Microstructural alterations of the human fornix in trigeminal neuralgia

Trigeminal neuralgia (TN), a severe chronic neuropathic pain disorder, has been associated with abnormalities in limbic structures, particularly the hippocampus. The fornix, the hippocampus's primary efferent pathway, is integral to limbic-cognitive networks and exhibits microstructural changes across the adult lifespan. Fornix white matter (WM) integrity abnormalities in TN, and potential modifications following surgical pain relief have not been previously characterized. We examined whether TN is associated with alterations in fornix microstructure and what happens to these abnormalities following surgical treatment. Diffusion MRI data were acquired in patients with TN scanned before and six months after Gamma Knife radiosurgery (GKRS) and compared with age- and sex-matched, baseline healthy control scans from the Cam-CAN dataset. Fornix integrity was evaluated using fractional anisotropy (FA), axial, mean, and radial diffusivities (AD, MD, RD). Compared with controls, presurgical TN patients exhibited lower fornix FA suggesting reduced fornix fibre organization. Fornix microstructural FA differences persisted at six-month post-GKRS. Exploratory analyses examined the influence of sex, treatment response status, and pain laterality on fornix diffusion measures. Postoperative reductions in fornix integrity were greater in TN males than TN females. No differences were observed with treatment response status or pain laterality. Together, these findings demonstrate a dissociation between clinical pain relief and fornix WM recovery following GKRS. The results support broader limbic network involvement in TN and provide new insight into TN-specific and sex-sensitive limbic microstructural alterations that may help inform personalized approaches to pain treatment. PERSPECTIVE: This article demonstrates that fornix microstructural abnormalities in trigeminal neuralgia persist six months after radiosurgery, indicating a dissociation between clinical pain relief and fornix white matter recovery. Trigeminal neuralgia related alterations in fornix integrity are sex-dependent and appear to deviate from those expected across the adult lifespan of healthy controls.