DTI-ALPS and subcortical structural-functional coupling mediate the impact of sleep quality on working memory in insomnia disorder

Abstract Background Working memory (WM) deficits are frequently observed in patients with insomnia disorder (ID), but their neural basis is unclear. Glymphatic dysfunction and disrupted structural-functional coupling have been implicated, yet they have rarely been examined together, particularly in clinical populations. Methods We conducted a multimodal MRI study in 391 ID patients. Glymphatic function was estimated using the diffusion tensor image analysis along the perivascular space (DTI-ALPS). The SFC was derived by correlating structural connectivity and functional connectivity. WM was measured by the longest span on the digit span backward task. Partial correlations and mediation analyses were performed to examine associations among sleep quality (Pittsburgh Sleep Quality Index, PSQI), DTI-ALPS, SFC, and WM performance. Results DTI-ALPS was negatively correlated with PSQI ( r = −0.17, p = 0.006), indicating reduced glymphatic clearance with poorer sleep quality. Global SFC was positively associated with DTI-ALPS ( r = 0.32, pFDR < 0.001), but not with WM ( r = 0.01, p = 0.84). At the network level, SFC within the subcortical network (Sub-SFC) correlated with both DTI-ALPS ( r = 0.29, pFDR < 0.001) and WM performance ( r = 0.28, pFDR < 0.001). Mediation analysis revealed that DTI-ALPS and Sub-SFC jointly mediated the association between PSQI and WM performance, with a significant indirect effect (indirect effect = −0.074). Conclusions This study provides novel evidence that impaired glymphatic clearance and reduced Sub-SFC form key neural pathways linking poor sleep quality to working-memory deficits in ID, and that DTI-ALPS and Sub-SFC may serve as useful biomarkers of cognitive vulnerability.