Background & Aims

Migraine is a highly debilitating condition and one of the most prevalent neurological disorders worldwide. Despite its impact, the pathophysiology of migraine remains insufficiently understood(1,2). In a recent human study with [11C]PBR28 Positron Emission Tomography/Magnetic Resonance Imaging(PET/MRI), we observed elevated brain levels of the neuroinflammatory marker 18kDa translocator protein(TSPO) in 13 individuals diagnosed with migraine with aura(3), in regions associated with nociceptive processing and Cortical Spreading Depression(CSD) generation(4). TSPO levels were also positively correlated with migraine attack frequency. However, the relationship of neuroinflammation to symptom initiation, and the generalizability of those findings to migraine without aura remain unknown (5). Our current study explores the heterogeneity of migraine pathophysiology in a more diverse cohort, including individuals with and without aura, and varying migraine frequency.

Methods

Forty participants with episodic migraine (age: 35.95±11.16 years, sex: 3M, 33F) were enrolled; 11 had migraine with aura. Participants were included if they were either high-affinity(N=20) or mixed-affinity(N=20) binders (HABs/MABs), based on their polymorphism in the TSPO gene(6). Inclusion criteria required a minimum 75% migraine prevalence diary completion, as well as at least four headaches over the four-week period leading up to the study. Subjects underwent [11C]PBR28 PET/MR imaging with a 3 T Tim Trio whole-body MRI with a brain PET insert(7). SUV ratio (SUVR) images were obtained and intensity normalized using the cerebellum as a pseudo-reference region(8). Daily diaries tracked headache days 15 days before and after the PET visit. Participants were median-split based on the number of headache days within a 30-day period cantered around the PET session (N?7=high frequency, HF;N<7=low frequency, LF). A non-parametric voxel-wise analysis correlated PET signal with headache days.

Results

No statistically significant correlation was observed between PET SUVR values and clinical variables across the entire migraineur population, or within the LF group. However, a robust positive correlation emerged within the HF group, where the number of pre-PET headache days was significantly associated with bilateral SUVR signal in the Frontal Medial Cortex, Frontal Orbital Cortex, Subcallosal Cortex, Insular Cortex, Lingual Gyrus, Parahippocampal Gyrus, and Superior Temporal Gyrus. Interestingly, no significant correlation was observed with post-PET headache days within the HF group. Importantly, PET SUVR values did not statistically differ in subjects with and without aura, and the presence of aura did not moderate the observed correlations. However, it is noteworthy that the subgroup with aura was significantly older (p<0.05) than the subgroup without aura.

Conclusions

This study supports our prior work linking neuroinflammation to migraine, extending it to migraine without aura. Additionally, by showing that neuroinflammation correlates with the number of headaches days before but not after the PET scans, our observations suggest that neuroinflammation, characterized by elevated PBR binding, could arise as a consequence of cortical spreading depression (CSD), rather than induce it — at least in migraineurs with a high frequency of attacks. These observations resonate with preclinical studies (9,10). Collectively, our data shed light on the intricate interplay between neuroinflammation and migraine pathophysiology and lay the foundation for potential advancements in personalized medicine.

References

1.Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet Lond Engl. 2012 Dec 15;380(9859):2197–223.
2.Gupta J, Gaurkar SS. Migraine: An Underestimated Neurological Condition Affecting Billions. Cureus. 14(8):e28347.
3.Albrecht DS, Mainero C, Ichijo E, Ward N, Granziera C, Zürcher NR, et al. Imaging of neuroinflammation in migraine with aura: A [11C]PBR28 PET/MRI study. Neurology. 2019 Apr 23;92(17):e2038–50.
4.Hadjikhani N, Sanchez del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4687–92.
5.Close LN, Eftekhari S, Wang M, Charles AC, Russo AF. Cortical spreading depression as a site of origin for migraine: Role of CGRP. Cephalalgia. 2019 Mar 1;39(3):428–34.
6.Owen DR, Guo Q, Rabiner EA, Gunn RN. The impact of the rs6971 polymorphism in TSPO for quantification and study design. Clin Transl Imaging. 2015 Dec 1;3(6):417–22.
7.Kolb A, Wehrl HF, Hofmann M, Judenhofer MS, Eriksson L, Ladebeck R, et al. Technical performance evaluation of a human brain PET/MRI system. Eur Radiol. 2012 Aug;22(8):1776–88.
8.Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW, et al. Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein. J Nucl Med Off Publ Soc Nucl Med. 2015 May;56(5):701–6.
9.Schain AJ, Melo-Carrillo A, Borsook D, Grutzendler J, Strassman AM, Burstein R. Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Ann Neurol. 2018;83(3):508–21.
10.Biscetti L, Cresta E, Cupini LM, Calabresi P, Sarchielli P. The putative role of neuroinflammation in the complex pathophysiology of migraine: From bench to bedside. Neurobiol Dis. 2023 May 1;180:106072.
11.de C Williams AC, Richardson PH. What does the BDI measure in chronic pain? Pain. 1993 Nov;55(2):259–66.

Presenting Author

Ludovica Brusaferri

Poster Authors

Ludovica Brusaferri

PhD

London South Bank University

Lead Author

Jack H. Schnieders

BS

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Michael Datko

PhD

Spaulding Rehabilitation Hospital

Lead Author

Sarasa Tohyama

PhD

Harvard Medical School

Lead Author

Lilian Kinder

BS

Massachusetts General Hospital

Lead Author

Minhae Kim

Massachusetts General Hospital

Lead Author

Megan Heffernan

Athinoula A. Martinos Center for Biomedical Imaging

Lead Author

Courtney Chane

BS

Athinoula A. Martinos Center for Biomedical Imaging

Lead Author

Jennifer P. Murphy

BS

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Grace Grmek

BA

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Ronald Garcia

MD

Harvard Medical School

Lead Author

Randy Gollub

MD

Harvard Medical School

Lead Author

Robert Edwards

PhD

Brigham & Women's Hospital/Harvard Medical School

Lead Author

Hslinlin Cheng

MD

Harvard Medical School

Lead Author

Zev Schuman-Olivier

MD

Harvard Medical School

Lead Author

Bruce Rosen

MD

Harvard Medical School

Lead Author

Vitaly Napadow

Spaulding Rehabilitation Hospital

Lead Author

Nouchine Hadjikhani

MD

Harvard Medical School

Lead Author

Marco L. Loggia

PhD

A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Migraine