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

Classical trigeminal neuralgia exhibits both peripheral neurovascular compression 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 classical trigeminal neuralgia patients and 87 healthy controls, using advanced multi-shell diffusion 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 index). Results demonstrated significant microstructural alterations at neurovascular compression sites, including lower fractional anisotropy and neurite density index, along with a higher fraction of isotropic water in affected trigeminal nerves compared to the unaffected sides and healthy controls (P_FDR < 0.050). The diffusion tensor imaging along the perivascular space index on the affected side was significantly lower than that on the unaffected side and that in healthy controls (P_FDR < 0.050). Tract-based spatial statistics analyses revealed bilateral microstructural changes regardless of pain laterality, with distinct neural remodelling patterns observed in the left- and right-pain side groups (P < 0.050, family-wise error-corrected). We also found that higher fraction of isotropic water at the neurovascular compression site correlated with higher pain intensity (P_FDR = 0.013), while reduced glymphatic function (both affected side and total diffusion tensor imaging along the perivascular space indexes) was associated with worse pain and psychological scores (P_FDR < 0.050). Mediation analyses in right-pain side patients indicated that neurite density index reduction at the neurovascular compression site influenced widespread white matter neurite density index reduction through impaired glymphatic function. Diagnostic receiver operating characteristic analyses showed that individual imaging markers could discriminate classical trigeminal neuralgia, and integrated models combining peripheral metrics, affected side diffusion tensor imaging along the perivascular space 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 classical trigeminal neuralgia, offering new imaging biomarkers for diagnosis and pathophysiological insight.