Trigeminal nerve microstructure is linked with neuroinflammation and brainstem activity in migraine

Abstract Although the pathophysiology of migraine involves a complex ensemble of peripheral and central nervous system changes that remain incompletely understood, the activation and sensitization of the trigeminovascular system is believed to play a major role. However, non-invasive, in vivo neuroimaging studies investigating the underlying neural mechanisms of trigeminal system abnormalities in human migraine patients are limited. Here, we studied 60 patients with migraine (55 females, mean age ± SD: 36.28 ± 11.95 years) and 20 age-/sex-matched healthy controls (19 females, mean age ± SD: 35.45 ± 13.30 years) using ultra-high field 7 Tesla diffusion tensor imaging and functional MRI, as well as PET with the translocator protein ligand [11C]-PBR28. We evaluated MRI diffusivity measures and PET signal at the trigeminal nerve root, as well as brainstem functional MRI response to innocuous, ophthalmic trigeminal nerve territory stimulation. Patients with migraine demonstrated altered white matter microstructure at the trigeminal nerve root (n=53), including reduced fractional anisotropy, compared to healthy controls (n=18). Furthermore, in patients, lower fractional anisotropy was accompanied by 1) higher neuroinflammation (i.e. elevated [11C]-PBR28 PET signal) at the nerve root (n=36) and 2) lower functional MRI activation in an ipsilateral pontine cluster consistent with spinal trigeminal nucleus (n=51). These findings were more robust on the right side, which was consistent with the observation that right headache dominant patients demonstrated higher migraine severity compared to left headache dominant patients in our cohort. Multimodal imaging of the integrated neural mechanisms that characterize migraine underscores the importance of trigeminal system remodeling as both a key aspect of the dynamics underlying migraine pathophysiology and a target for therapeutic interventions.