Cortical Inflammation in Migraine Measured with Quantitative Magnetic Resonance Imaging: A Reform Study

Background: The involvement of cortical inflammation in migraine, particularly migraine with aura, has been a subject of considerable interest. However, neuroimaging studies have reported varied and often conflicting results. To address this gap, we aimed to detect and characterize cortical inflammation in adults with migraine using a novel, quantitative and multimodal magnetic resonance imaging (MRI) technique.Methods: Adults with migraine and age- and sex-matched healthy controls were enrolled and underwent a single MRI session. We used T2 mapping to measure water content/cellularity, T1 mapping to measure tissue microstructure integrity, and apparent diffusion coefficient (ADC) mapping to measure the presence of intra – or extracellular edema. We compared these values between participants with migraine (with and without aura) and healthy controls using a general linear model adjusted for age and sex.Findings: A total of 296 participants with migraine and 155 healthy controls provided eligible imaging data. The participants’ mean age was 41·6 (SD: 12·4) years, and 261 (88·2%) were female. Among the participants with migraine, 103 had migraine with aura, 180 had chronic migraine, and 88 were ictal during the scan. The participants with migraine had higher quantitative T2 (qT2) values in the left occipital cortex, compared with healthy controls (p<0·0001). For those with migraine with aura, the increased qT2 was more widespread and located bilaterally in the occipital cortices, compared with controls (left, p<0·0001; right p=0·004). Post-hoc analysis revealed overlapping ADC increases in the participants with migraine with aura compared with controls (p=0·0069).Interpretation: Compared with healthy controls, quantitative MRI changes compatible with cortical inflammation were detected in participants with migraine and more so in those with migraine with aura. The increased qT2 values in the occipital cortices of people with migraine with aura might represent either extracellular edema or accumulation of inflammatory microglia or astrocytes. These results support the importance of cortical inflammation in migraine pathophysiology, particularly in migraine with aura.Trial Registration: Preregistered on ClinicTrials.gov (NCT04674020).Funding: Lundbeck Foundation Professor Grant (R310-2018-3711).Declaration of Interest: HA reports personal fees from Teva, outside of the submitted work. HMA reports personal fees from Pfizer, outside of the submitted work RR received support from the MSIF‐ECTRIMS McDonald fellowship, Multiple Sclerosis International Federation (MSIF‐ECTRIMS.2019) and the Swiss Government Excellence Scholarship (Nr.2019.0539). CG received support from: The University Hospital Basel (USB), as the employer of Cristina Granziera has received the following fees, which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Novartis, Sanofi-Genzyme, Jannsen, and F. Hoffmann-La Roche; (ii) speaker fees from Biogen, F. Hoffmann-La Roche, Novartis, Jannsen, and Genzyme-Sanofi; (iii) research support by F. Hoffmann-La Roche. F.M.A. has received personal fees from Pfizer, Teva, Lundbeck, Novartis, Eli Lilly, outside of the submitted work. FMA has received honoraria for delivering lectures and/or participation in advisory boards for Pfizer, Teva, Lundbeck, Novartis and Eli Lilly. Faisal Mohammad Amin serves as associate editor for the journals Headache Medicine, Acta Neurologica Scandinavica, Frontiers In Neurology and Frontiers In Pain Research. Faisal Mohammad Amin serves as president of the Danish Headache Society and a member of the Board of Directors in European Headache Federation. Faisal Mohammad Amin has no ownership interest and does not own stocks of any pharmaceutical company. MA acts as a consultant, speaker, or scientific advisor for AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva and a primary investigator for ongoing AbbVie/Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva trials. Messoud Ashina holds no ownership interest and or stocks of any pharmaceutical company. Messoud Ashina serves as associate editor of Cephalalgia, the Journal of Headache and Pain, and Brain. RC, MOP, and NH report no relevant conflicts of interest.Ethical Approval: The study protocol received approval from the ethics committee of the Capital Region of Denmark (H-20033264). All participants provided written informed consent before undergoing any study-related procedures.