Controlled Clinical Trial

. 2024 May;102(9):e209305.

doi: 10.1212/WNL.0000000000209305. Epub 2024 Apr 17.

Differences in Cortical Morphology in People With and Without Migraine: A Registry for Migraine (REFORM) MRI Study

Affiliations

Affiliation

¹ From the Department of Neurology (R.H.C., H.A., H.M.A.-K., A.H.P., F.M.A., M.A.), Danish Headache Center, Copenhagen University Hospital-Rigshospitalet; Department of Clinical Medicine (R.H.C., H.A., H.M.A.-K., F.M.A., M.A.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Harvard Medical School (R.H.C., H.A., H.M.A-K.), Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (R.H.C., H.A., H.M.A-K.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Brain and Spinal Cord Injury (H.A., F.M.A.), Copenhagen University Hospital-Rigshospitalet, Denmark; Department of Neurology (Y.Z.), The First Affiliated Hospital of Chongqing Medical University, China; Department of Radiology (D.T.), Rigshospitalet Glostrup, Denmark; Translational Imaging in Neurology (ThINk) Basel (A.C., C.G.), Department of Biomedical Engineering, University Hospital Basel, University of Basel; Neurologic Clinic and Policlinic (A.C., C.G.), MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Switzerland; Gillberg Neuropsychiatry Centre (N.H.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden; Athinoula A. Martinos Center for Biomedical Imaging (N.H.), Massachusetts General Hospital, Boston; and Danish Knowledge Center on Headache Disorders (M.A.), Glostrup, Denmark.

PMID: 38630960
PMCID: PMC11175630
DOI: 10.1212/WNL.0000000000209305

Controlled Clinical Trial

Differences in Cortical Morphology in People With and Without Migraine: A Registry for Migraine (REFORM) MRI Study

Rune H Christensen et al. Neurology. 2024 May.

. 2024 May;102(9):e209305.

doi: 10.1212/WNL.0000000000209305. Epub 2024 Apr 17.

Affiliation

¹ From the Department of Neurology (R.H.C., H.A., H.M.A.-K., A.H.P., F.M.A., M.A.), Danish Headache Center, Copenhagen University Hospital-Rigshospitalet; Department of Clinical Medicine (R.H.C., H.A., H.M.A.-K., F.M.A., M.A.), Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Harvard Medical School (R.H.C., H.A., H.M.A-K.), Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (R.H.C., H.A., H.M.A-K.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Brain and Spinal Cord Injury (H.A., F.M.A.), Copenhagen University Hospital-Rigshospitalet, Denmark; Department of Neurology (Y.Z.), The First Affiliated Hospital of Chongqing Medical University, China; Department of Radiology (D.T.), Rigshospitalet Glostrup, Denmark; Translational Imaging in Neurology (ThINk) Basel (A.C., C.G.), Department of Biomedical Engineering, University Hospital Basel, University of Basel; Neurologic Clinic and Policlinic (A.C., C.G.), MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Switzerland; Gillberg Neuropsychiatry Centre (N.H.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden; Athinoula A. Martinos Center for Biomedical Imaging (N.H.), Massachusetts General Hospital, Boston; and Danish Knowledge Center on Headache Disorders (M.A.), Glostrup, Denmark.

PMID: 38630960
PMCID: PMC11175630
DOI: 10.1212/WNL.0000000000209305

Abstract

Background and objectives: Structural imaging can offer insights into the cortical morphometry of migraine, which might reflect adaptations to recurring nociceptive messaging. This study compares cortical morphometry between a large sample of people with migraine and healthy controls, as well as across migraine subtypes.

Methods: Adult participants with migraine and age-matched and sex-matched healthy controls attended a single MRI session with magnetization-prepared rapid acquisition gradient echo and fluid-attenuated inversion recovery sequences at 3T. Cortical surface area, thickness, and volume were compared between participants with migraine (including subgroups) and healthy controls across the whole cortex within FreeSurfer and reported according to the Desikan-Killiany atlas. The analysis used cluster-determining thresholds of p < 0.0001 and cluster-wise thresholds of p < 0.05, adjusted for age, sex, and total intracranial volume.

Results: A total of 296 participants with migraine (mean age 41.6 years ± 12.4 SD, 261 women) and 155 healthy controls (mean age 41.1 years ± 11.7 SD, 133 women) were included. Among the participants with migraine, 180 (63.5%) had chronic migraine, 103 (34.8%) had migraine with aura, and 88 (29.7%) experienced a migraine headache during the scan. The total cohort of participants with migraine had reduced cortical surface area in the left insula, compared with controls (p < 0.0001). Furthermore, participants with chronic migraine (n = 180) exhibited reduced surface area in the left insula (p < 0.0001) and increased surface area in the right caudal anterior cingulate cortex (p < 0.0001), compared with controls. We found no differences specific to participants with aura or ongoing migraine headache. Post hoc tests revealed a positive correlation between monthly headache days and surface area within the identified anterior cingulate cluster (p = 0.014).

