AimsEmerging evidence suggests that cerebral small vessel disease (CSVD) pathology changes brain structural connectivity (SC) and functional connectivity (FC) networks. Although network-level SC and FC are closely coupled in the healthy population, how SC-FC coupling correlates with neurocognitive outcomes in patients with different CSVD burdens remains largely unknown.MethodsUsing multimodal MRI, we reconstructed whole-brain SC and FC networks for 54 patients with severe CSVD burden (CSVD-s), 106 patients with mild CSVD burden (CSVD-m), and 79 healthy controls. We then investigated the aberrant SC-FC coupling and functional network topology in CSVD and their correlations with cognitive dysfunction.ResultsCompared with controls, the CSVD-m patients showed no significant change in any SC-FC coupling, but the CSVD-s patients exhibited significantly decreased whole-brain (p = 0.014), auditory/motor (p = 0.033), and limbic modular (p = 0.011) SC-FC coupling. For functional network topology, despite no change in global efficiency, CSVD-s patients exhibited significantly reduced nodal efficiency of the bilateral amygdala (p = 0.024 and 0.035) and heschl gyrus (p = 0.001 and 0.005). Notably, for the CSVD-s patients, whole-brain SC-FC coupling showed a significantly positive correlation with MoCA (r = 0.327, p = 0.020) and SDMT (r = 0.373, p = 0.008) scores, limbic/subcortical modular SC-FC coupling showed a negative correlation (r = -0.316, p = 0.025) with SCWT score, and global/local efficiency (r = 0.367, p = 0.009 and r = 0.353, p = 0.012) showed a positive correlation with AVLT score. For the CSVD-m group, whole-brain and auditory/motor modular SC-FC couplings showed significantly positive correlations with SCWT (r = 0.217, p = 0.028 and r = 0.219, p = 0.027) and TMT (r = 0.324, p = 0.001 and r = 0.245, p = 0.013) scores, and global/local efficiency showed positive correlations with AVLT (r = 0.230, p = 0.020 and r = 0.248, p = 0.012) and SDMT (r = 0.263, p = 0.008 and r = 0.263, p = 0.007) scores.ConclusionOur findings demonstrated that decreased whole-brain and module-dependent SC-FC coupling associated with reduced functional efficiency might underlie more severe burden and worse cognitive decline in CSVD. SC-FC coupling might serve as a more sensitive neuroimaging biomarker of CSVD burden and provided new insights into the pathophysiologic mechanisms of clinical development of CSVD. We reconstructed whole-brain structural connectivity (SC) and functional connectivity (FC) networks for severe cerebral small vessel disease (CSVD) burden patients (CSVD-s), CSVD mild burden patients (CSVD-m), and healthy controls. The CSVD-s group showed considerably decreased SC-FC coupling in the limbic/subcortical module compared with the CSVD-m group, while there was no difference in SC-FC coupling between the CSVD-m and control groups.image