Alterations of functional connectivities associated with autism spectrum disorder symptom severity: a multi-site study using multivariate pattern analysis

Abstract

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder. The estimation of ASD severity is very important in clinical practice due to providing a more elaborate diagnosis. Although several studies have revealed some resting-state functional connectivities (RSFCs) that are related to the ASD severity, they have all been based on small-sample data and local RSFCs. The aim of the present study is to adopt multivariate pattern analysis to investigate a subset of connectivities among whole-brain RSFCs that are more contributive to ASD severity estimation based on large-sample data. Regression estimation shows a Pearson correlation value of 0.5 between the estimated and observed severity, with a mean absolute error of 1.41. The results provide obvious evidence that some RSFCs undergo notable alterations with the severity of ASD. More importantly, these selected RSFCs have an abnormality in the connection modes of the inter-network and intra-network connections. In addition, these selected abnormal RSFCs are mainly associated with the sensorimotor network, the default mode network, and inter-hemispheric connectivities, while exhibiting significant left hemisphere lateralization. Overall, this study indicates that some RSFCs suffer from abnormal alterations in patients with ASD, providing additional evidence of large-scale functional network alterations in ASD.

Figure 1

Correlation between the estimated and observed severity scores of 174 ASD patients from three sites. R: Pearson correlation coefficient; P: significance; MAE: mean absolute error.

Figure 2

Contributions and distribution of selected RSFCs in the whole brain. The selected RSFCs are displayed on a surface rendering of the brain using the BrainNet Viewer software. The orange/green lines indicate that the RSFCs were positively/negatively correlated with the severity scores. The 116 ROIs were divided into six different functional networks. The contributions of the selected RSFCs/ROIs are reflected by their thicknesses/sizes. Specifically, the contribution of an RSFC is defined by the ratio of the folds from the LOOCV in which the RSFC was chosen as a feature to all folds, and the contribution of the ROI is evaluated by the contributions of all the RSFCs associated with it.

Figure 3

Distribution of all selected RSFCs based on the AAL brain template. Sixty-two RSFCs out of the 6670 RSFCs were selected at least once, and 59 ROIs were related to the selected RSFCs. The contribution of an RSFC is defined by the ratio of the folds from the LOOCV in which the RSFC was chosen as a feature to all folds. Red/green lines indicate the contributions of RSFCs above/below 0.5. All 116 ROIs were assigned to six different functional networks represented by the six different colours.

Figure 4

Distribution of intra-network and inter-network RSFCs in the cerebral cortex from three perspectives. (a) only shows the inter-hemispherical RSFCs. (b),(c) draw the RSFCs within the left and right hemisphere, respectively. An RSFC whose two ends come from the same network is defined as an intra-network connection, and it has the same colour as the associated ROIs. An RSFC whose two ends come from different networks represents an inter-network connection and is coloured grey. Here, the intra-network RSFCs only involve three functional networks: the SMN, DMN and SBN. The inter-network RSFCs are widely distributed among five functional networks in the cerebral cortex.

Figure 5

Quantitative summary of the contributions of different divisions of RSFCs to ASD severity. Each pie slice in the inner ring indicates a division, and the contribution of each division is the normalized sum of the contributions of all the connectivities whose ROIs are within the division: (a) reflects the contributions of the inter-network and intra-network connectivities. (b) indicates the contributions of connectivities related to the six functional networks. (c) indicates the contributions of the inter-hemispheric, left hemisphere, right hemisphere and the cerebellar connectivities, respectively. (d) shows the contributions of connectivities related to the six brain lobes. The outer pie slices indicate the contributions of the positive/negative-correlation RSFCs corresponding to the pie slice in the inner ring.