AAN 2025 | The role of the glymphatic system in the pathophysiology of migraine

Over the last years there has been an increasing interest in studying the glymphatic system and neurological conditions. This is because we know that the glymphatic system is constituted by perivascular spaces and lymphatic vessels that are involved in the clearance of waste products as well as in fluid exchange. And there are previous studies show that investigated whether the glymphatic system could be implicated in migraine pathophysiology, showing that there are no alterations in the glymphatic system in patients with episodic migraine, while contradictory results have been revealed regarding chronic migraine. So against this background, the aim of our study was to investigate whether a glymphatic dysfunction could be involved in the acute headache phase of a migraine as well as in the mechanism of migraine chronification and medication overuse. In previous studies investigating the glymphatic system, I have mainly used the so-called diffusion tensor imaging along the perivascular space method that provides information regarding the so-called DTI-ALPS index, which provides information regarding the indirect function of the glymphatic system evaluated close to the lateral ventricle. However, as I said, the previous studies investigating migraine found contradictory results regarding this index, but there are also other imaging approaches that could provide information regarding the function of the glymphatic system. And among these, there is also data showing that alterations or changes at the level of the intracellular and extracellular volume fraction could provide indirect information regarding the glymphatic activity. So in this study, we combine these two DTI approaches. So we use the DTI-ALPS index, as well as we quantify the intracellular and extracellular volume fraction in a migraine patient group and a group of healthy controls. So in this study, we recruited 120 migraine patients and among these, we identified different subgroups which were 25 patients who were studied while they were having migraine episodes and 95 patients who were studied during the interictal phase while 93 patients had episodic migraine and 27 patients had chronic migraine and medication overuse. All patients underwent a three-tesla MRI scan, including SWI and DTI images, and we compared the patient’s group to a group of 52 healthy controls. So what we found was that we, interestingly, did not find any significant differences between patients and controls regarding the DTI-ALPS index. However, we found that when we compared the group of patients who were experiencing a migraine episode during the MRI to healthy controls and patients who were interictal, we found a significant decrease in the extracellular volume fraction, which was associated with an increase of the intracellular volume fraction, and similar results were found when we compared the group of chronic migraine patients to controls. So our results suggest that a glymphatic impairment could be implicated in migraine pathogenesis and specifically in the acute headache phase. This is because, as I said, there is evidence showing that a decrease when we evaluate the intracellular and extracellular volume fraction, a decrease in the extracellular volume fraction associated with an increase of intracellular volume fraction could suggest and implicate an impaired glymphatic activity. So the impairment of the glymphatic system function that we found in our migraine patients could facilitate the accumulation of neuropeptides and neurotransmitters that could facilitate the onset of the acute headache episodes and that over time could facilitate the mechanism of chronification and medication overuse.

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