Trigeminal nerve microstructure is linked with neuroinflammation and brainstem activity in migraine
Sarasa Tohyama, Michael Datko, Ludovica Brusaferri, Lillian Kinder, Jack H. Schnieders, Mackenzie Hyman, Alison M. Goldstein, M. Gilbert, Hope Housman, Vi Donna Le, Kassandra Round, Frances Marin, Megan Heffernan, Ronald G. García, Randy L. Gollub, Robert R. Edwards, Bruce R. Rosen, Nouchine Hadjikhani, Hsinlin T. Cheng, Zev Schuman‐Olivier, Marco L. Loggia, Vitaly Napadow
Abstract
Although the pathophysiology of migraine involves a complex ensemble of peripheral and CNS changes that remain incompletely understood, the activation and sensitization of the trigeminovascular system are 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 ± standard deviation age: 36.28 ± 11.95 years) and 20 age- and sex-matched healthy controls (19 females, age: 35.45 ± 13.30 years) using ultra-high field 7 T diffusion tensor imaging and functional MRI, in addition to PET with the translocator protein ligand 11C-PBR28. We evaluated MRI diffusivity measures and the PET signal at the trigeminal nerve root, in addition to the 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, in comparison to healthy controls (n = 18). Furthermore, in patients, lower fractional anisotropy was accompanied by higher neuroinflammation (i.e. elevated 11C-PBR28 PET signal) at the nerve root (n = 36) and by lower functional MRI activation in an ipsilateral pontine cluster consistent with the 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 in comparison to left headache-dominant patients in our cohort. Multimodal imaging of the integrated neural mechanisms that characterize migraine underscores the importance of trigeminal system remodelling as both a key aspect of the dynamics underlying migraine pathophysiology and a target for therapeutic interventions.