Contracted functional connectivity profiles in autism

Abstract

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental condition that is associated with atypical brain network organization, with prior work suggesting differential connectivity alterations with respect to functional connection length. Here, we tested whether functional connectopathy in ASD specifically relates to disruptions in long- relative to short-range functional connections. Our approach combined functional connectomics with geodesic distance mapping, and we studied associations to macroscale networks, microarchitectural patterns, as well as socio-demographic and clinical phenotypes.

Methods: We studied 211 males from three sites of the ABIDE-I dataset comprising 103 participants with an ASD diagnosis (mean ± SD age = 20.8 ± 8.1 years) and 108 neurotypical controls (NT, 19.2 ± 7.2 years). For each participant, we computed cortex-wide connectivity distance (CD) measures by combining geodesic distance mapping with resting-state functional connectivity profiling. We compared CD between ASD and NT participants using surface-based linear models, and studied associations with age, symptom severity, and intelligence scores. We contextualized CD alterations relative to canonical networks and explored spatial associations with functional and microstructural cortical gradients as well as cytoarchitectonic cortical types.

Results: Compared to NT, ASD participants presented with widespread reductions in CD, generally indicating shorter average connection length and thus suggesting reduced long-range connectivity but increased short-range connections. Peak reductions were localized in transmodal systems (i.e., heteromodal and paralimbic regions in the prefrontal, temporal, and parietal and temporo-parieto-occipital cortex), and effect sizes correlated with the sensory-transmodal gradient of brain function. ASD-related CD reductions appeared consistent across inter-individual differences in age and symptom severity, and we observed a positive correlation of CD to IQ scores.

Limitations: Despite rigorous harmonization across the three different acquisition sites, heterogeneity in autism poses a potential limitation to the generalizability of our results. Additionally, we focussed male participants, warranting future studies in more balanced cohorts.

Conclusions: Our study showed reductions in CD as a relatively stable imaging phenotype of ASD that preferentially impacted paralimbic and heteromodal association systems. CD reductions in ASD corroborate previous reports of ASD-related imbalance between short-range overconnectivity and long-range underconnectivity.

Keywords: Autism spectrum disorder; Connectivity disruptions; Distance profiling; Functional connectivity; Magnetic resonance imaging; Neurodevelopmental disorders.

Fig. 1

A | Workflow for CD computation and average CD maps. B | Effect size map for group differences (ASD vs. NT). Clusters of significant changes after multiple comparisons correction are outlined (p_FDR<0.05, vertex-based linear model). C | Distribution of CD values within clusters of significant reduction

Fig. 2

A | Clusters of significant CD reduction in ASD vs. NT. Color intensity does not reflect effect size but as a visual differentiation between clusters. B-E | Correlation between mean CD in clusters and age, age group (children < 18 years, adults > 18 years), total ADOS score, ADOS subscores for communication, social interaction, and repetitive behavior, as well as full IQ and IQ subscores for verbal and nonverbal IQ. IQ ratio denotes the ratio of verbal over nonverbal IQ. Correlation coefficients are listed in Table 2

Fig. 3

Relation to cortical organization. A | Effect sizes of between-group differences (ASD vs. NT) in functional CD measures, stratified within seven intrinsic networks proposed by Yeo, Krienen, et al. [21] B | Correlation to the principal functional gradient [24]. Spatial associations were assessed using Spearman’s rank test, and p-values were adjusted for spatial autocorrelation using a spin test [91, 129]. C | Effect size for the between-group difference in functional CD in each cortical type as proposed by Von Economo and Koskinas [58]. D | Association to microstructural gradients derived from the 3D BigBrain [59]. Abbreviations: SMN = somatomotor network, DAN = dorsal attention network, VAN = ventral attention network, FPN = frontoparietal network, DMN = default mode network