Functional Dysconnectivity of White Matter Networks Is Associated With Clinical Impairment in Autism Spectrum Disorder

BACKGROUND: Structural white matter (WM) alterations are recognized in Autism Spectrum Disorder (ASD), yet the functional connectivity (FC) of WM networks and its clinical significance remain largely underexplored. METHODS: This study aimed to investigate aberrant FC patterns within intra-WM (WM-WM) and WM-grey matter (WM-GM) networks in a large ASD cohort. Resting-state fMRI data from 272 ASD individuals and 368 typical controls (TC) from the ABIDE-II dataset were analysed. We constructed WM-WM and WM-GM FC networks using Pearson correlations between atlas-defined regions, applied ComBat harmonization and employed Network-Based Statistic (NBS) to identify group differences. Associations with clinical symptoms were assessed using the Social Responsiveness Scale (SRS) scores, and a CatBoost algorithm was used for diagnostic classification based on connectivity features. RESULTS: NBS analyses revealed significantly increased connectivity in ASD for 116 WM-WM pairs and 58 WM-GM pairs (p < 0.05, FWER-corrected). Critically, the strength of these aberrant WM-WM functional connections exhibited a significant negative correlation with SRS total scores (r = -0.22, p < 0.001), whereas WM-GM connectivity showed no such significant association. The hybrid CatBoost classifier, integrating both WM-WM and WM-GM features, achieved moderate diagnostic discrimination (AUC = 0.669 ± 0.040). CONCLUSION: These results offer novel insights into the aberrant functional architecture of WM-related networks in ASD, particularly linking intra-WM dysconnectivity to symptom severity, thereby enhancing our understanding of the neural substrates underlying social-communicative deficits.