Causal Central Network Remodeling in Diabetic Neuropathy: An Integrated MR-fMRI Study

Diabetic peripheral neuropathy (DPN) is traditionally viewed as a peripheral disorder, yet emerging evidence implicates central nervous system (CNS) network dysfunction in its pathogenesis, though causal mechanisms remain incompletely understood. Bidirectional two-sample Mendelian randomization (MR) analysis examined causal relationships between Resting-State Functional Magnetic Resonance Imaging (rs-fMRI) phenotypes (n=34,691) and DPN (n=96,474). For validation, amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were conducted using rs-fMRI scans from DPN patients (n=16), diabetic controls without DPN (NDPN, n=24), and healthy controls (HC, n=20). Bidirectional MR demonstrated that: (a) reduced default mode-visual network connectivity causally elevates DPN risk (OR=0.61, P=0.04); (b) DPN promotes subcortical-cerebellar hyperconnectivity (OR=1.04, P=0.01). DPN patients exhibited significantly higher age, triglyceride levels, pain scores, and cognitive impairment relative to comparison groups (all P<0.001). Neuroimaging identified increased ALFF in the left superior frontal gyrus (LSFG) (AUC=0.79, P<0.05), which correlated positively with disease duration, accompanied by decoupled FC with the lingual gyrus but enhanced FC with the precuneus. This study establishes DPN as a CNS-periphery integrated network disorder: genetic drivers disrupt default mode-visual integration, while compensatory subcortical-cerebellar hyperconnectivity stabilizes motor function via adaptive mechanisms. The LSFG emerges as a neuroadaptive hub, where elevated ALFF and connectivity reorganization (↓lingual gyrus/↑precuneus) reflect dynamic rebalancing between impaired basic vision and enhanced visuospatial processing. These findings redefine DPN pathogenesis beyond pure peripheral neurodegeneration, providing a theoretical foundation for early detection and circuit-targeted neuromodulation therapies.