Investigating Glymphatic Dysfunction in Migraine: A Role in Headache Pain and Migraine Chronification?
Roberta Messina1, Elisabetta Pagani2, Francesca Genovese1, Ilaria Cetta1, Laura Zanandrea3, Bruno Colombo4, Maria Rocca1, Massimo Filippi1
1Neuroimaging Research Unit, Division of Neuroscience; and Neurology Unit, IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University, 2Neuroimaging Research Unit, Division of Neuroscience, 3Neuroimaging Research Unit, Division of Neuroscience; and Neurology Unit, 4Neurology Unit, IRCCS San Raffaele Scientific Institute
Objective:
To investigate the role of glymphatic dysfunction in the acute headache phase of migraine and in mechanisms of chronification and medication overuse (MO).
Background:
The glymphatic system facilitates fluid exchange and waste removal in the brain. What is the involvement of glymphatic dysfunction in migraine is still unclear.
Design/Methods:
One hundred twenty migraine patients and 52 controls underwent diffusion tensor (DTI) and susceptibility weighted (SWI) magnetic resonance imaging (MRI). Using DTI and SWI, we computed the Diffusion Along Perivascular Space (DTI-ALPS) index, reflecting diffusivity in the perivascular space near the left lateral ventricle. Based on previous evidence linking glymphatic function to changes in intra/extracellular compartments, we also used neurite orientation dispersion and density imaging to evaluate voxel-wise maps of white matter extracellular (EVF) and intracellular (IVF) volume fraction. Age- and sex-adjusted between-group comparisons were run using R and FSL software.
Results:
Compared to controls, migraine patients were older and had a higher proportion of female subjects. Among patients, 95 were headache-free (MwoH), 25 experienced headache during the MRI (MwH), 93 had episodic migraine (EM), 24 had chronic migraine (CM) with MO, and three CM without MO. We found no significant differences between patients and controls, neither concerning the DTI-ALPS index nor regarding EVF and IVF. No differences in the DTI-ALPS index were observed between subgroups of patients. Compared to MwoH and controls, MwH patients had decreased EVF and increased IVF. Likewise, compared to controls, CM patients with MO showed decreased EVF and increased IVF.
Conclusions:
Despite no significant differences in the DTI-ALPS index, our results of reduced EVF and concomitant expansion of IVF suggest impaired glymphatic clearance in CM patients with MO and in MwH patients. These findings suggest potential involvement of glymphatic dysfunction in the acute pain phase of migraine and the mechanisms underlying chronification and MO.
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