Discussion: The identified cortical changes in migraine were limited to specific pain processing regions, including the insula and caudal anterior cingulate gyrus, and were most notable in participants with chronic migraine. These findings suggest persistent cortical changes associated with migraine.

Trial registration information: The REFORM study (clinicaltrials.gov identifier: NCT04674020).

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Conflict of interest statement

H. Ashina reports personal fees from Teva, outside of the submitted work. A. Cagol is supported by the Horizon 2020 Eurostar program (grant E!113682), and received speaker honoraria from Novartis. C. Granziera is supported by: The University Hospital Basel (USB), as the employer of Cristina Granziera has received the following fees, which were used exclusively for research support: (1) advisory board and consultancy fees from Actelion, Novartis, Sanofi-Genzyme, Jannsen, and F. Hoffmann-La Roche; (2) speaker fees from Biogen, F. Hoffmann-La Roche, Novartis, Jannsen, and Genzyme-Sanofi; (3) research support by F. Hoffmann-La Roche. F.M. Amin has received personal fees from Pfizer, Teva, Lundbeck, Novartis, Eli Lilly, outside of the submitted work. M. Ashina is 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. M. Ashina has no ownership interest and does not own stocks of any pharmaceutical company. M. Ashina serves as associate editor of Cephalalgia, associate editor of the Journal of Headache and Pain, and associate editor of Brain. R.H. Christensen, H.M. Al-Khazali, Y. Zhang, D. Tolnai, A. Poulsen, and N. Hadjikhani report no relevant conflicts of interest. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Overview of the Statistical Analyses**
For each comparison, general linear models were used for analysis of (1) cortical surface area, (2) cortical thickness, and (3) cortical volume. (A) Comparisons with healthy controls. (B) Comparisons between subgroups of participants with migraine.

**Figure 2. Overview of Study Participants and Healthy Controls, With Reasons for Exclusions**

**Figure 3. Whole-Brain Analysis of Migraine Compared With Healthy Controls**
Frontal-lateral view of the right and left hemispheres. Decreased cortical surface area in left anterior insula of participants with chronic migraine compared to healthy controls (white arrowhead). Surface area in the same region was decreased for participants with migraine overall compared with controls. Significant at cluster-determining threshold of p < 0.0001 and cluster-wise threshold of p < 0.05. Cluster size of 138.88 mm², Montreal Neurological Institute coordinates X: −33.8, Y: 6.8, Z: −12.8.

**Figure 4. Whole-Brain Analysis of Migraine Without Aura Compared With Healthy Controls**
Medial view of the right hemisphere. Increased cortical surface area at the transition of the right posterior to anterior cingulate cortex in participants with migraine without aura compared to healthy controls (white arrowhead). Surface area in the same region was increased for participants with chronic migraine compared to healthy controls. Significant at cluster-determining threshold of p < 0.0001 and cluster-wise threshold of p < 0.05. Cluster size of 195.88 mm², Montreal Neurological Institute coordinates X: 3.2, Y: 13.8, Z: 23.3.

**Figure 5. Whole-Brain Analysis Participants With Medication-Overuse Headache Compared With Those Without**
Medial (A) and lateral (B) view of the left hemisphere. Decreased cortical surface area in the lingual and postcentral gyri of participants with medication-overuse headache compared with those without (white arrowhead). Significant at cluster-determining threshold of p < 0.0001 and cluster-wise threshold of p < 0.05. Left lingual gyrus: Cluster size of 273.52 mm², Montreal Neurological Institute coordinates X: −14.8, Y: −56.8, Z: −5.1. Left postcentral gyrus: Cluster size of 126.21 mm², Montreal Neurological Institute coordinates X: −51.7, Y: −12.5, Z: 15.9.

See this image and copyright information in PMC

References

1. Stovner LJ, Nichols E, Steiner TJ, et al. . Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(11):954-976. doi:10.1016/S1474-4422(18)30322-3 - DOI - PMC - PubMed
1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. doi:10.1177/0333102417738202 - DOI - PubMed
1. Gaist D, Hougaard A, Garde E, et al. . Migraine with visual aura associated with thicker visual cortex. Brain. 2018;141(3):776-785. doi:10.1093/brain/awx382 - DOI - PubMed
1. DaSilva AFM, Granziera C, Snyder J, Hadjikhani N. Thickening in the somatosensory cortex of patients with migraine. Neurology. 2007;69(21):1990-1995. doi:10.1212/01.wnl.0000291618.32247.2d - DOI - PMC - PubMed
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Differences in Cortical Morphology in People With and Without Migraine: A Registry for Migraine (REFORM) MRI Study

Affiliation

Differences in Cortical Morphology in People With and Without Migraine: A Registry for Migraine (REFORM) MRI Study

Authors

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Abstract

Conflict of interest statement

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References

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