Glymphatic system bridges peripheral and central nervous system changes in classic trigeminal neuralgia

Classical trigeminal neuralgia (CTN) exhibits both peripheral neurovascular compression (NVC) and widespread central white matter alterations, but the mechanisms bridging peripheral and central pathology remain elusive. This study investigated the role of glymphatic system dysfunction in linking peripheral and central pathology. We prospectively enrolled 115 CTN patients and 87 healthy controls, using advanced multi-shell diffusion magnetic resonance imaging (MRI) to assess microstructural integrity (via neurite orientation dispersion and density imaging metrics) and glymphatic function (via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index). Results demonstrated significant microstructural alterations at NVC sites, including lower fractional anisotropy (FA) and neurite density index (NDI), along with a higher fraction of isotropic water (FISO) in affected trigeminal nerves compared to the unaffected sides and healthy controls (pFDR < 0.050). The DTI-ALPS index on the affected side was significantly lower than that on the unaffected side and that in healthy controls (pFDR < 0.050). Tract-based spatial statistics analyses revealed bilateral microstructural changes regardless of pain laterality, with distinct neural remodeling patterns observed in the left- and right-pain side groups (p < 0.050, family-wise error-corrected). We also found that higher FISO at the NVC site correlated with higher pain intensity (pFDR = 0.013), while reduced glymphatic function (both affected side and total DTI-ALPS indexes) was associated with worse pain and psychological scores (pFDR < 0.050). Mediation analyses in right-pain side patients indicated that NDI reduction at the NVC site influenced widespread white matter NDI reduction through impaired glymphatic function. Diagnostic receiver operating characteristic (ROC) analyses showed that individual imaging markers could discriminate CTN, and integrated models combining peripheral metrics, affected side DTI-ALPS indexes, and central metrics achieved superior diagnostic power. Our findings provide novel evidence that glymphatic dysfunction may be a key mechanism linking peripheral compression to global neural degeneration in CTN, offering new imaging biomarkers for diagnosis and pathophysiological insight.