Patterns of connectome variability in autism across five functional activation tasks: findings from the LEAP project

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.

Keywords: Autism; Canonical correlation analysis; Functional connectivity; Heterogeneity; Normative modeling; fMRI.

Fig. 1

Violin plot of subject distributions for atypicality subject scores in each task. Independent t tests are performed between the subject distributions for each task. Derived p values (p), and Cohen’s d effect size (D) are displayed above the respective tasks. (**p < 0.01, ***p < 0.001)

Fig. 2

The top 10% brain regions with the greatest atypicality score in autism as summed over edges. From top to bottom: Hariri, Flanker, social reward, nonsocial reward, and theory of mind

Fig. 3

Heatmap of cross-task Pearson correlation of the edgewise group-level mean atypicality pattern in the brain for TD and ASD. Correlations are higher across the board for autism (mean correlation: 0.43), than for TD (mean correlation 0.07). Wilcoxon signed rank test shows a significant difference at p < 0.002

Fig. 4

Behavioral loadings for each task in the CCA analysis

Fig. 5

The top 10% brain regions with the greatest CCA loadings in autism as summed over edges. From top to bottom: Hariri, Flanker, social reward, nonsocial reward, and theory of mind