Imaging of neuroinflammation in migraine with aura: A [11C]PBR28 PET/MRI study

Abstract

Objective: To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.

Methods: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [¹¹C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.

Results: Compared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.

Conclusions: These findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Figure 1. No group difference in pseudoreference uptake

(A) Pseudoreference region used to create standardized uptake value (SUV) ratio images, computed by identifying regions showing no differences (p > 0.84) in SUV between groups, regressing out effects of TSPO polymorphism, age, and injected dose. (B) For visualization purposes, average adjusted SUV for each group is displayed in box plots, where boxes represent the 25th to 75th interquartile range, and the horizontal line represents the median.

Figure 2. Region of interest (ROI) [¹¹C]PBR28 standardized uptake value ratio (SUVR) is elevated in migraineurs with aura

Group comparison of ROI SUVR. SUVR adjusted for age, TSPO polymorphism, and injected dose is displayed. Boxes represent the 25th to 75th interquartile range, and the horizontal line represents the median. **Significant group differences at p < 0.01, corrected; *significant group differences at p < 0.05, corrected; ^#group differences at p < 0.10, corrected.

Figure 3. Voxelwise [¹¹C]PBR28 standardized uptake value ratio (SUVR) is elevated in migraineurs with aura

Regions of elevated PET signal in migraineurs with aura compared to controls are shown in red–yellow color scale. (A) Group differences in cortical [¹¹C]PBR28 SUVR are displayed on surface projections. There were no significant regions for the controls > migraineurs contrast. (B) Flat map of occipital cortex. Left hemisphere is shown on the left, right hemisphere on the right. Lighter gray = gyrus, darker gray = sulcus. (C) An axial slice is shown to display subcortical SUVR differences. CS = calcarine sulcus; M1 = primary motor cortex; MTG = middle temporal gyrus; pIns = posterior insula; OFC = orbitofrontal cortex; S1/S2 = primary/secondary somatosensory cortex; SMG = supramarginal gyrus; STG = superior temporal gyrus; TOS = transverse occipital sulcus; V1 = primary visual cortex; vmPFC = ventromedial prefrontal cortex.

Figure 4. Migraine frequency is positively associated with [¹¹C]PBR28 standardized uptake value ratio (SUVR)

(A) Regions showing a significant positive correlation between [¹¹C]PBR28 SUVR and migraine attacks per month preceding the scan in migraineurs are shown in red–yellow color scale (p < 0.05, cluster-corrected). Regions in green showed significant effects in both voxel-wise analyses, that is, SUVR in these regions was significantly higher in migraineurs compared to controls (see figure 3), and also significantly positively correlated with migraine frequency. No regions displayed significant negative associations between SUVR and migraine frequency. pIns = posterior insula; S1/S2 = primary/secondary somatosensory cortex; SMA = supplementary motor area. (B) Average SUVR from several regions showing a positive association between migraine attacks per month and SUVR. SUVR in migraineurs is plotted against migraine frequency; healthy control SUVR is displayed to the left for comparison. Group differences were significant for right posterior insula/S2 (p = 0.012), S1 (p = 0.016), and frontoinsular cortex (p = 0.001). All data are adjusted for age, TSPO polymorphism, and injected dose.