Investigation of the large-scale white-matter functional networks in spinocerebellar ataxia type 3.

Background: Substantial evidence has shown the widespread structural and functional alterations within the white matter (WM) in patients with spinocerebellar ataxia type 3 (SCA3). However, investigation of the large-scale WM functional networks (WMFNs) remains incomplete in SCA3. This study aimed to comprehensively explore the functional organization, neural activity, and inter-network causal interactions within WMFNs relative to healthy controls (HCs). Methods: A total of 70 patients with SCA3 and 98 HCs underwent resting-state functional magnetic resonance imaging (rs-fMRI) and voxel-based morphometry. A total of 14 WMFNs were identified by K-means clustering algorithm, which were further classified as infratentorial, deep, middle, and superficial layers. Results: Dysfunctional WMFNs in SCA3 were mainly infratentorial, middle-layer, and deep-layer, with significantly decreased amplitudes in comparison with HCs [false discovery rate (FDR) corrected P<0.05]. In addition, the effective connectivity pattern within WMFNs in SCA3 was overall sparser than in HCs, whereas the directed connections from the dysfunctional WMFNs to the normal superficial-layer WMFNs and connections within the dysfunctional WMFNs were enhanced in SCA3 (FDR corrected P<0.05). Concurrently, the normal WMFNs showed reduced outflow strength of inter-network connections, whereas the dysfunctional WMFNs exhibited elevated outflow strength (FDR corrected P<0.05). Furthermore, the decline in neural activity and altered interactions observed can be partially attributed to the extent of WM volume (WMV) loss within the WMFNs, and are associated with the ataxia severity in SCA3 (P<0.05). Conclusions: This study aimed to comprehensively explore the functional organization, neural activity, and inter-network causal interactions within WMFNs relative to HCs. The findings may improve understanding of the neuropathology of SCA3 and its progression throughout the nervous system from the perspective of WM function.