Gahan , Persico Antonio M. , Rausch Annika , Ruggeri Barbara , Ruigrok Amber , Sabet Jessica , Sacco Roberto , Cáceres Antonia San José , Simonoff Emily , Spooren Will , Tillmann Julian , Toro Roberto , Tost Heike , Waldman Jack , Williams Steve C. R. , Wooldridge Caroline , Ilioska Iva , Mei Ting , Zwiers Marcel P. 
Published: December 2022

Abstract
Background
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.