Glymphatic dysfunction in trigeminal neuralgia: A multimodal MRI study

Trigeminal neuralgia (TN) has traditionally been attributed to peripheral neurovascular compression at the trigeminal nerve root entry zone. Recent evidence, however, suggests central mechanisms may contribute to disease pathogenesis. We investigated whether glymphatic system dysfunction occurs in TN and contributes to its pathophysiology. This cross-sectional study enrolled 71 patients with classical TN and 52 age-matched healthy controls. All participants underwent comprehensive multimodal MRI assessment, including: (1) diffusion tensor imaging along perivascular spaces (DTI-ALPS) index measurement, (2) free water fraction (FWF) mapping, (3) perivascular space (PVS) burden quantification, and (4) choroid plexus (CP) volumetric analysis using deep learning segmentation to evaluate glymphatic system function. TN patients demonstrated selective glymphatic dysfunction characterized by reduced DTI-ALPS index and increased FWF. Compared to controls, patients showed significantly reduced DTI-ALPS indices (1.34 ± 0.12 vs. 1.41 ± 0.13; p = 0.027) and elevated FWF values (0.34 ± 0.04 vs. 0.32 ± 0.03, p = 0.027), indicating compromised cerebrospinal fluid dynamics. In contrast, structural measures including PVS burden and CP volumes remained comparable between groups (all p > 0.05). Age-related analysis revealed significant correlations with DTI-ALPS decline (ρ = −0.286, p = 0.020) and FWF elevation (ρ = 0.658, p < 0.001), suggesting progressive glymphatic deterioration with aging. However, there is a lack of correlation between glymphatic indicators and pain intensity as well as disease course. These findings indicate that TN is associated with functional impairment of the glymphatic system in the absence of overt perivascular structural abnormalities. This dissociation between functional and structural glymphatic measures challenges conventional neuroimaging paradigms in TN and highlights a previously underrecognized central mechanism. The key physiological processes within the PVS network and fundamental MRI measurement concepts. Briefly, CSF flows from arteries through the PVS, enters the interstitial space via AQP-4 channels, and ultimately migrates toward the perivenous space. The count of PVS and CPV were obtained by automatic segmentation of the T1-weighted MRI dataset using trained deep learning architectures. The interstitial water content is estimated as FWF within a voxel using a bitensor model. DTI-ALPS quantifies diffusivity along deep medullary veins, reflecting perivascular clearance processes. AQP-4, aquaporin-4; CPV, choroid plexus volume; CSF, cerebrospinal fluid; DTI-ALPS, diffusion tensor imaging along the perivascular space; FWF, free water fraction; MRI, magnetic resonance imaging; PVS, perivascular space. • A multimodal neuroimaging study of glymphatic function in trigeminal neuralgia (TN). • TN patients exhibit glymphatic dysfunction characterized by ALPS and FWF changes. • Right-hemisphere glymphatic impairment is specific to TN patients. • Glymphatic changes in TN are age-linked but pain-unrelated.