To assess neuronal microstructure and glymphatic system integrity in patients with migraine with aura interictally using high-gradient diffusion magnetic resonance imaging (MRI).

Migraine, a primary headache disorder, is among the most prevalent neurological conditions. Recent data shows there is reduced gray matter (GM) and white matter (WM) volume and increased incidence of white matter lesions (WML) in migraine patients, particularly in those with aura. Advanced MRI techniques allow to better understand the underlying microstructural substrate.

Using a Connectome scanner, we used the diffusion weighted imaging (DWI) models TractCaliber and Soma and Neurite Density Imaging (SANDI) to characterize the microstructure of both GM and WM in 16 patients with migraine with aura and 16 matched healthy controls (HC). We further assessed glymphatic activity with diffusion-tensor image analysis along the perivascular space (DTI-ALPS).

The GM of migraine patients exhibits reduced neuronal density with increased soma radius of the remaining cells. These microstructural changes are present in both cortex and deep GM structures including the thalamus, putamen, hippocampus, and amygdala. In WM of migraine patients that appears normal on conventional MRI, microstructural analysis shows axonal loss and increased axonal diameter, which is even more pronounced in WML. There is no significant difference in DTI-ALPS-based activity of the glymphatic system between migraine patients and HC.

High-gradient diffusion MRI shows occult changes in the microstructural integrity of GM and WM in migraine patients. These changes may precede previously shown GM/WM volume loss as well as the development of WML. Our findings suggest that migraine is associated with neuronal remodeling, which may contribute to increased cerebral vulnerability to insults.