Fixel‑based analysis reveals distributed white matter alterations associated with pain severity in trigeminal neuralgia

Trigeminal neuralgia (TN) is a severe neuropathic pain disorder in which peripheral neurovascular compression alone does not fully explain the associated central pain manifestations. Although diffusion tensor imaging studies have reported white matter (WM) alterations in TN, findings have been heterogeneous, partly due to limited sensitivity to complex fibre architecture. Fixel‑based analysis (FBA) enables fibre‑specific assessment of WM microstructural and macrostructural properties and may provide improved anatomical and biological specificity. This cross‑sectional study included 65 patients with primary TN and 42 healthy controls (HCs). Diffusion MRI data were analyzed using FBA to quantify fibre density (FD), fibre‑bundle cross‑section (FC), and the combined metric (FDC). Group differences were assessed using connectivity‑based fixel enhancement with family‑wise error correction. Associations between fixel‑based metrics and clinical variables were subsequently examined. Compared to controls, patients with TN showed reduced FD in the splenium of the corpus callosum, fornix, and superior cerebellar peduncle. Reductions in FC were observed in the corticospinal tracts (CST), inferior fronto‑occipital, and inferior longitudinal fasciculi. Decreased FDC involved the bilateral CST, middle cerebellar peduncle, and anterior spinocerebellar tract (all FWE‑corrected P < 0.05). Pain severity was associated with reduced FC and FDC in motor and cerebellar pathways, whereas FD showed no consistent associations. Age‑related reductions in FC and FDC were present in the TN group but not in HCs. TN is characterized by distributed, tract‑specific WM alterations extending beyond trigeminal pathways to involve motor, cerebellar, interhemispheric, and associative networks. The selective association between pain severity and macrostructural bundle measures supports a network‑level model of TN and suggests that chronic neuropathic pain is linked to large‑scale WM alterations rather than isolated axonal changes. FBA provides a sensitive framework for investigating clinically relevant central mechanisms in TN.